GIFT  OF 

/.H.  OcMj«K5> 


BIOLOGY 
LIBRARY 


A  TEXT-BOOK  " 

'  1 1        V   •  ' 

PATHOLOGY 


By 

W.  G.  MAcCALLUM 

Professor  of  Pathology  and  Bacteriology 

The  Johns  Hopkins  University 

Baltimore 


Second  Edition,  Thoroughly  Revised 


PHILADELPHIA  AND  LONDON 

W.    B.    SAUNDERS    COMPANY 

1920 


\  D  II. 

Ma 


BIOLOGY 
LIBRARY 


Copyright,  1916,  by  W.  B.  Saunders  Company.     Reprinted 

March,  1917,  March,  1918,  and  April,  1919.    Revised, 

reprinted,  and  recopyrighted  August,  1920 


Copyright,  1920,  by  W.  B.  Saunders  Company 

-       -     •  ~~ ~ 


PRESS    OF 


To 

G.  A.  MacCallum,  M.D. 

My  Father 
With  Gratitude  and  Affection 


494228 


PREFACE  TO  THE  SECOND  EDITION 


THE  four  years  which  have  passed  since  this  book  was  first  published 
have  witnessed  most  of  the  unheard  of  physical  and  mental  insults 
brought  by  the  war  to  human  beings,  most  of  the  great  epidemics,  and 
all  the  misery  and  disease  that  have  followed  famine  and  cold.  It  is 
quite  natural,  therefore,  that  the  minds  of  nearly  all  those  who  could  be 
classed  as  investigators  have  been  concentrated  upon  the  study  of  infec- 
tious diseases,  including  those  caused  by  animal  parasites,  upon  wounds 
and  the  effects  of  poisonous  gases  and  upon  the  results  of  malnutrition, 
to  the  exclusion  of  all  those  diseases  which  we  have  constantly  with  us 
in  times  of  peace. 

Great  advances  have  been  made  along  these  lines,  and  I  have  at- 
tempted to  follow  these  advances  either  by  inserting  paragraphs  summa- 
rizing the  new  work  or  by  rewriting  whole  chapters. 

The  sections  on  shock,  acid-base  equilibrium,  hydrocephalus,  immunity 
in  tuberculosis,  meningococcal  infections,  pneumonia  after  measles,  in- 
fluenza, cholera,  leprosy,  etc.,  are  rewritten  in  this  way  in  large  part  from 
our  own  experience.  Parasitic  diseases  are  treated  more  at  length  because 
of  the  excellent  work  of  the  English  and  Japanese  and  because  of  the 
wider  recognition  of  their  importance. 

Many  new  illustrations  have  been  added  and  those  which  were  unsat- 
isfactory have  in  many  cases  been  replaced  by  better  ones.  The  index 
has  been  revised  by  my  assistant,  Dr.  Cash,  to  whom  I  am  indebted.  But 
no  special  change  has  been  made  in  the  plan  of  the  book. 

W.  G.  MACCALLUM. 
THE  JOHNS  HOPKINS  HOSPITAL, 
August,  1920. 


HI 


PREFACE 


IN  this  book,  which  represents  in  its  order  and  contents  the  course  in  Pathol- 
ogy given  in  the  second  year  to  the  students  of  the  College  of  Physicians 
and  Surgeons,  an  effort  has  been  made  to  discuss  the  general  principles  of 
Pathology  as  illustrated  by  a  study  of  the  commoner  and  more  important 
diseases. 

It  is  therefore  in  no  sense  intended  as  a  book  of  reference.  No  attempt 
has  been  made  to  describe  systematically  all  the  diseased  conditions  which 
may  occur  in  each  organ,  and  for  that  reason  there  is  no  division  into  general 
and  special  pathology.  Instead  the  whole  is  constructed  upon  the  idea 
that  all  pathological  disturbances  are  the  result  of  some  form  of  injury,  or 
of  the  immediate  or  more  remote  reactions  of  the  body  to  injury.  It  has 
been  found  possible  to  carry  out  this  conception  quite  logically  except  when, 
as  in  the  case  of  tumors,  we  are  quite  ignorant  of  the  causes  of  the  disease. 
For  that  reason,  after  a  few  chapters  devoted  to  the  general  working 
principles  with  illustrations  from  the  most  common  conditions,  the  rest  of 
the  book  is  divided  into  chapters  which  deal  with  various  types  of,  injury 
and  their  immediate  and  remote  effects.  The  discussion  of  tumors  neces- 
sarily forms  a  separate  part,  since  they  seem  to  be  so  little  controlled  by  the 
laws  which  govern  other  pathological  processes. 

The  whole  book  is  planned  therefore  to  discuss  disease  as  far  as  possible 
upon  the  basis  of  etiology,  and  the  usual  subdivision  of  the  material  accord- 
ing to  its  anatomical  distribution  has  not  been  employed.  Nevertheless 
the  index  is  so  arranged  as  to  facilitate  reference  to  lesions  of  the  heart, 
lungs,  etc. 

Partly  because  of  lack  of  space,  but  chiefly  because  they  are  admirably 
treated  in  great  detail  in  books  easily  accessible  to  students,  several  whole 
sections  usually  included  in  books  on  pathology  have  been  omitted.  This 
is  true  of  the  relations  of  heredity  to  disease,  of  the  biology  of  bacteria  and 
other  parasites,  of  malformations,  and  of  many  diseases  of  the  nervous 
system.  The  whole  subject  of  resistance  and  immunity  is  touched  upon 
only  in  the  briefest  way.  Nevertheless,  even  though  such  subjects  are  in- 
tentionally omitted,  it  is  realized  that  criticism  may  well  be  offered  when  it 
is  found  that  the  diseases  chosen  to  illustrate  the  principles  of  pathology 
do  not  include  many  important  affections,  such  as  multiple  sclerosis,  pro- 
gressive muscular  atrophy,  rabies,  yellow  fever,  and  a  host  of  others. 

In  discussing  the  prominent  types  of  injury  an  attempt  has  been  made 
to  give  an  impression  of  the  far-reaching  interdependence  of  pathological 


VI  PREFACE 

conditions  by  making  a  continuous  story  of  the  whole  with  numerous  digres- 
sions for  the  description  of  special  lesions  or  their  causes.  Several  chap- 
ters are  devoted  to  the  results  of  obstruction  of  the  flow  of  contents  of 
hollow  organs,  and  while  it  may  seem  that  this  is  a  rather  forced  arrange- 
ment the  type  of  injury  is  one  whose  effects  depend  in  each  instance  upon 
certain  common  principles. 

A  constant  effort  has  been  made  to  speak  of  the  disturbances  of  function 
and  of  chemical  interchange  in  the  course  of  disease,  as  far  as  that  was 
possible,  and  even  to  describe  symptoms.  If  this  makes  the  book  seem  like 
a  treatise  on  clinical  medicine,  it  is  only  because  pathology  and  clinical 
medicine  are,  after  all,  the  same  thing  viewed  from  slightly  different  angles. 

References  to  the  literature  given  with  each  chapter  have  been  chosen,  as 
far  as  possible,  to  direct  the  student  to  readable  and  comprehensive  papers 
which  review  the  subject  and  give  further  and  more  complete  references. 

The  illustrations  are  almost  entirely  from  specimens  which  we  have 
studied  in  this  laboratory,  but  I  have  to  thank  many  friends  in  other 
laboratories  for  their  kindness  in  sending  me  material  or  for  allowing  me 
use  of  photographs.  The  drawings  with  very  few  exceptions  have  been 
made  by  Mr.  Alfred  Feinberg. 

I  am  indebted  to  my  assistants  for  much  help,  and  especially  to  Dr.  A. 
M.  Pappenheimer,  who  furnished  the  material  for  the  section  on  the  thymus 
and  aided  me  in  reading  the  proof,  and  to  Dr.  R.  A.  Lambert  who  made  the 
index. 

W.  G.  MAcCALLUM. 


CONTENTS 


CHAPTER  I  PAGC 

DISTURBANCES  OF  THE  FLUIDS  OF  THE  BODY 1 

Relation  of  Fluids  to  Tissues;  Blood,  Lymph,  Tissue  Fluids.  The  Blood:  Va- 
riations in  Quality  and  Quantity.  Readjustment.  Plethora  and  Oligacmia. 
Clotting.  Thrombosis. 

CHAPTER  II 

LOCAL  DISTURBANCES  IN  THE  CIRCULATION  OF  THE  BLOOD 15 

Hyperacmia;  Anaemia.  Postmortem  Changes  in  Distribution.  Active  and 
Passive  Hyperacmia.  Local  Anaemia.  Embolism.  Infarction.  Gangrene. 

CHAPTER  III 

DISTURBANCES  OF  INTERCELLULAR  FLUIDS  AND  LYMPH 43 

Their  Movement,  Character,  and  Excessive  Accumulation.     (Edema,  Ascites. 

CHAPTER  IV 

THE  STRUCTURE  AND  METABOLISM  OF  CELLS 48 

Cellular  Doctrine;  Ultimate  Unit  of  Life.  Nucleus  and  Cytoplasm.  Mito- 
chondria, Plasmosomes,  Paraplasmic  Substances,  Intercellular  Substances. 
Tissues  and  Motile  Cells.  Variations  in  the  Appearance  of  Cells.  Necrosis, 
Coagulation  and  Autolysis.  Death. 

CHAPTER  V 

DISTURBANCES  IN  THE  NUTRITION  AND  METABOLISM  OF  CELLS CO 

Nature  of  Metabolism.  Disturbances  Resulting  from  Slight  Injuries.  De- 
generations. Atrophy:  Its  Causes.  Hypertrophy  and  Hyperplasia. 

CHAPTER  VI 

DISTURBANCES  OF  FAT  METABOLISM 72 

Neutral  Fats  and  Lipoids.  Their  Source,  Absorption,  Distribution  and 
Functions.  Pathological  Disturbances. 

CHAPTER  VII 

DISTURBANCES  OF  PROTEIN  AND  CARBOHYDRATE  METABOLISM 87 

General  Character  of  Protein  Metabolism.  The  Purine  Bodies.  Gout. 
Cloudy  Swelling.  Hyaline  Metamorphosis.  Amyloid  Infiltration.  Carbohy- 
drate Metabolism.  Glycogen. 

CHAPTER  VIII 

DISTURBANCES  OF  MINERAL  AND  PIGMENT  METABOLISM 106 

Calcium:  Its  Source,  Distribution,  Deposition  in  Necrotic  and  Other  Tissues; 
Its  Relation  to  Various  Functions  of  the  Body.  Iron:  Its  Distribution  and 
Functional  Importance.  Disturbance  in  Its  Quantitative  Relations.  Chloro- 
sis. Haemochromatosis.  Pigment:  Function  and  Distribution.  Endogenous 
and  Exogenous  Pigmentation.  Jaundice.  Dust  Diseases. 

vii 


Vlll  CONTENTS 

CHAPTER  IX  PAGE 

DEFENCES  OF  THE  BODY  AGAINST  INJURY 132 

Immediate  and  Late  Reactions  to  Injury.  Inflammation,  Fever,  Immunity 
Production,  and  Repair.  Inflammation  an  Elaborate  Mechanism  to  Combat 
Injury.  Details  of  Vascular  and  Phagocytic  Phenomena.  The  Wandering 
Cells. 

CHAPTER  X 

DEFENCES  OF  THE  BODY  (CONTINUED) 158 

Fever.  General  Nature  of  the  Reaction.  Its  Chemical  Characters  and  Rela- 
tion to  Immunity.  Immunity.  Nature  of  Injurious  Agents.  Types  of 
Resistance.  Artificial  Immunity.  Phagocytosis.  Lysins,  Agglutinins,  Anti- 
toxins, etc.  Maintenance  of  Acid-base  Equilibrium.  Mechanism  of  Preserva- 
tion of  Neutrality.  Acidosis. 

CHAPTER  XI 

DEFENCES  OF  THE  BODY  (CONTINUED) 170 

New-growth  of  Tissue.  General  Characters.  Influences  of  Various  Agencies 
on  Growth.  Growth  Stimuli. 

CHAPTER  XII 

DEFENCES  OF  THE  BODY  (CONTINUED) 191 

Repair.  Established  Character  of  Tissues.  Their  Early  Differentiation. 
Metaplasia.  Regeneration  as  Exemplified  in  the  New  Formation  of  Various 
Tissues. 

CHAPTER  XIII 

DEFENCES  OF  THE  BODY  (CONTINUED) 211 

Transplantation  of  Tissues  and  Organs,  Its  Limitations.  Healing  of  Wounds 
— by  Direct  Union,  Under  a  Crust,  by  Granulation  Tissue,  etc.  Healing  of 
an  Open  Ulcer,  of  Inflamed  Wounds  and  Abscesses.  Healing  of  Special 
Tissues. 

CHAPTER  XIV 

ILLUSTRATIVE  EXAMPLES  OF  INFLAMMATORY  PROCESSES 229 

Catarrhal  Inflammation.  Serofibrinous  and  Fibrinopurulent  Pericarditis, 
Pleuritis,  Peritonitis,  Appendicitis,  Endocarditis,  Lobular  Pneumonia,  Puer- 
peral Infection.  Pyaemia,  Abscess  Formation,  Diphtheritic  Inflammation. 

CHAPTER  XV 

INJURY  WITH  INFLAMMATORY  REACTION  AND  ATTEMPTED  REPAIR 269 

Nephritis:  General  Nature  of  the  Process.  Its  Diffuse  Character.  Acute 
and  Chronic  Glomerulonephritis,  Tubular  Nephritis,  and  Interstitial  Neph- 
ritis. Arteriosclerotic  Disease  of  the  Kidney.  Combined  Inflammatory  and 
Arteriosclerotic  Disease.  Amyloid  Deposit.  Summary.  Functional  Altera- 
tions. Renal  Insufficiency. 

CHAPTER  XVI 

INJURY  WITH  INFLAMMATORY  REACTION  AND  ATTEMPTED  REPAIR  (CONTINUED). 

— INJURY  AND  REPAIR  OF  THE  LIVER 310 

Cirrhosis  of  the  Liver.     Structure  of  the  Liver  in  Relation  to  Disease.     Direct 


CONTENTS  IX 

PAGE 

Injury  to  Liver-cells.  Acute  Yellow  Atrophy.  Eclampsia,  and  Infections. 
Repair  and  Compensatory  Hyperplasia.  Cirrhosis:  Its  Various  Types. 
The  Alterations  in  Architecture  Involved.  Obstruction  of  Portal  Circulation. 
Collateral  Circulation.  Biliary  and  Hypertrophic  Cirrhosis. 

CHAPTER  XVII 

FURTHER  ILLUSTRATIVE  EXAMPLES  OF  DESTRUCTIVE  AND  REPARATIVE  PROCESSES.  335 
Arteriosclerosis.  Structure  of  Arteries.  Anatomical  Changes  in  Arterioscle- 
rosis in  Aorta  and  Other  Vessels.  Pathogenesis  and  ^Etiology.  Syphilitic  Ar- 
teritis  in  Aorta  and  Smaller  Vessels.  Obliterative  Endarteritis.  Thrombo- 
angeitis  Obliterans.  Aneurysms,  Various  Types;  Their  Effects  and  Their 
Relation  to  SypMlis.  Apoplexy;  Location  of  Haemorrhage  in  Brain. 

CHAPTER  XVIII 

TYPES  OF  INJURY:   PHYSICAL  AND  MECHANICAL  INJURIES 369 

Mechanical  Injuries:  Pressure,  Direct  Violence  Affecting  Bones,  Central 
Nervous  System,  etc.  Gunshot  and  Other  Wounds.  Secondary  Effects: 
Complication  with  Infection.  Shock.  Experimental  Study  and  Various 
Theories.  Effects  of  Heat:  Burns,  Heat-stroke,  Insolation.  Effects  of  Cold: 
Freezing.  Effects  of  Light-rays  and  Radiant  Energy  on  Skin,  Blood-forming 
Organs,  etc.  Electricity:  Effects  of  Strong  Currents. 

CHAPTER  XIX 

TYPES  OF  INJURY  (CONTINUED). — CHEMICAL  INJURIES 394 

Nature  of  Poisons:  Their  Varying  Effects.  Reaction  of  Organism;  Elimi- 
nation, Detoxication,  Resistance.  Auto-intoxication.  Poisoning  by  Illumi- 
nating Gas,  Corrosive  Substances,  Cyanides,  Chloroform,  Alcohol,  Metallic 
Poisons,  etc. 

CHAPTER  XX 

TYPES  OF  INJURY  (CONTINUED). — EFFECTS  OF  OBSTRUCTION  OF  THE  FLOW  OF 

CONTENTS  OF  HOLLOW  ORGANS.  OBSTRUCTION  IN  THE  ALIMENTARY  TRACT  407 
Salivary  Ducts.  Bile-ducts  (Gall-stones,  Cholecystitis,  Jaundice).  Pan- 
creatic Ducts  (Pancreatic  Cirrhosis,  Acute  Pancreatitis).  Obstruction  of 
Digestive  Tract:  (Esophagus,  Stomach  (Gastric  Ulcer).  Intestine;  Varying 
Mechanism  of  Obstruction  (Hernias,  Intussusception,  Volvulus,  Compression 
or  Kinking  by  Adhesions,  Paralysis,  Stenosis). 

CHAPTER  XXI 

TYPES  OF  INJURY — OBSTRUCTION  (CONTINUED). — OBSTRUCTION  OF  RESPIRATORY 

TRACT 430 

Nose  (Coryza,  Adenoids,  etc.).  Larynx  ((Edema,  Diphtheria,  Foreign  Bodies, 
Compression,  Stenosis).  Bronchi  (Foreign  Bodies,  Stenosis).  Atelectasis: 
Its  Causes.  Mechanism  of  Bronchial  Dilatation.  Bronchiectasis.  Emphy- 
sema. 

CHAPTER  XXII 

TYPES  OF  INJURY — OBSTRUCTION  (CONTINUED). — OBSTRUCTION  OF  THE  URINARY 

TRACT 441 

Urethral  Stricture.  Prostatic  Obstruction;  Hypertrophy  of  Prostate.  Cyst- 
itis. Urinary  Calculi.  Hydronephrosis.  Renal  Calculi.  Ascending  Renal 
Infection;  Pyelonephritis. 


X  CONTENTS 

CHAPTER  XXIII 
TYPES  OF    INJURY — OBSTRUCTION    (CONTINUED). — GENERAL    DISTURBANCES   OF 

CIRCULATION  . : 401 

Mechanism  of  Circulatory  Organs.  Pericardial  and  Pleural  Effusions. 
Emphysema.  Chemical  Influences.  Effects  of  Arterial  and  Myocardial  Dis- 
ease. Myocarditis.  Valvular  Disease.  General  Mechanism  of  the  Obstruc- 
tion Thus  Produced.  Various  Valvular  Lesions  and  Their  Special  Effects. 
Cardiac  Hypertrophy  and  Dilatation.  Decompensation;  Chronic  Passive 
Congestion.  Disturbances  of  Conduction  System  in  Heart. 

CHAPTER  XXIV 
TYPES  OF  INJURY  (CONTINUED). — OBSTRUCTION  OF  THE  CEREBROSPINAL  FLUID: 

HYDROCEPHALUS 504 

CHAPTER  XXV 

TYPES  OF  INJURY  (CONTINUED). — BACTERIAL  DISEASE. — STREPTOCOCCUS  INFEC- 
TIONS    509 

General  Character  of  Bacterial  Infection:  Nature  of  Bacterial  Action.  Pyo- 
genic  Micrococci.  Streptococcus  Infections — cf  the  Throat,  the  Middle  Ear, 
the  Digestive  Tract.  Streptococcus  Wound  Infection,  Erysipelas,  Pneu- 
monia, Endocarditis.  General  Septicaemia  (Acute  Splenic  Tumor). 

CHAPTER  XXVI 

TYPES   OF    INJURY. — BACTERIAL   DISEASE    (CONTINUED). — STAPHYLOCOCCUS   IN- 
FECTIONS    533 

General  Character.  Furunculosis.  Paronychia,  Impetigo,  etc.  General  Sep- 
ticaemia, Pyaemia,  Suppurative  Nephritis,  Endocarditis,  Lobular  Pneumonia, 
Osteomyelitis. 

CHAPTER  XXVII 

TYPES  OF  INJURY.     BACTERIAL  DISEASE  (CONTINUED). — PNEUMOCOCCUS  INFEC- 
TIONS  , 543 

Character  of  Organism.  Lobar  Pneumcnia.  Consolidation.  Resolution. 
Organization,  etc.  Septicaemia.  Endocarditis. 

CHAPTER  XXVIII 
TYPES   OF   INJURY. — BACTERIAL   DISEASE    (CONTINUED). — MENINGOCOCCUS   AND 

GONOCOCCUS  INFECTIONS.     RHEUMATISM 556 

Meningococcus  Infections:  Epidemic  Cerebrospinal  Meningitis.  Endocar- 
ditis. Gonococcus  Infections:  Urethritis  and  Sequelae.  Salpingitis  and 
Sequelae.  Arthritis.  Ophthalmia.  Dermatitis,  Endocarditis,  Vulvovagini- 
tis  in  Children.  Acute  Rheumatism:  Tonsillitis,  Arthritis,  Endocarditis, 
Pericarditis,  Myocarditis. 

CHAPTER  XXIX 

TYPES  OF  INJURY. — BACTERIAL  DISEASE  (CONTINUED). — DIPHTHERIA.     TETANUS.  574 
Diphtherial   Infection:     Diphtheria  of   Respiratory   Tract.     General   Effects 
upon  the  Heart,  Kidneys,  etc.     Paralysis.     Tetanus  Infection:    Mode  of  Oc- 
currence and  Mechanism  of  Distribution  of  Toxin. 

CHAPTER  XXX 

TYPES    OF    INJURY. — BACTERIAL    DISEASE    (CONTINUED). — CHOLERA.     PLAGUE. 

GLANDERS.     ANTHRAX.     INFLUENZAL  INFECTION 581 

Asiatic  Cholera:  Intestinal  Lesions.  General  Intoxication.  Bubonic  Plague: 
Transmission.  Bubonic  Type.  Pneumonic  Type.  Glanders:  Acute  and 


CONTENTS  xi 

PAGB 

Chronic  Forms.  Anthrax:  Infection  through  Skin,  Digestive  Tract,  Lungs. 
Influenzal  Infection:  Relation  to  Epidemic  Influenza,  Pneumonia,  Meningitis. 

CHAPTER  XXXI 

TYPES   OF    INJURY. — BACTERIAL   DISEASE    (CONTINUED). — TYPHOID   AND   PARA- 
TYPHOID INFECTIONS 599 

Typhoid  Infection:  General  Relations.  Intestinal,  Lymphatic,  Splenic,  and 
Other  Lesions.  Necrosis  in  Various  Organs.  Affections  of  Circulatory,  Re- 
spiratory, and  Nervous  System.  Paratyphoid  Infection:  Relation  to  Typhoid 
and  Enteritis  Infection.  Acute  Gastro-enteritis,  Accessory  Lesions.  Dysen- 
tery: Various  Organisms  Concerned.  Intestinal  Lesions. 

CHAPTER  XXXII 
TYPES  OF  INJURY. — BACTERIAL  DISEASE    (CONTINUED). — LEPROSY.     ACTINOMY- 

cosis 62] 

Leprosy:  Nodular  and  Anaesthetic  Forms.  The  Bacillus  and  Transmission. 
Lesions  of  the  Internal  Organs.  Affections  of  Nerves  and  Their  Sequelae.  Ac- 
tinomycosis:  General  Character  of  the  Disease  and  Organism.  Related 
Organisms.  Mode  of  Infection.  Destructive  Lesions. 

CHAPTER  XXXIII 

TYPES  OF  INJURY. — BACTERIAL  DISEASE  (CONTINUED). — TUBERCULOSIS 034 

Tuberculosis:  ^Etiology.  Distribution  and  Transportation  of  Bacilli.  Modes 
of  Infection,  Immunity  and  Hypersensitization.  The  Tubercle,  Tuberculous 
Granulation  Tissue,  Acute  Tuberculous  Inflammation,  Distribution  of  the 
Bacilli  in  the  Body.  Acute  Miliary  Tuberculosis.  Tuberculosis  of  Respiratory 
Organs,  Digestive  Tract,  Serous  Surfaces,  Lymph-glands,  Genito-urinary 
Tract,  Nervous  System,  Skin,  Bones,  and  Joints. 

CHAPTER  XXXIV 

TYPES  OF  INJURY. — INFECTIONS  OF  UNCERTAIN  NATURE G8G 

Typhus:  Epidemic  Distribution.  Anatomical  Lesions.  Experimental 
Studies,  Transmission  by  Lice.  A  Bacillus  Recently  Discovered.  Acute 
Poliomyelitis:  Infectious  Nature.  The  Organism.  Febrile  Illness,  Subse- 
quent Paralysis.  Lesions  of  Nervous  System. 

CHAPTER  XXXV 

TYPES  OF  INJURY. — SPIROCH/ETAL  INFECTION 692 

Syphilis:  /Etiology  and  Distribution.  Course  of  the  Disease.  Nature  of 
Different  Stages.  Immunity  and  Transmission.  Primary  Stage,  Secondary 
Lesions,  Tertiary  Stage.  Lymph-glands,  Blood,  Digestive  Tract,  Liver,  Re- 
spiratory Tract,  Bones  and  Joints,  Heart  and  Blood-vessels,  Nervous  System. 
Syphilitic  Lesions  of  Genital  Organs.  Orchitis. 

CHAPTER  XXXVI 

TYPES  OF  INJURY. — SPIROCH^ETAL  INFECTION  (CONTINUED) 726 

Syphilis:  Syphilitic  Lesions  of  Nervous  System.  Syphilitic  Meningitis. 
Tabes  Dorsalis.  General  Symptoms.  Lesions  of  the  Nervous  System. 
Theories  Concerning  it.  Dementia  Paralytica,  Its  Relation  to  Tabes;  Symp- 
toms. Anatomical  Changes  in  Brain  and  Cord.  Congenital  Syphilis.  Gen- 
eral Relations.  Lesions  in  Respiratory  Organs,  Liver,  Pancreas,  Bones,  etc. 
Late  Forms  of  Congenital  Syphilis. 


Xll  CONTENTS 

CHAPTER  XXXVII  PAGE 

TYPES  OF  INJURY. — EXANTHEMATIC  DISEASES 753 

Introduction.  Measles:  Susceptibility,  ./Etiology,  Course  of  Disease,  and 
Pathological  Anatomy.  Scarlet  Fever:  ^Etiology  Complicating  Streptococcus 
Infection,  Transmission;  Course  and  Pathological  Anatomy.  Scarlatinal 
Nephritis.  Smallpox:  Relation  to  Vaccinia;  Vaccination;  ^Etiology;  Symp- 
toms and  Pathological  Anatomy. 

CHAPTER  XXXVIII 

TYPES  OF  INJURY.— DISEASES  DUE  TO  ANIMAL  PARASITES 704 

Introduction.  General  Relation  of  Parasites  to  Host.  Table  of  Main  Zoo- 
logical Divisions.  Amoebic  Infections:  Types  of  Parasites  and  Life-history; 
Intestinal  Infection;  Abscess  of  Liver;  Abscess  of  Lung.  Pyorrhoea  Alveo- 
laris.  Malaria:  Types  and  Life-history  of  Parasites;  Symptoms  and  Patho- 
logical Anatomy;  Blackwater  Fever.  Trypanosome  Infections:  Biology; 
Sleeping  Sickness. 

CHAPTER  XXXIX 

TYPES  OF  INJURY. — DISEASES  DUE  TO  ANIMAL  PARASITES  (CONTINUED) 780 

Cestode  Infections:  Taenia  and  Bothriocephalus;  T.  Echinococcus;  Echino- 
coccus  Cysts  in  Man.  Trematode  Infections:  Bilharziosis;  Paragonimus 
and  Clonorchis.  Trichiniasis :  Biology  of  the  Parasite,  Symptomatology, 
Pathological  Anatomy.  Uncinariasis :  Symptomatology;  Life  History  of  Para- 
site; Pathological  Anatomy.  Infections  with  Ascaris,  Oxyuris,  Trichoceph- 
alus,  and  Filaria.  Elephantiasis. 

CHAPTER  XL 

THE  EFFECTS  OF  INJURIES  UPON  THE  BLOOD  AND  BLOOD-FORMING  ORGANS 795 

Importance  of  Changes  in  Blood-formation.  The  Bone-marrow:  Its  Regen- 
erative Changes.  The  Spleen.  The  Lymphoid  Tissues  with  the  Haemolymph 
Nodes.  Injuries  of  Red  Corpuscles  and  Erythrogenic  Tissue:  Polycythemia. 
Anaemia  or  Oligocythemia.  Post-haemorrhagic  and  Other  Secondary  Anae- 
mias. Pernicious  Anaemia.  Aplastic  Anaemia.  Haemochromatosis.  Haemo- 
lytic  Icterus.  Osteosclerotic  Anaemia.  Banti's  Disease.  Splenomegaly  of 
Gaucher. 

CHAPTER  XLI 

EFFECTS  OF  INJURIES  TO  THE  BLOOD  AND  BLOOD-FORMING  ORGANS  (CONTINUED)  .  822 
Leucocytosis;  Leucopenia.  Lymphocytosis.  Eosinophilia.  Corresponding 
Changes  of  Haematopoietic  Organs.  Independent  Disease  of  the  Blood-forming 
Organs:  General  Characters;  Classification  in  Lack  of  Information  as  to 
^Etiology.  Chronic  Lymphoid  Leukaemia.  Acute  Lymphoid  Leukaemia. 
Leucosarcoma,  or  Chloroleucosarcoma  (Chloroma).  Lymphoid  Myeloma. 
Pseudoleukaemia.  Lymphosarcoma.  Status  Lymphaticus. 

CHAPTER  XLII 

EFFECTS  OF  INJURIES  TO  THE  BLOOD  AND  BLOOD-FORMING  ORGANS  (CONTINUED)  845 
Chronic  Myeloid  Leukaemia.     Acute  Myeloid  Leukaemia.     Myeloblastic  Leu- 
kaemia.    Myeloid   Chloroma  or   Chloromyelosarcoma.     Myeloid    Myeloma. 
Hodgkin's  Disease  or  Lymphogranulomatosis. 

CHAPTER  XLIII 

DISEASES  DUE  TO  INJURIES  OF  THE  ORGANS  OF  INTERNAL  SECRETION 860 

Pancreas.     Diabetes  Mellitus;  General  Character  of  Process.     Pathological 


CONTENTS  xiii 

PAGE 

Anatomy.  Nature  of  Disturbance  of  Carbohydrate  Metabolism.  Relation  of 
Other  Organs.  Diabetic  Acidosis.  Resume.  Thyroid :  Anatomy  and  Physi- 
ology. Myxcedema,  Effects  of  Extracts.  Cretinism,  Goitre.  Exophthalmic 
Goitre:  General  Symptoms,  Pathological  Nature  of  Disease. 

CHAPTER  XLIV 

DISEASES  DUE  TO  INJURIES  OF  THE  ORGANS  OF  INTERNAL  SECRETION  (CON- 
TINUED)   884 

The  Parathyroid:  Anatomy,  Physiology.  Tetany:  Hyperexcitability  of 
Nerves.  Relation  to  Calcium  Metabolism,  Pathological  Anatomy.  Other 
Types  of  Tetany.  Thymus:  Anatomy,  Evolution  and  Involution.  Hyper- 
plasia.  Thymus  in  Exophthalmic  Goitre,  in  Myasthenia  Gravis,  in  Status 
Thymico-lymphaticus;  Accidental  Involution.  Adrenal:  Anatomy.  Function 
of  Medulla,  Functions  of  Cortex.  Addison's  Disease. 

CHAPTER  XLV 

DISEASES  DUE  TO  INJURY  TO  THE  ORGANS  OF  INTERNAL  SECRETION  (CONTINUED)  897 
Hypophysis.  Structure.  Properties  of  Extracts  of  Different  Lobes.  Experi- 
mental Extirpation.  Effects  of  Hyperactivity  and  Hypoactivity  at  Different 
Periods  of  Life.  Gigantism.  Acromegaly.  Frohlich's  Syndrome.  Adiposity. 
Relation  of  Genital  Function.  Diabetes  Insipidus.  Histological  Changes 
in  the  Hypophysis  in  Pregnancy,  Acromegaly,  etc.  Hypertrophic  Pulmonary 
Osteoarthropathy. 

CHAPTER  XLVI 

INJURIES  CAUSING  METABOLIC  DISTURBANCES  AND  CONSEQUENT  DISEASE  OF  THE 

BONES 909 

Chemical  Interchanges  in  Growth  of  Bone.  Importance  of  Calcium.  Rela- 
tion of  Internal  Secretions  to  Bone  Formation.  Normal  Ossification.  Rick- 
ets. Osteomalacia.  Chondrodystrophia  Fcetalis.  Scurvy  and  Moller-Bar- 
low's  Disease;  Osteogenesis  Imperfecta;  Osteopsathyrosis;  Paget's  Disease. 

CHAPTER  XLVII 

ARTHRITIS  DEFORMANS 926 

Confusion  as  to  Classification;  Infectious,  Traumatic,  Neuropathic,  and 
Gouty  Forms.  Terminology:  1.  Proliferative  Arthritis  Deformans  or  Pro- 
gressive Polyarthritis;  Clinical  and  Gross  Pathological  Characters;  Histology. 
Spondylitis  of  Bechterew  and  Marie.  2.  Degenerative  Arthritis  Deformans. 
Clinical  and  Gross  Pathological  Changes;  Histology.  Malum  Coxae  Senile; 
Spondylitis  Deformans. 

CHAPTER  XLVIII 

TUMORS 936 

General  Nature  of  Tumors;  Difficulty  of  Classification.  Fibromata.  Neuro- 
fibromata,  Keloids.  Lipomata.  Chondromata.  Osteomata.  (Xanthomata.) 
Myomata;  Leiomyomata,  Rhabdomyomata. 

CHAPTER  XLIX 

TUMORS  (CONTINUED) 955 

Tumors  Derived  from  Elements  of  the  Nervous  System.  General  Relations 
to  Various  Stages  in  Development  of  the  Nervous  System.  Neurocytoma, 
Neuroblastoma,  Chromaffine  Tumors.  Gliomata.  Angiomata:  Hsemangio- 
mata,  Lymphangiomata.  Sarcomata:  General  Characters.  Spindle-cell, 
Mixed-cell,  Round-cell,  and  Alveolar  Sarcomata.  Giant-cell  Sarcomata. 
Osteosarcomata.  Myxomata. 


XIV  CONTENTS 

CHAPTER  L  PAGE 

TUMORS  (CONTINUED) 983 

Pigmented  Tumors:  Nsevi.  Their  Relation  to  Epithelium  and  Connective 
Tissue.  Melanomata  or  Melanotic  Sarcomata.  Tumors  of  Adrenal  Origin: 
Hypernephromata;  Relation  to  Aberrant  Adrenal  Tissue.  Endotheliomata: 
Difficulty  of  Establishing  Their  Relation  to  Endothelium.  Endotheliomata 
from  Lymphatic  Endothelium.  Cylindromata.  Pleural  and  Peritoneal 
Tumors.  Endotheliomata  of  the  Meninges.  Tumors  Derived  from  Endothe- 
lium of  the  Blood-vessels.  "Perithelial"  Tumors. 

CHAPTER  LI 

TUMORS  OF  EPITHELIAL  ORIGIN 999 

Relation  of  Epithelium  to  Stroma.  Papillomata:  Origin  from  Skin  and 
Mucosse,  Papillomata  of  Bladder  and  Ovary.  Adenomata:  Origin  from 
Skin,  Salivary  Glands,  Gastric  and  Intestinal  Mucosse,  Kidney,  Liver,  Ad- 
renal, Hypophysis,  and  Prostate.  Adenomata  of  the  Breast;  Intracanalicular 
Forms.  Cystadenomata  of  Ovary:  Their  Origin  and  Form;  Papillomatous 
Types.  Adenomata  of  the  Uterus. 

CHAPTER  LII 

CARCINOMATA 1018 

General  Characters,  Grouping.  Flat-cell  Carcinomata.  Epitheliomata  of 
Lip,  Skin,  etc.  Mode  of  Growth  and  Metastasis.  Epitheliomata  of  Tongue, 
Tonsils,  Bronchi,  (Esophagus,  Gail-Bladder,  Urinary  Bladder.  Epitheliomata 
of  the  Vaginal  Portion  of  the  Cervix  Uteri.  Their  Frequency  and  Importance. 
.  Adamantinomata.  Basal-cell  Carcinomata.  Their  Relatively  Benign  Char- 
acter. Distribution,  Peculiar  Morphology.  Relation  to  Narvi.  Other 
Tumors  Assigned  to  This  Group.  Analogous  Tumors  of  Intestine  and 
Appendix. 

CHAPTER  LIII 

CARCINOMATA  (CONTINUED) 103G 

Adenocarcinomata:  General  Characters  and  Distribution.  Carcinomata  of 
the  Stomach:  Polypoid,  Solid  and  Scirrhous  Forms.  Their  Histology  and 
Mode  of  Growth;  Metastasis.  Colloid  Forms,  Their  Somewhat  Different 
Mode  of  Growth.  Carcinomata  of  the  Gall-bladder  and  Ducts.  Carcino- 
mata of  the  Pancreas,  of  the  Colon,  of  the  Prostate.  Metastasis  of  Prostatic 
Tumors  in  Bones.  Adenocarcinomata  of  the  Uterus  and  of  the  Ovary. 

CHAPTER  LIV 

CARCINOMATA  (CONTINUED) 1058 

Gland-cell  Carcinomata:  Carcinomata  of  the  Breast:  Epitheliomata,  Tu- 
mors Derived  from  the  Acini  (General  Form,  Mode  of  Extension  and  Metas- 
tasis, Histology,  Relation  to  Adenomata  and  Chronic  Cystic  Mastitis,  Scir- 
rhous Forms).  Tumors  Derived  from  the  Ducts.  Colloid  Cancers.  Carcino- 
mata of  the  Ovary;  Carcinomata  of  the  Thyroid;  Primary  Carcinomata  of 
the  Liver  with  Cirrhosis.  Chorionic  Epitheliomata:  Histogenesis  of  Cho- 
rionic  Epithelium,  Its  Normal  Invasive  Growth.  Hydatidiform  Mole.  Cho- 
rionic Epithelioma;  Gross  Appearance,  Metastasis,  Histology,  and  Histo- 
genesis; Relation  to  Corpus  Luteum. 

CHAPTER  LV 

TERATOMATA;  COMPOSITE  TUMORS 1075 

Chorionic  Epithelium  in  Tumors  of  the  Male.  Teratomata.  Early  Develop- 
ment of  the  Ovum.  Potency  of  Blastomeres.  Their  Inclusion  in  the  Forma- 


CONTENTS  XV 

PAGE 

tion  of  Double  Monsters.  Formation  of  Solid  Teratomata.  Dermoid  Cysts. 
Cutaneous  and  Branchial  Cysts.  Cholesteatomata.  Mixed  Tumors  of 
Salivary  Glands;  of  the  Kidney.  Congenital  Cystic  Kidney.  Mixed  Tumors 
of  the  Breast  and  of  the  Testicle.  Chordoma. 

CHAPTER  LVI 

CLASSIFICATION  OF  TUMORS 1090 

CHAPTER  LVII 

GENERAL  DISCUSSION  OF  TUMORS 1092 

General  Character  of  Tumors;  Relation  to  Tissues  of  Host.  Their  Indepen- 
dence of  the  Laws  Governing  the  Growth  of  Normal  Tissues ;  Consequent  Ab- 
normal Architecture  and  Metabolism.  Distinction  Between  Tumors  and 
Infectious  Processes.  Nature  of  Cells  of  Tumors;  Specific  Relation  to  Those 
of  Host;  Relation  to  Embryonic  Stages  of  Cell  Development;  Atypical 
Character.  Growth;  Implantation,  Extension,  Metastasis,  Recurrence. 
Contributory  Causes  of  Tumor  Growth:  Injury  and  Irritation  (Physical, 
Chemical,  Parasitic;  Rous'  Filterable  Tumor);  Internal  Secretions;  Malfor- 
mations; Disposition;  Senility;  Heredity.  Resistance  and  Immunity. 
Theories  as  to  the  ^Etiology  of  Tumors:  Theory  of  Parasitic  Origin  of  Tumors; 
Theory  of  Tumor  Growth  as  the  Effect  of  Irritants;  Theories  Emphasizing  a 
Disturbance  of  Equilibrium  of  Tissues;  Cohnheim's  Theory;  Ribbert's 
Theory;  Theories  of  Tumor  Growth  Depending  upon  Changes  in  the  Cells. 


INDEX. .  .1117 


TEXT-BOOK  OF  PATHOLOGY 


CHAPTER  I 
DISTURBANCES  OF  THE  FLUIDS  OF  THE  BODY 

Relation  of  fluids  to  tissues;  blood,  lymph,  tissue  fluids.  The  blood:  variations  in 
quality  and  quantity.  Readjustment.  Plethora  and  oligcemia.  Clotting.  Thrombosis. 

Relation  of  Fluids  to  Tissues. — The  cells  of  the  tissues  are,  like  other  living 
beings,  dependent  for  their  life  and  activity  upon  a  constant  and  abundant 
supply  of  food  and  oxygen  and  an  equally  adequate  removal  of  their  waste- 
products.  This  service  is  rendered  them  by  the  circulation  of  the  various 
fluids  through  every  part,  propelled  by  a  mechanical  arrangement,  the  per- 
fection of  which  we  shall  have  frequent  occasion  to  admire.  There  are 
three  main  types  into  which  we  may  divide  these  circulating  fluids,  the 
blood,  the  tissue  fluids,  and  the  lymph. 

The  blood  is  practically  everywhere  separated  from  actual  contact  with 
the  cells  of  the  tissues  by  a  semi-permeable  membrane  composed  of  other 
cells,  the  endothelium.  It  flows  through  the  whole  body,  giving  off  cer- 
tain substances  and  withdrawing  others,  always  through  this  membrane. 
Between  the  cells  outside  the  blood-vessels  there  are  spaces,  or  at  least 
potential  spaces,  in  which  a  small  amount  of  fluid  collects  which  directly 
bathes  the  cells  and  directly  receives  their  waste.  This  tissue  fluid  is 
constantly  being  changed  too,  by  interaction  with  the  blood.  But  it  also 
stands  in  exactly  the  same  relation  to  the  lymph,  which,  like  the  blood, 
flows  inside  channels  with  semi-permeable  walls  composed  of  endothelial 
cells  and  goes  to  empty  into  the  vein.  We  do  not  believe  now  that  there 
are  open  communications  between  the  lymphatic  channels  and  the  tissue 
crevices.  That  idea,  it  seems,  has  been  thoroughly  disproved  by  the  recent 
work  which  shows  the  completeness  of  the  endothelial  lining  of  these 
channels. 

It  will  be  realized,  then,  that  there  must  be  qualitative  differences  at  all 
times  between  these  three  fluids,  although  by  processes  of  diffusion  and 
osmosis  there  is  constantly  going  on  an  attempt  to  establish  a  balance 
between  them.  Uniformity  is  never  reached,  though,  on  account  of  the 
metabolic  activity  of  the  tissue-cells  and  the  immediate  removal  of  the 
blood  and  lymph  before  equilibrium  is  established.  These  qualitative 
differences  and,  indeed,  the  question  of  the  chemical  composition  of  the 
fluids  need  not  arrest  us  here.  Materials  pass  from  the  arterial  side  of  the 
2  1 


TEXT-BOOK   OF   PATHOLOGY 


capillaries  into  the  tissue  spaces,  and  from  there  either  into  the  lymphatics 
or  into  the  veins,  and  it  is  obvious  that,  according  to  the  character  of  the 
cells  which  make  up  the  tissue,  the  nature  of  the  lymph  and  of  the  venous 
blood  produced  in  this  way  must  vary  greatly  in  different  parts  of  the  body. 
The  portal  blood  is  filled  with  materials  which  could  not  be  found  in  any 
such  quantities  in  the  blood  of  the  femoral  vein,  and  the  hepatic  vein  con- 
tains blood  which  is  altogether  changed  by  passing  through  the  liver. 
The  degree  of  activity  of  the  organs  plays  a  great  part  also,  so  that  during 
digestion  portal  blood  undoubtedly  differs  very  greatly  from  the  blood  of 
the  same  vein  at  other  times. 

THE  QUANTITY  OF  BLOOD  IN  THE  BODY 

Normally  the  quantity  of  blood  in  the  body  bears  a  fairly  definite  relation 
to  the  weight  of  the  body.  Until  recently  the  determinations  of  this 
quantity  were  notoriously  inaccurate,  and  even  yet  little  is  known  about 
the  possible  variations.  But  with  the  method  of  Haldane-Smith,  which 
consists  essentially  in  administering  a  known  amount  of  carbon  monoxide 
and  estimating  its  concentration  in  a  sample  of  the  blood,  the  quantity 
has  been  shown  to  be  from  5  to  5.3  per  cent,  of  the  body  weight. 

Experimental  efforts  to  increase  or  decrease  the  amount  of  blood  in 
proportion  to  the  tissues  fail  except  for  very  short  periods,  because  the 
excess  of  fluid  introduced  is  immediately  excreted,  and  that  which  is  re- 
moved from  the  blood-vessels  by  bleeding  is  quickly  made  up  by  the  filtra- 
tion of  fluid  from  the  tissues  into  the  capillaries.  Blood-pressure  is  scarcely 
changed  by  any  such  measures  because  the  vasomotor  mechanism  imme- 
diately adapts  the  capacity  of  the  stream-bed  as  nearly  as  possible  to  its 
new  contents. 

The  adjustment  is  especially  rapid  and  effective  when  an  excess  of  fluid 
is  introduced,  and  if  it  does  not  enter  the  veins  too  abruptly  and  rapidly 
the  excretion  by  the  kidneys  keeps  pace  with  it  almost  perfectly.  In  the 
other  case,  the  removal  of  blood,  there  are  naturally  limits  to  the  power  of 
the  tissues  to  give  up  fluid  to  restore  its  bulk.  Even  under  the  best  cir- 
cumstances this  is  a  slower  process  than  the  removal  of  fluid  by  excretion. 
The  terms  plethora  and  ancemia  or  oligcemia  have  long  been  in  use  to  imply 
an  excess  of  blood,  on  the  one  hand,  and  a  poverty  of  blood,  on  the  other, 
but  with  this  extraordinary  compensatory  power  of  the  body  in  view,  it 
seems  that  we  must  use  them  with  some  caution.  Nevertheless  it  is  per- 
fectly obvious  at  autopsy,  if  not  during  life,  that  in  some  persons  the  vessels 
are  distended  with  an  enormous  quantity  of  blood,  while  in  others  not 
only  do  the  vessels  seem  collapsed,  but  all  the  tissues  are  shrunken  and  dry 
looking.  Especially  is  the  latter  true  in  old  persons  and  those  who  have 
long  suffered  from  a  wasting  disease. 

Plethora. — Apparently  the  existence  of  actual  changes  in  the  amount  of 
blood  which  last  for  any  time  is  dependent  chiefly  upon  qualitative  changes 
in  the  blood  itself  and  in  the  tissues.  A  true  plethora,  in  which  the  blood 


CLOTTING,    THROMBOSIS,    ETC.  3 

is  increased  without  change  in  its  composition,  probably  occurs  with  de- 
fects in  the  action  of  the  heart  which  then  allows  a  part  of  the  blood  to 
remain  practically  stagnant  in  the  veins  and  propels  an  abnormally  small 
part  of  it  into  the  arteries.  The  compensation  for  this  diminution  of  the 
arterial  circulation  by  introduction  of  more  fluid  may  restore  the  normal 
amount  in  active  circulation,  but  increases  the  total  amount  in  the  body. 
Hydraemic  or  serous  plethora  is  spoken  of  as  a  condition  in  which  the 
quantity  of  blood  is  increased  by  a  relative  increase  in  its  watery  part. 
As  has  been  said,  it  is  impossible  to  maintain  this  for  any  length  of  time 
experimentally  because  the  kidneys  promptly  excrete  the  excess  of  water, 
but  it  is  conceivable,  though  not  proven,  that  it  may  arise  when  the  excre- 
tory power  of  the  kidneys  is  lowered  by  disease. 

Oligsemia. — Practically  the  same  things  may  be  said  of  oligaemia  or 
anaemia.  The  simplest  type  of  general  anaemia  is  undoubtedly  that  which 
is  produced  when  a  considerable  amount  of  blood  is  lost  through  the  opening 
of  a  blood-vessel.  The  person  becomes  blanched,  makes  forced  respira- 
tions, and  may  become  unconscious  on  account  of  the  poor  supply  of  nu- 
trition to  the  brain.  He  becomes  very  weak  and  thirsty,  and  his  pulse  is 
low  and  scarcely  perceptible,  but  often  very  rapid.  An  immediate  attempt 
is  made  by  the  tissues  to  pour  back  again  into  the  vessels  enough  fluid  to 
fill  them  again  and  to  raise  the  blood-pressure,  and  consequently,  for  some 
time,  on  account  of  this  adding  of  fluid  both  from  the  tissues  and  from  water 
taken  in  by  mouth,  the  blood  becomes  dilute.  The  proportion  of  red  cor- 
puscles, which  can  be  determined  by  counting,  sinks  for  two  or  three  days, 
at  which  time  the  inflow  of  fluid  ceases  and  the  reproduction  of  corpuscles 
by  the  blood-forming  organs  begins  to  make  itself  evident.  From  that 
time  onward  there  is  a  steady  increase  in  the  number  of  corpuscles  to  each 
cubic  millimetre  until  the  blood  reaches  its  normal  state.  There  seems  to 
be  also  the  other  form  of  oligaemia  in  which  the  quantity  is  reduced  by  loss 
of  water.  Naturally  this  will  be  compensated  as  quickly  as  possible,  too, 
but  in  such  diseases  as  cholera  the  loss  is  so  rapid  that  the  tissues  become 
desiccated  as  well.  It  is  quite  possible,  therefore,  that  the  decrease  in  the 
quantity  of  blood  is  merely  proportional  to  the  desiccation  of  all  the  tissues. 

CLOTTING,  THROMBOSIS,  ETC. 

Clotting. — We  are  not  well  informed  as  to  the  nature  df  the  process  through 
which  an  injury  to  a  single  cell  or  a  unicellular  animal  is  healed.  The 
wound  is  closed  very  rapidly,  and  apparently  by  a  process  rather  more 
complex  than  the  mere  flowing  together  of  the  protoplasm.  We  do  know, 
however,  that  in  such  animals  as  the  Crustacea  and  in  the  higher  types, 
where  there  is  a  circulation  of  blood  and  other  body  juices,  these  fluids 
possess  the  peculiar  property  of  clotting,  or  coagulating  as  soon  as  they 
are  exposed  to  contact  with  anything  which  has  not  the  character  of  the 
living  vessel-wall.  It  is  through  this  property  that  the  loss  of  blood  from 
every  trifling  wound  is  checked,  although  otherwise  it  might  well  prove 


TEXT-BOOK    OF    PATHOLOGY 

fatal.  In  this  sense  the  clotting  is  distinctly  a  protective  process,  probably 
developed  from  the  time  of  the  first  appearance  of  animal  life  as  a  factor 
indispensable  to  the  preservation  of  the  animal.  The  same  process  ap- 
pears again  and  again  under  the  greatest  variety  of  circumstances  in  patho- 
logical conditions,  but  it  will  be  seen  that  in  all — in  spite  of  many  imper- 
fections in  the  mechanism — it  has  a  protective  significance. 

Clotting,  even  in  its  simplest  form,  is  a  complex  process  which  has  been 
diligently  studied  for  many  years,  but  even  yet  there  are  many  important 
parts  of  it  which  are  not  at  all  well  understood.  The  names  of  Alexander 
Schmidt,  Arthus,  Hammarsten,  Pekelharing,  Loeb,  Fuld,  Spiro,  and 
Morawitz  are  especially  prominent  in  this  connection,  and  the  following 
may  be  regarded  as  the  most  generally  accepted  results  of  their  work,  which 
have  been  clearly  stated  by  Morawitz. 

When  blood  and  lymph  are  allowed  to  escape  into  a  glass  dish  they 
clot,  usually  in  a  very  short  time.  If  the  blood  is  continually  stirred, 
the  clot  adheres  to  the  stirring  rod,  leaving  a  permanently  fluid  blood 
(defibrinated  blood).  If  it  is  not  stirred,  the  clot  forms  uniformly 
throughout  the  whole  quantity  of  blood,  converting  it  into  a  solid, 
rather  dry,  firm  mass,  often  so  tenacious  that  the  dish,  if  it  be  not  too 
wide  and  shallow,  may  be  inverted  without  spilling.  Such  a  clot  is  of 
a  uniform  dark-red  color.  If  it  be  squeezed,  a  red  fluid  is  forced  out 
which  is  identical  with  defibrinated  blood.  If  the  spongy  mass  be  washed 
in  running  water,  all  the  red  blood-corpuscles  may  be  washed  away,  leaving 
a  stringy,  yellowish  white,  elastic  mass  of  fibrin.  If  the  fresh  blood  be 
kept  very  cold,  or  if  it  be  received  into  an  oiled  dish,  it  will  not  clot  so 
quickly,  and  since  the  red  corpuscles  are  heavier  than  the  plasma,  there 
may  be  time  for  them  to  sink  to  the  bottom  in  a  very  thick  layer.  The 
leucocytes  are  lighter  and  rest  in  a  layer  on  top  of  the  red  corpuscles,  while 
above  there  is  some  plasma  almost  free  from  cells.  By  this  time  clotting 
occurs  throughout,  the  clot  differing  from  the  uniform  red  one  formed  by 
rapid  coagulation,  in  the  presence  of  a  grayish-yellow  upper  layer  which 
contains  most  of  the  leucocytes  and  platelets.  This  was  called  the  "buffy 
coat"  by  the  old  bloodletters,  and  its  thickness  was,  in  their  hands,  an 
index  of  the  rapidity  with  which  the  blood  clotted,  and  of  the  number  of 
leucocytes  contained,  although  their  deductions  usually  took  various  other 
turns. 

This  slow  clotting  showing  the  effects  of  gravity  is  seen  very  commonly 
in  the  heart  at  autopsy,  for  the  intact  endothelial  lining  of  the  heart  keeps 
its  contents  a  long  time  without  clotting.  There  the  deep-red  portion  of  the 
clot  ("cruor  clot")  is  in  the  dependent  part,  while  the  tough,  elastic, 
translucent,  yellowish  substance  (chicken-fat  or  turtle-fat  clot)  occupies 
the  uppermost  part  of  the  heart  as  the  body  lies  on  the  table  (Fig.  1). 
The  homogeneous  elasticity  of  this  kind  of  clot  and  the  fact  that  it  is  readily 
removed  from  the  heart-wall,  leaving  it  unaltered,  make  it  quite  easy  to 
distinguish  it  from  the  thrombus  formed  on  injured  areas  of  the  heart-wall 


CLOTTING,    THROMBOSIS,    ETC.  5 

during  life,  although  extraordinary  mistakes  have  been  made  and  the  post- 
mortem clot  held  to  be  the  cause  of  death. 

At  first — and  especially  when  it  is  rapidly  formed — the  clot  is  quite  dry. 
Indeed,  it  is  this  which  confers  the  dry  ness  and  firmness  upon  the  lung  in 
the  early  stages  of  pneumonia,  where  a  fresh  clot  occupies  each  air-cell. 
Later,  however,  through  its  own  elasticity,  the  clot  contracts  away  from 
the  wall  of  the  glass  and  shrinks  together.  In  thisVay  it  expresses  from 
its  meshes  a  clear  fluid,  the  serum,  in  which  it  is  finally  bathed.  If  we 
examine  the  clot  microscopically,  we  shall  find  it  to  be  composed  of  a  deli- 
cate network  of  fine  fibrils,  among  which  there  are  entangled  the  cells  of 
the  blood.  In  the  rapidly  formed  clot  these  are  perfectly  homogeneously 
distributed  in  the  proportions  in  which  they  existed  in  the  circulating 


Fig.  1. — Postmortem  clot  in  the  cavity  of  the  heart. 

blood,  but  in  the  layered  clot  which  has  slowly  formed  there  are  red  cor- 
puscles, but  fewer  leucocytes  in  the  lower  red  part  of  the  clot,  while  in 
the  upper  layer  there  are  numerous  leucocytes  with  platelets,  but  no  red 
cells;  there  may  even  be  a  layer  in  which  there  are  very  few  cells  of  any 
kind  (Fig.  2). 

Throughout  the  clot  one  may  sometimes  recognize  minute  centres  about 
which  the  fibrin  radiates,  or  if  the  corpuscles  are  not  too  much  crowded,  it 
may  be  possible  to  see  star-like  radiations  of  filaments  of  fibrin  about  single 
cells.  One  sometimes  sees  these  radial  arrangements  of  fibrin  about  bac- 
teria in  the  blood,  and  this  may  be  especially  striking  in  cases  of  anthrax 
or  other  such  infection  in  which  the  blood  contains  many  foreign  cells. 
Besides  these,  in  clots  which  are  formed  after  death  in  the  heart-  or  large 
blood-vessels,  it  is  generally  possible  to  find  in  sections  pale,  pink-staining 


6 


TEXT-BOOK    OF    PATHOLOGY 


clumps  to  which  a  number  of  leucocytes  adhere  buried  deeply  and  irregu- 
larly among  the  red  corpuscles.  These  have  been  described  by  Rost  and 
others  and  seem  to  consist  chiefly  of  groups  of  blood-platelets.  Never- 
theless, the  distinctive  character  of  the  clot  formed  after  death  in  the  stag- 
nant blood  is  its  general  homogeneity  of  structure,  in  which  respect  it 
differs  so  sharply  from  the  clots  formed  during  life  in  the  streaming  blood. 

As  to  the  mechanism  of  the 
clotting,  it  is  generally  agreed 
that  the  fibrin  is  formed  by 
the  action  of  a  ferment-like 
substance  called  by  Morawitz 
thrombin,  upon  a  proteid  sub- 
stance, fibrinogen,  which  oc- 
curs in  the  plasma.  The  throm- 
bin is  in  itself,  according  to  this 
theory,  a  complex  result  of  the 
interaction  of  two  substances. 
The  first  is  a  material  called 
thrombokinase,  which  is  derived 
from  the  formed  elements  of 
the  blood  (leucocytes  or  plat- 
elets) or  from  any  tissue  with 
which  the  blood  may  come 
into  contact.  It  does  not 
seem  necessary  that  these  cells 
should  be  actually  destroyed, 
but  merely  altered  in  some 
particular  which  we  cannot 
recognize.  The  second  con- 
stituent occurs  in  the  plasma 
and  is  called  prothrombin.  What 
the  character  of  the  union  or 
interaction  of  thrombokinase 
with  prothrombin  is  we  do  not 
know,  but  it  is  known  that  the 
presence  of  a  soluble  salt  of 
calcium  is  required  to  complete 
it  and  bring  about  the  forma- 
tion of  thrombin.  After  the 

thrombin  is  formed,  the  calcium  is  no  longer  necessary  to  carry  out  the 
second  phase  of  the  clotting,  although  it  accelerates  it.  This  second 
phase  consists  in  the  interaction  between  the  thrombin  and  fibrinogen, 
which  is  present  in  the  plasma  with  the  formation  of  a  fine  fibrillary 
network  of  fibrin. 

The  blood  ordinarily  remains  fluid  in  the  vessels  because  the  leucocytes 


Fig.  2. — Postmortem  clot:  a,  Fibrin;  6,  layer 
of  leucocytes;  c,  cruor  clot  with  red  corpuscles 
and  platelets  in  clumps. 


CLOTTING,    THROMBOSIS,    ETC.  7 

and  other  cells  are  not  injured  enough  to  liberate  thrombokinase — what- 
ever small  amounts  are  set  free  are  neutralized  by  the  antithrombin  which 
has  been  shown  to  exist  in  the  plasma.  The  conversion  of  fibrinogen  to 
fibrin  is  irreversible,  but  the  nature  of  the  change  is  not  known — possibly 
one  is  a  hydrosol,  the  other  a  hydrogel.  The  recent  work  of  Howell  and  his 
many  students  has  brought  to  light  several  new  factors  in  the  process  of 
clotting  and  has  explained  in  a  new  way  their  interaction.  He  has  devised 
methods  for  obtaining  prothrombin  and  thrombin  in  a  state  of  purity 
sufficient  for  the  exclusion  of  other  related  factors,  and  in  the  substance 
derived  from  injured  tissue  and  known  as  thrombokinase  he  recognizes  a 
phosphorus-containing  lipoid  or  phosphatid,  cephalin.  This  he  called  a 
thromboplastic  substance.  He  has  also  discovered  another  phosphatid  in 
extracts  from  the  liver  and  other  organs  which  he  has  named  heparin,  and 
a  protein  material  in  the  plasma,  which  is  the  mother  substance  of  anti- 
thrombin, and  called  pro-antithrombin. 

Prothrombin,  which  is  normally  present  in  the  plasma,  is  apparently  de- 
rived from  the  bone-marrow,  which  is  also  the  site  of  formation  of  the  blood- 
platelets.  In  the  presence  of  calcium  if  there  were  nothing  to  interfere, 
the  prothrombin  would  be  converted  into  thrombin  capable  of  causing 
the  formation  of  a  clot  from  the  fibrinogen.  But  this  is  prevented  in  the 
circulating  blood  by  something  which  protects  the  prothrombin  from  the 
action  of  the  calcium.  This  may  be  heparin,  which  was  at  first  known  as 
antiprothrombin.  Antithrombin  could  prevent  the  clotting  by  neutralizing 
the  formed  thrombin,  but  that  would  entail  the  continuous  conversion  of 
prothrombin  into  thrombin  and  the  accumulation  of  neutralized  prothrom- 
bin.* 

Heparin  is  able  to  neutralize  prothrombin  and  to  render  the  blood  quite 
incoagulable.  On  the  other  hand,  heparin  forms  a  combination  of  some 
kind  with  pro-antithrombin  to  produce  antithrombin.  Hence,  pro-anti- 
thrombin, heparin,  and  antithrombin  are  ranged  on  one  side  to  interfere 
with  clotting  which  would  otherwise  occur  in  the  series  prothrombin,  cal- 
cium, thrombin,  and  fibrinogen  on  the  other  side.  There  remains,  however, 
the  thromboplastic  substance,  cephalin,  which  is  powerfully  antagonistic 
to  heparin  and  antithrombin,  and,  by  overpowering  them  in  situations 
where  blood  impinges  upon  injured  tissues,  frees  the  prothrombin  to  become 
thrombin  or  allows  the  activity  of  the  thrombin  in  forming  the  clot.  It  is 
at  this  point  that  Howell's  explanation  of  clotting  differs  radically  from 
the  older  view,  in  which  it  was  thought  that  thrombokinase  was  necessary  in 
the  formation  of  thrombin. 

The  clot  itself  has  been  watched  in  process  of  formation  with  the  aid 
of  the  ultramicroscope.  At  first  there  is  a  clear  field,  but  as  the  clotting 

*  In  vitro  the  combination  of  thrombin  and  antithrombin  appears  as  metathrombin,  an 
inert  substance  which  can  be  activated  into  thrombin  by  alkalies  or  acids,  but  no  meta- 
thrombin is  found  in  the  circulating  blood,  and  even  if  it  be  injected  into  the  veins  it 
disappears  at  once. 


8  TEXT-BOOK    OF    PATHOLOGY 

begins,  shining  needle-shaped  crystals  appear  in  great  numbers,  dancing 
about,  and  later  arranging  themselves  in  strands,  which  are  the  fibrils  of 
fibrin.  Fibrin  is  thus  one  of  the  rare  examples  of  crystalline  gels. 

The  origin  of  the  thromboplastic  substance  was  long  discussed,  but  it 
seems  now  to  be  a  matter  of  less  interest  than  the  origin  of  the  prothrombin, 
which  Drinker  has  shown  to  depend  largely  on  the  integrity  of  the  bone- 
marrow.  Duke  thought  that  the  absence  of  platelets  which  also  originate 
in  the  bone-marrow  might  account  for  the  prolonged  bleeding  in  purpura. 
There  are  some  conditions,  particularly  such  infectious  processes  as  pneu- 
monia, in  which  clotting  occurs  very  rapidly,  and  shortly  after  death  com- 
plete moulds  of  the  vessel  may  be  pulled  out  from  the  large  vascular  trunks. 
In  such  cases  the  clots  are  dry  and  uniformly  deep  red  throughout.  On 
the  other  hand,  there  are  other  conditions,  such  as  haemophilia,  icterus,  etc., 
in  which  coagulation  is  greatly  delayed,  and  serious  haemorrhage  may  occur 
during  and  after  the  slightest  surgical  operation.  Whipple  thinks  that 
the  delay  in  clotting  of  blood  in  diseases  of  the  liver  with  jaundice  is  due 
to  an  excess  of  antithrombin  in  the  blood,  while  Howell  thought  that  in 
haemophilia  the  blood  was  deficient  in  prothrombin,  but  now  suggests 
that  the  prothrombin  may  there  be  rendered  inactive  by  an  excess  of  he- 
parin. 

Spontaneous  clotting  in  the  veins  during  life  may  be  due  to  a  deficiency 
in  antithrombin,  but  other  explanations,  such  as  are  given  in  the  next 
section,  seem  more  plausible. 

Thrombosis. — On  the  basis  of  either  theory  of  clotting  it  is  easy  to  under- 
stand that  a  coagulum  might  form  about  any  mass  of  cells  which,  after 
suffering  some  injury,  had  become  clumped  together  or  agglutinated  in 
the  blood,  and,  indeed,  Loeb  and  others  have  observed  that  an  agglutina- 
tion of  formed  elements  always  precedes  the  formation  of  the  fibrin.  The 
part  played  by  the  platelets  is  perhaps  important  in  postmortem  or  extra- 
corporeal  clotting,  but  it  becomes  especially  prominent  in  the  inception  of 
thrombi,  which  are  peculiar  clots  formed  during  life  in  the  streaming 
blood. 

The  character  of  these  thrombi  is  very  different  in  some  respects  from 
that  of  the  postmortem  clots,  although  the  principles  concerned  in  their 
formation  are  the  same,  except  that  the  single  mechanical  factor  of  the 
streaming  movement  of  the  blood  disturbs  the  ordinary  process  of  clotting 
and  brings  into  prominence  the  feature  of  preliminary  agglutination  of 
the  platelets. 

A  thrombus  begins  by  the  deposition,  on  the  wall  of  the  blood-channel, 
of  a  minute,  pearly,  translucent  mass  of  platelets  which  grows  by  the  ad- 
hesion of  other  platelets  as  they  come  by.  These  produce  curious  upstand- 
ing laminae  or  walls  running  transversely  to  the  blood-stream  and  anasto- 
mosing freely  with  one  another;  the  platelets  are  so  welded  together  that 
their  outlines  can  no  longer  be  seen,  and  in  section  these  laminae  appear  as 
faintly  pink-staining,  finely  granular  bands  in  the  substance  of  the  throm- 


CLOTTING,    THROMBOSIS,    ETC. 


9 


bus  (Fig.  3).  However,  it  must  not  be  supposed  that  they  rise  up  alone  and 
unsupported  in  the  current.  Instead  of  that,  they  quickly  catch  the  passing 
leucocytes  and  hold  them  all  along  their  surfaces  (borders  in  the  section), 
like  flies  on  sheets  of  sticky  fly-paper;  and  at  the  same  time  they  seem  to 
liberate  thromboplastic  substance,  so  that  filaments  of  fibrin  spread  out 
from  them  on  all  sides,  and,  meeting  with  filaments  from  the  next  lamella, 
hang  in  festoons  between  them.  In  this  way  the  branching  and  anastomos- 
ing lamellae  are  guyed  and  braced  together  by  fibrin,  which,  needless  to 
say,  entangles  quantities  of  red  corpuscles,  so  that  finally  the  whole  is  a 
solid  mass  of  peculiarly  constructed  clot.  At  first,  of  course,  this  thrombus 


•  . 

"  "  ' 


Fig.  3. — Thrombus:  coral-like  laminae  of  platelets  with  marginal  leucocytes  and  inter- 
vening red  corpuscles  and  fibrin. 


is  predominantly  a  red  mass,  although  the  grayish-white  lamellae  of  plate- 
lets can  be  seen  in  a  cross-section  forming  a  web  all  through  the  red.  On 
the  free  surface  of  the  thrombus  these  same  lamellae  project  slightly  above 
the  red  part  of  the  clot,  and  these  corrugations  are  known  as  the  "lines  of 
Zahn"  (Fig.  4).  Red  corpuscles,  under  such  circumstances,  soon  die,  lose 
their  haemoglobin,  and  finally  disappear  into  a  formless  debris  which  in 
time  assumes  a  semitranslucent  appearance.  A  thrombus,  therefore, 
which  is  largely  red  at  first,  becomes  yellowish  gray  after  a  time,  and  the 
contrasting  color  of  the  platelet  sheets  is  lost  in  the  homogeneous  mass. 


10 


TEXT-BOOK   OF    PATHOLOGY 


Fig.  4. — Thrombus:  the  strands  of  platelets  form  superficial  corrugations. 

Nevertheless,  since  a  thrombus  continually  tends  to  grow  by  accretion, 
the  parts  of  different  ages  show  differences  in  color.     Indeed,  when  a 


Fig.  5. — Thrombus  in  auricular  appendage. 


CLOTTING,    THROMBOSIS,    ETC. 


11 


thrombus  forms  in  a  vein,  occluding  it,  there  is  left  a  perfectly  stagnant 
column  of  blood  reaching  to  the  next  affluent  of  the  vein,  and  in  this  an 
ordinary  homogeneous  clot  is  formed,  just  as  it  would  be  in  a  test-tube — 
not  exactly,  however,  for  there  is  some  motion  communicated  to  this  column 
of  blood  and  clumps  of  platelets  are  formed.  At  the  inflow  of  the  next 


Fig.  6. — Thrombus  in  vena  cava. 


branch  the  clotting  may  stop  or  begin  once  more  to  assume  the  character 
of  the  thrombus.  Thus,  as  Aschoff  says,  a  thrombus  has  a  head,  and  then, 
perhaps,  extending  both  ways  in  the  vein,  a  propagated  part  or  tail,  which 
differs  from  it,  being  more  like  a  postmortem  clot. 

Thrombi  may  be  formed  anywhere  in  the  blood-stream,  even  on  the  walls 


12  TEXT-BOOK    OF    PATHOLOGY 

of  the  aorta,  where  it  might  seem  that  the  pulsating  torrent  of  blood  would 
allow  no  chance  for  the  deposition  of  the  pioneer  platelets.  But  most 
commonly  they  appear  in  the  veins  or  in  the  auricular  appendages  or  inter- 
trabecular  spaces  of  the  heart  or  upon  the  valves  of  the  heart.  In  the  veins 
they  seem  to  start  from  the  region  of  a  valve,  where  the  slight  obstruction 
gives  rise  to  eddies.  In  the  heart  (Fig.  5)  they  bulge  forward  from  the 
recess  as  pinkish  yellow,  distinctly  corrugated  masses,  generally  coated  with 
an  adherent  red  clot — sometimes  they  are  quite  smooth  and  globular,  and 
these,  which  seem  to  be  old  ones,  are  frequently  found  to  be  softened  into  a 
semifluid  or  fluid  material  in  their  central  parts.  In  the  veins  (Fig.  6)  the 
lumen  is  usually,  though  not  always,  obliterated,  and  at  the  lower  end  the 
vein  is  plugged  for  a  long  way  with  a  soft  red  clot.  The  thrombus  itself 
differs  from  a  postmortem  clot  in  being  inelastic,  friable,  and  granular,  and 
in  adhering  to  the  wall  of  the  vein  so  that  when  it  is  removed  the  lining 
of  the  vein  is  left  roughened  and  dull  looking.  In  the  propagated  clot 
one  may  find  for  some  distance  indications  of  the  general  characters  of  the 
thrombus,  and  such  freshly  formed  thrombi  are  hard  to  tell  from  post- 
mortem clots.  Any  part  of  the  thrombus  may  break  off  and  be  swept 
along  in  the  blood-stream  to  plug  some  distant  vessel. 

It  may  be  difficult  to  avoid  looking  upon  thrombosis  as  a  process  harm- 
ful to  the  body,  since  it  causes  the  obstruction  of  blood-vessels,  and  through 
the  dislocation  of  part  of  the  material  of  the  thrombus  frequently  gives 
rise  to  embolism  of  distant  organs,  with  death  of  some  part  of  their  tissue 
or  even  death  of  the  individual. 

But  it  might  be  argued  that  this  is  only  a  form  of  the  very  useful  and 
protective  clotting  of  the  blood,  and  that  these  inconveniences  represent 
the  usual  imperfection  in  a  mechanism  of  defence.  Indeed,  there  are  in- 
numerable instances  in  which  thrombosis  has  the  character  of  a  life-saving 
process.  Even  the  final  cessation  of  bleeding  from  a  cut  vessel  is  really 
due  to  a  form  of  thrombosis,  since  the  clot  is  produced  in  streaming  blood. 
The  covering  of  bacteria  lodged  in  a  heart  valve  or  on  any  part  of  the  wall 
of  the  circulatory  system  by  a  thrombus  is  a  distinct  protection  inasmuch 
a?  it  prevents  the  bacteria  from  being  spread  through  the  whole  body. 
When  thrombosis  occurs  in  a  blood-vessel  on  account  of  injury  and  weak- 
ening of  its  wall,  either  from  within  or  from  the  advance  of  an  infectious  or 
other  destructive  process  from  the  outside,  it  prevents  haemorrhage  by 
obstructing  the  vessel  and  withdrawing  it  from  the  pressure  of  the  blood. 
This  is  well  illustrated  in  the  blood-vessels  about  ulcerative  processes  of 
all  sorts,  whether  in  the  intestinal  walls,  lungs,  or  elsewhere.  It  must  be 
said,  however,  that  thickening  of  the  walls  of  the  vessels  usually  plays  a 
large  part  in  shutting  off  the  current  of  blood,  especially  when  the  erosion 
of  tissue  proceeds  slowly,  so  that  it  may  be  agreed  that  were  it  not  for 
thrombosis  more  serious  consequences  might  follow  the  injury  of  the  walls 
of  the  blood-channels.  Less  can  be  said  for  the  advantages  conferred  by 
embolism. 


CLOTTING,    THROMBOSIS,    ETC.  13 

The  question  as  to  the  cause  of  the  formation  of  thrombi  has  been  answered  in  various 
ways.  The  wall  of  the  vessel  underlying  them  is  always  injured,  but  whether  by  the 
presence  of  the  thrombus  or  by  something  which  in  that  way  provoked  the  formation  of 
the  thrombus  is  hard  to  say.  Most  of  the  older  writers  assumed  a  primary  injury  of  the 
wall  (Eberth  and  Schimmelbusch,  Welch)  which  allowed  the  production  of  thrombokinase 
or  thromboplastin.  This  seems  especially  true  of  those  instances  in  which  thrombi  are 
formed  in  the  aorta  upon  ragged,  arteriosclerotic  patches  or  in  the  venous  sinus  of  the 
dura  at  a  point  where  an  abscess  extending  from  the  middle  ear  encroaches  upon  it. 
For  a  time  there  was  great  enthusiasm  over  the  idea  that  thrombi  occurring  in  general 
infections  and  after  surgical  operations  were  due  to  the  presence  of  bacteria  which  injured 
the  vessel-wall.  Perhaps  this  was  going  too  far,  but  now  the  pendulum  has  swung  the 
other  way,  and  Aschoff  and  his  colleagues  contend  that  thrombi  are  essentially  produced 
by  some  mechanical  obstruction  or  slowing  of  the  stream,  and  that  the  bacteria  which  are 
found  in  them  are  brought  to  the  thrombus  after  it  is  well  formed.  Aschoff  has  made 
elaborate  studies  to  show  that,  in  a  stream  of  water  with  obstructions  of  various  forms, 
sawdust  or  sand  floating  in  the  stream  will  accumulate  according  to  definite  laws  in  a 
certain  relation  to  the  obstructions,  and  especially  where  eddies  are  formed  and  where 
consequently  the  stream  is  slowed.  The  distribution  of  little  sand-banks  in  the  course 
of  a  crooked  stream  with  many  obstructions  is  familiar  enough  to  every  one,  and  it  is 
easily  credible  that  such  mechanical  factors  are  of  great  importance  in  determining  where 
the  thrombus  shall  start  and  how  the  deposition  shall  proceed.  Indeed,  the  difficulty  is 
confined  to  the  explanation  of  the  first  deposit  of  platelets — after  that  the  growth  of  the 
thrombus  is  easily  explained  by  the  ordinary  principles  of  clotting  and  by  the  obstruction 
produced  by  the  thrombus  itself.  Schwalbe  has  shown  that  if  the  wall  of  the  vein  be 
scraped  from  within  after  the  blood  is  rendered  incoagulable  with  hirudin,  platelets 
accumulate  on  the  injured  area  in  quantity,  but  no  fibrin  is  formed  and  no  red  corpus- 
cles entangled.  But  I  must  still  believe  that  many  thrombi  arise  because  an  injured 
or  dead  surface  is  exposed  to  the  coagulable  circulating  blood,  as  in  the  sclerotic  patches 
of  the  aorta,  the  infected  cranial  sinus  in  otitis  media,  the  uterine  veins  in  puerperal 
sepsis,  or  the  portal  branches  leading  away  from  an  appendix  abscess.  No  one  thinks 
of  the  thrombus  formed  upon  a  heart  valve  as  caused  by  mechanical  slowing  of  the 
stream  with  secondary  deposit  of  bacteria.  Why,  therefore,  is  there  any  difficulty  in  be- 
lieving that  bacteria  may  lodge  on  the  endothelium  of  a  valve  in  a  vein  where  the  current 
is  vastly  slower,  and  there,  by  injuring  the  endothelium,  make  possible  the  first  step  in 
the  formation  of  the  thrombus?  As  a  predisposing  and  later  as  a  guiding  factor  controlling 
the  architecture  of  the  thrombus,  modifications  of  the  velocity  and  direction  of  the 
current  are  undoubtedly  of  great  importance,  but  for  the  first  step  in  the  lodgment  of 
platelets  injury  to  the  endothelium  seems  to  me  to  be  of  prime  significance.  Me- 
chanical injury  to  the  vessel  quite  naturally  brings  about  thrombus  formation.  If  a 
vessel  be  ligated  very  gently  in  two  places,  so  that  the  endothelium  is  not  injured,  but 
merely  gently  pressed  together,  clotting  of  the  contained  blood  will  not  occur  for  a  long 
time,  but  if  the  vessel  walls  are  crushed  and  torn,  it  ensues  almost  at  once.  Cut  vessels 
of  small  size  close  themselves  partly  by  contraction  and  partly  by  the  formation  of  a 
thrombus  at  the  bleeding  end. 

Aschoff,  in  his  classification,  describes  three  other  forms  of  thrombi:  Agglutination 
thrombi,  which  occur  in  capillaries  such  as  those  of  the  glomeruli  of  the  kidney  and  are 
really  formless  masses  of  agglutinated  red  corpuscles  (Flexner).  Precipitation  thrombi, 
which  are  produced  in  the  capillaries  of  exposed  tissue,  like  the  mucosa  of  the  stomach, 
by  strong  chemical  poisons  which  coagulate  or  precipitate  the  whole  protein-rich  blood, 
and,  third,  thrombi  which  are  composed  of  the  debris  of  red  corpuscles  and  other  cells 
which  may  appear  in  quantities  after  some  haBmolytic  process. 


14  TEXT-BOOK   OF   PATHOLOGY 

LITERATURE 

Welch:  Allbutt's  System  of  Medicine,  1899,  vi,  155. 

Eberth  and  Schimmelbusch :  Thrombose,  Stuttgart,  1888. 

Aschoff,  Beck,  de  la  Camp,  and  Kronig:  Beitrage  zur  Thrombosefrage,  Leipzig,  1912. 

Whipple:  Arch.  Int.  Med.,  1913,  xii,  637;  Amer.  Jour.  Physiol.,  1914,  xxxiii,  50. 

Howell:  Amer.  Jour.  Physiol.,  1910,  xxvi,  453;  Arch.  Int.  Med.,  1914,  xiii,  76;  Amer. 

Jour.  Physiol.,  1912,  xxxi,  1;  1913,  xxxii,   264;  1918,  xlvii,  328;  Harvey  Lectures, 

1916-17,  273. 

Morawitz :  Oppenheimer's  Handb.  der  Biochemie,  1909,  ii,  40. 
Aschoff:  Arch.  Int.  Med.,  1913,  xii,  503. 


CHAPTER  II 
LOCAL  DISTURBANCES  IN  THE  CIRCULATION  OF  THE  BLOOD 

Hypercemia;  anosmia.  Postmortem  changes  in  distribution;  active  and  passive  hypercemia. 
Local  ancemia.  Embolism.  Infarction.  Gangrene. 

THE  circulation  through  a  tissue  is  modified  by  three  main  factors:  the 
activity  of  the  heart,  the  changes  in  the  calibre  of  the  blood-vessels, 
and  the  amount  of  blood.  Of  these,  the  changes  in  the  calibre  of  the  blood- 
vessels are  of  special  importance  as  far  as  the  local  conditions  are  con- 
cerned. The  muscular  walls  of  the  arteries,  and  to  a  less  extent  the  veins, 
are  controlled,  as  is  well  known,  by  the  vasomotor  nerves,  so  that  the 
amount  of  blood  which  passes  through  any  given  tissue  depends  largely 
on  the  activity  of  these  nerves.  Quite  aside,  therefore,  from  any  patho- 
logical conditions,  there  are  remarkable  changes  from  time  to  time  in  the 
amount  of  blood  which  passes  through  the  different  tissues,  the  arterial 
blood  supply  generally  increasing  with  the  activity  of  that  particular  tissue.* 

*  Postmortem  Changes. — During  life  the  distribution  of  the  blood  in  any  organ  or 
tissue  is  a  very  uniform  one,  as  a  rule,  but  on  the  cessation  of  the  action  of  the  heart 
numerous  alterations  take  place,  so  that  in  the  tissues,  as  observed  in  the  dead  body, 
the  distribution  of  the  blood  is  very  much  changed,  and  it  is  necessary  to  be  familiar 
with  these  changes  in  order  to  appreciate  those  which  are  actually  the  results  of  patho- 
logical conditions  which  have  existed  during  life.  The  contractility  of  the  arte- 
rial walls  is  dependent  not  only  upon  their  muscular  structures,  which  aid.  by  a 
sort  of  peristaltic  movement,  the  action  of  the  heart,  but  also  upon  the  large  amount 
of  elastic  tissue  which  exists  in  their  walls.  The  combined  effect  of  the  contraction  of 
these  two  tissues,  as  soon  as  the  heart  stops  beating,  is  to  drive  the  blood  out  of  the 
arterial  side  into  the  venous  side  of  the  circulation  in  each  organ,  in  that  way  imme- 
diately producing  a  change  in  the  appearance  of  the  organ. 

The  liver,  which  is  in  life  of  a  uniform  red  color,  shows  at  once  on  cessation  of  the 
heart-beat  the  lobulation  with  its  darker  blood-filled  central  portion  and  paler  periphery, 
a  mottling  being  produced  by  the  collection  of  blood  in  the  central  portion  of  each  lobule, 
while  the  periphery  is  left  pale.  In  the  same  way  the  great  veins  in  the  abdomen  become 
filled  with  blood,  whereas  the  arteries  everywhere  are  found  collapsed  and  nearly  empty. 

Other  influences  are  brought  to  bear  also,  and  especially  that  of  gravity,  so  that  all 
dependent  portions,  as  the  body  lies,  become  overfilled  with  blood  and  assume  a  dark 
purplish  hue,  while  the  upper  portions  are  relatively  pale.  This  is  true  even  of  the  differ- 
ent parts  of  the  internal  organs,  so  that  the  loops  of  intestine  which  lie  in  the  pelvis 
and  in  the  lower  part  of  the  peritoneal  cavity  show  a  great  distension  of  the  veins,  although 
the  upper  portions  of  the  loops  are  pale.  When  the  intestine  is  opened  and  stretched  put, 
these  areas  appear  as  patches  of  congestion,  the  nature  of  which  is  not  always  recognized 
by  the  beginner. 

The  purplish  discoloration  of  the  skin  of  the  back  is  not  seen  in  those  parts  upon  which 
the  body  has  lain;  thus,  for  example,  the  backs  of  the  shoulders,  the  buttocks,  and  heels 
usually  appear  quite  white,  because,  owing  to  the  pressure  of  the  weight  of  the  body,  the 
blood  has  not  been  allowed  to  sink  into  them.  Firm  pressure  of  the  fingers  upon  the 
purple  area  is  sufficient  to  drive  the  blood  out  of  those  veins  and  to  leave  white  marks. 
This  overdistension  of  the  veins  through  gravity  is  spoken  of  as  livor  mortis,  and  it  must 
be  distinguished  from  accumulations  of  blood  in  the  tissues  themselves — haemorrhage. 
This  distinction  is  readily  made  because  in  livor  mortis  (hypostasis)  the  blood  is  still 

15 


16  TEXT-BOOK   OF   PATHOLOGY 

An  increase  in  the  amount  of  blood  to  any  part  is  spoken  of  as  hyperoemia; 
and  such  hyperaemia  may  be  active,  when  there  is  an  actual  increase  in  the 
amount  of  arterial  blood,  or  passive  when,  through  any  obstruction,  the 
outflow  of  venous  blood  is  retarded.  On  the  other  hand,  decrease  of  the 
supply  of  blood  in  any  area  is  known  as  partial  or  complete  anaemia  and 
results  from  obstruction  of  the  arterial  flow. 


HYPER^MIA 

Active  hyper  cemia  is  usually  the  result  of  vasomotor  effects  upon  the  vessels, 
and  is  essentially  a  physiological  process,  being  concerned  so  largely  with 
the  supply  of  increased  nutritive  fluid  to  tissues  which  are  assuming  for  the 
time  a  heightened  activity.  It,  however,  appears  in  certain  nervous  dis- 
turbances, and  also  may  be  brought  about  by  the  direct  application  of  heat 
and  irritants,  which  cause  the  blood-vessels  to  dilate.  It  is  probably  in 
just  this  way  that  the  irritant,  which  is  sufficiently  intense  to  bring  about 
an  inflammatory  reaction,  causes  the  active  hypersemia  which  forms  so 
striking  a  feature  of  that  process.  The  tissues  through  which  such  a  rapid 
stream  of  arterial  blood  is  passing  are  usually  somewhat  swollen  and  red 
and  warmer  than  the  surrounding  tissue. 

Passive  hypercemia  is  more  commonly  a  pathological  or  abnormal  process, 
inasmuch  as  it  is  the  result  of  interference  with  the  outflow  of  blood.  It  is 
usually  a  very  wide-spread  obstruction,  due  to  some  inability  on  the  part 
of  the  heart  which  dams  back  blood  into  the  whole  venous  tract,  but  oc- 
casionally it  may  be  quite  local.  This  is  especially  due  to  the  fact  that  the 
veins  are  more  easily  compressed  than  the  arteries,  so  that  pressure  from 
without  which  will  occlude  the  veins  can  still  allow  the  blood  to  be  poured 
in  from  the  more  resistant  arteries,  congesting  and  distending  the  tissues 
with  stagnant  blood. 

It  is  by  no  means  uncommon  to  find  a  loop  of  intestine  pushed  through 
an  aperture  in  the  abdominal  wall,  thus  constituting  a  hernia.  Such  a  loop 
may,  in  most  cases,  be  pushed  back  into  the  peritoneum;  but  sometimes, 
when  it  has  escaped  habitually  through  this  newly  formed  aperture  into  the 
sac  which  is  formed  outside,  it  may  become  so  enlarged  by  an  increase  of  its 


within  the  veins,  while  in  haemorrhage  it  has  escaped  from  the  blood-vessels  and  can  no 
longer  be  pressed  away  with  the  fingers. 

If  the  body  has  lain  for  some  time,  and  especially  if  the  temperature  of  the  surrounding 
air  has  been  high,  there  may  appear  other  discolorations  which  are  due  not  particularly 
to  the  distribution  of  blood  nor  to  its  escape  from  the  vessels,  but  to  the  disintegration 
of  the  red  corpuscles  by  a  physico-chemical  process  which  we  shall  discuss  later  under 
the  name  of  haemolysis.  This  sets  free  into  the  fluid  the  red  staining  matter  of  the  blood 
(haemoglobin),  which  tinges  diffusely  all  dead  tissues  with  which  it  comes  into  contact; 
the  lining  of  the  aorta,  for  example,  and  of  the  heart  itself  may  assume  a  dull  red  color 
which  is  in  sharp  contrast  to  the  normal.  Such  blood  staining  of  the  tissues  may  appear 
with  great  rapidity  in  persons  who  have  died  from  infection  with  one  of  those  bacteria 
which  have  the  property  of  destroying  the  red  corpuscles  rapidly  by  the  poison  which 
they  produce.  In  such  infections,  notably  the  streptococcus  infections,  the  blood  in  the 
vessels  stains  the  surrounding  tissues  to  such  an  extent  that  the  course  of  the  subcu- 
taneous veins  may  be  seen  through  the  skin  in  the  form  of  a  network  of  purplish  lines. 


HYPER^EMIA  17 

contents  that  it  can  no  longer  be  returned,  and  indeed  so  large  that  its 
blood-vessels,  which,  of  course,  stretch  through  the  aperture,  also  become 
constricted  there,  and  the  circulation  is  brought  to  a  full  stop,  not  because 
blood  cannot  get  in  through  the  artery,  but  because  it  cannot  escape 
through  the  more  readily  compressed  vein.  This  is  a  condition  which  is 
known  as  " strangulated  hernia." 

A  local  congestion  of  not  quite  so  extreme  a  degree  may  often  be  seen  in 
the  liver  when  a  tumor  nodule  embedded  in  the  liver  substance  presses  on 
the  efferent  vein  and  causes  that  portion  of  the  liver  ordinarily  drained 
by  the  vein  to  become  congested.  The  process  is  put  to  therapeutic 
use  in  Bier's  treatment  of  various  local  infections  in  which  a  stagnation 
of  blood  is  produced  for  a  time  in  the  inflamed  area  by  the  applica- 
tion of  a  tight  bandage  which  obstructs  the  veins  and  leaves  the  arteries 
open. 

Ordinarily,  the  communications  between  veins  are  very  abundant,  so 
that  the  obstruction  of  any  one  vein  is  hardly  likely  to  cause  such  conges- 
tion. Nevertheless,  the  surgeon  must  be  careful  in  operating  to  leave  the 
tissues  not  only  with  a  sufficient  arterial  supply,  but  also  with  an  adequate 
venous  outflow  if  they  are  to  remain  alive;  for  the  stoppage  of  the  stream 
from  the  venous  side  is  just  as  important  as  the  obstruction  of  the  arterial 
side.  In  the  case  of  mesenteric  veins,  renal  veins,  etc.,  ligation  or  occlusion 
may  readily  lead  to  the  death  of  the  tissue  which  they  drain.  In  other 
places  where  anastomosis  is  free  there  may  be  no  effect,  but  if  the  obstruc- 
tion, as  in  the  case  of  a  long  thrombus  of  the  femoral  vein,  is  extensive 
enough  to  plug  the  communicating  branches,  the  accessory  channels  are 
also  closed  and  the  circulation  is  greatly  disturbed.  In  such  a  case  great 
pain  is  experienced,  the  leg  becomes  swollen  and  livid,  or  later  pale,  with 
purplish  blotches,  and,  because  of  the  malnutrition  and  oedema,  it  can 
scarcely  be  moved  (milk-leg) .  (Edema  or  oozing  of  the  fluid  of  the  blood 
into  the  tissue-spaces  is  characteristic  of  all  instances  of  marked  passive 
hypersemia,  and  in  extreme  cases,  with  great  disturbance  of  the  nutrition 
of  tissues,  haemorrhage  may  also  occur. 

Passive  hypersemia  may  be  the  effect  also  of  nervous  disturbances  which 
render  immobile  for  a  long  time  the  muscles  of  an  extremity.  The  same 
result  follows  to  a  slight  extent  if  disease  of  the  joints  with  ankylosis  makes 
them  immovable.  In  both  these  cases  the  passive  hypersemia  is  relatively 
slight,  and  is  essentially  the  effect  of  gravity.  In  this  respect  it  resembles 
the  condition  which  is  found  in  the  dependent  portions  of  organs  in  persons 
who  are  constrained  to  lie  in  bed  for  a  long  time  in  one  position.  It  is 
spoken  of  as  hypostasis,  and  becomes  particularly  striking  in  the  lungs, 
where  it  may  so  lower  the  nutrition,  and  consequently  the  power  of 
resistance,  of  the  tissues  as  to  allow  bacteria  to  take  root  there  and  produce 
the  so-called  hypostatic  pneumonia. 


18  TEXT-BOOK   OF   PATHOLOGY 

LOCAL  ANEMIA 

In  a  general  anaemia,  such  as  has  been  mentioned,  each  individual  tis- 
sue may,  of  course,  suffer  somewhat,  but  the  most  intense  effects  of  this 
type  may  be  brought  about  locally  without  regard  to  the  general  condi- 
tion of  the  circulation.  Such  local  anaemia  must  always  result  from  an 
obstruction  opposed  to  the  inflow  of  arterial  blood.  This  may  be  an 
effect  of  the  active  contraction  of  the  blood-vessels  through  the  intermedia- 
tion of  the  vasomotors,  or  it  may  be  due  to  pressure  on  these  vessels  from 
without,  or  to  thickening  of  the  walls  of  the  vessels  with  narrowing  of  their 
lumen,  or,  finally,  and  most  commonly,  to  a  complete  obstruction  or  plug- 
ging of  the  artery  by  some  foreign  material  which  is  lodged  there.  Com- 
binations of  all  these  things  very  commonly  occur.  The  vasomotor  nar- 
rowing of  the  vessel  is  ordinarily  a  normal  process,  aimed  at  the  withhold- 
ing of  blood  from  a  vessel  which  does  not  need  it  at  that  particular  stage  of 
its  activity,  but  sometimes  it  may  become  pathological,  as  in  the  so-called 
Raynaud's  disease,  which  consists  in  such  a  constriction  of  the  vessels  of 
the  fingers  and  toes  as  to  cause  even  the  death  of  those  tissues.  Apparently 
the  familiar  chilblains  depend  upon  such  excessive  narrowing  of  the  vessels 
when  the  hands  or  feet  are  exposed  to  cold.  That  seems  to  happen  in 
particularly  susceptible  persons,  and  probably  especially  in  those  whose 
habits  are  sedentary  and  in  whom  the  circulation  is  ordinarily  not  very 
active. 

Pressure  from  without  might  cause  the  closure  of  an  artery  if  it  were 
directly  enough  applied.  It  is  difficult,  however,  to  obstruct  the  arteries 
by  pressure  from  without,  because  they  are  so  protected  by  other  tissues; 
and  it  is  well  known  that  a  ligature  tied  tightly  around  an  extremity  will 
cause  rather  an  increase  of  blood  in  the  ligated  part,  because  it  obstructs 
the  outflow  through  the  veins  long  before  it  can  obstruct  the  artery.  In 
order  to  render  a  limb  bloodless  for  the  purpose  of  carrying  on  an  operation 
in  a  clean  field,  as  in  the  method  of  Esmarch,  a  rubber  bandage  must  be 
applied  with  great  force. 

The  pressure  of  tumor-nodules  and  of  aneurysms  upon  arteries  may 
sometimes  cause  their  obstruction  in  such  a  way  as  to  cut  off  completely 
the  supply  of  blood  from  the  part.  The  pedicle  of  a  tumor  or  the  long 
mesentery  of  a  loop  of  intestine  may  become  twisted  so  as  to  shut  the  lumen 
of  the  artery  and  cause  the  death  of  the  tissue  supplied  by  it;  but  usually, 
as  we  have  stated  in  speaking  of  strangulated  hernia,  this  first  results  in  the 
obstruction  of  the  vein,  so  that  the  tissue  becomes  engorged  with  stagnant 
blood  and  the  final  effect  of  shutting  off  the  artery  masked. 

The  walls  of  the  arteries  themselves  may  undergo  structural  changes 
which  finally  lead  to  such  narrowing  of  the  lumen  as  to  prevent  the  further 
flow  of  blood.  This  usually  occurs  when  an  organ  has  passed  its  stage  of 
usefulness,  and  such  an  abundant  blood  supply  is  no  longer  necessary.  It 


EMBOLISM 


19 


is  somewhat  difficult  to  draw  a  line  between  this  more  or  less  physiological 
process  of  narrowing  the  artery  and  that  which  comes  from  actual  disease 
of  the  artery  wall.  Still,  in  extreme  cases,  the  pathological  character  of 
the  process  is  very  evident.  There  are  various  forms  of  disease  of  the 
artery  wall,  roughly  classed  under  the  general  name  of  arteriosclerosis, 
which  bring  about  this  effect,  and  so  completely  may  the  vessel  be  ob- 
structed that  all  the  tissue  ordinarily  supplied  by  it  dies.  When,  in  the 
legs,  for  example,  this  extreme  is  not  reached,  the  narrowing  of  the  artery 
may  be  only  sufficient  so  to  cut  down  the  blood-supply  that  the  person  is 
able  to  walk  perfectly  well  for  a  short 
distance,  when  his  muscles  fail  him 
solely  on  account  of  their  insufficient 
nutrition.  After  a  rest  he  is  able  to 
go  on  again  for  a  time.  This  is  often 
spoken  of  as  intermittent  daudication. 
Harmful  in  some  cases,  this  shutting- 
off  of  the  blood-stream  by  thickening 
of  the  vessel  walls  is  useful  in  others 
—it  is  the  physiological  method  by 
which  the  ductus  Botalli  is  closed;  it 
appears  in  organs  such  as  the  senile 
uterus  and  breast,  which  have  out- 
lived their  usefulness,  and  it  forms  a 
safeguard  against  haemorrhage  from 
the  erosion  of  arteries  in  the  lung  by 
advancing  tuberculosis :  as  the  cavity 
extends  and  cuts  across  these  arteries 
it  finds  them  reduced  to  bloodless 
cords.  Nevertheless  in  the  kidney 
the  same  sort  of  narrowing  of  the 
small  vessels  produces  local  anaemia 
and  destruction  of  patches  of  tissue 
which  can  only  be  replaced  by  scars 
(Fig.  7).  Arteries  thus  narrowed  by 
changes  in  their  walls  are  very  often 

finally  and  completely  closed  by  the  formation  of  a  thrombus  throughout 
the  narrowed  portion. 

EMBOLISM 

Local  anaemia  of  extreme  degree  is  produced  most  commonly  by  some  sort 
of  plug  which  obstructs  the  artery  supplying  blood  to  the  part.  Such  a 
plug  is  known  as  an  embolus,  and  embolism  is  defined  by  W.  H.  Welch  as 
the  impaction  in  some  part  of  the  vascular  system  of  any  undissolved 
material  brought  there  by  the  blood-current.  Naturally,  the  number  of 


Fig.    7. — Arteriosclerotic    scarring    of 
kidney. 


20  TEXT-BOOK   OF   PATHOLOGY 

kinds  of  material  +hat  can  get  into  the  blood-stream  is  limited,  but  there  is, 
nevertheless,  a  surprising  variety.  The  commonest  are  thrombi  or  frag- 
ments of  thrombi,  but  tumor  cells,  tissue  fragments,  clumps  of  bacteria, 
protozoan  and  worm  parasites,  as  well  as  oil-globules  and  gas-bubbles, 
may  play  the  same  role.  Of  these,  only  the  thrombi  are  from  the  first 
within  the  blood-vessels:  the  others  must  gain  access  to  the  stream  before 
they  can  act  as  emboli. 

It  has  been  shown  that  thrombi  form  most  commonly  on  the  venous  side 
of  the  circulation,  although  they  are  occasionally  found  in  the  arteries,  and 
are  common  enough  upon  the  heart-valves.  Their  rather  intimate  ad- 
hesion to  the  underlying  vessel-wall  was  mentioned,  though  not  the  fact 
that,  after  they  remain  in  position  for  a  time,  they  become  firmly  fixed  to  the 
wall  by  blood-vessels  and  connective-tissue  cells  which  grow  into  them  and 
ultimately  replace  them  completely  with  fibrous  tissue.  Before  this  so- 
called  organization  begins  they  can  be  dislodged  by  violent  movements  or  by 
manipulation,  and  then  arises  at  once  the  condition  which  makes  embolism 
of  some  distant  part  of  the  blood-channel  inevitable.  A  loose  mould  of  the 
vein  or  a  fragment  of  it  caught  in  the  current  of  the  blood-stream  must 
move  along  toward  the  heart  because  the  vein  becomes  larger  and  larger. 
Sometimes  the  whole  thrombus,  with  its  long  adherent  propagated  clot,  is 
thus  dislodged;  sometimes  only  a  fragment,  the  original  situation  of  which 
might  perhaps  be  recognized  by  fitting  together  the  surfaces  of  fracture. 
When  the  crumbly  thrombi  which  form  on  the  heart-valves  are  the  source 
of  such  emboli,  the  dislodged  fragments  may  be  large  enough  to  plug  the 
aorta,  or  at  the  other  extreme  sifted  off  as  fine  particles  which  go  on  to  the 
smaller  arterioles.  It  must  be  remembered  that  a  long  narrow  thrombus 
may  become  folded  and  doubled  on  itself  and  thus  occlude  a  much  larger 
cavity  than  that  in  which  it  formed.  This  is  the  case  when  dislodged  clots 
from  the  femoral  vein  are  swept  into  the  pulmonary  artery,  blocking  it 
completely.  This  whole  process  may  occupy  only  a  few  seconds  after  the 
loosening  of  the  thrombus,  and  death  may  follow  instantly. 

Such  an  embolus  when  formed  from  a  part  of  an  old  thrombus  can  usu- 
ally be  recognized  easily  enough  by  its  evident  age,  although  in  its  new 
lodging-place  it  is  almost  at  once  surrounded  by  propagated  clots. 

Seats  of  Embolism. — Given  its  size  and  its  point  of  origin,  the  site  at 
which  the  embolus  will  lodge  may  be  foretold  with  some  accuracy,  al- 
though the  actual  distribution  of  multiple  small  emboli  has  been  learned 
only  by  experiment.  It  was  found,  for  example,  that  the  great  majority  of 
a  large  number  of  recognizable  particles  introduced  into  the  blood-stream 
of  the  aorta  were  hurried  past  the  mouths  of  arteries  supplying  the  vis- 
cera into  the  vessels  of  the  muscles  of  the  legs.  After  that  only  came  the 
embolism  of  the  brain,  liver,  kidney,  spleen,  skin,  etc. 

Briefly,  one  may  say  that  an  embolus  set  free  in  any  of  the  systemic 
veins,  and  caught  in  the  current  entering  from  the  next  branch  above  the 


EMBOLISM  21 

part  of  the  vein  which  had  been  completely  occluded,  is  swept  through  the 
vena  cava  into  the  right  side  of  the  heart,  and  thence  thrown  violently 
into  the  pulmonary  artery.  Only  the  exceptional  chance  of  its  passing 
through  a  wide-open  foramen  ovale  will  allow  it  to  reach  the  systemic 
arteries  unless  it  is  a  particle  so  minute  that  it  can  pass  through  the  capil- 
laries of  the  lung.  The  same  course  is  followed  by  a  thrombus  mass  origi- 
nating in  the  right  auricle  or  in  the  intertrabecular  spaces  of  the  right  ven- 
tricle, and  obviously  this  holds  true  also  for  vegetations  dislodged  from  the 
tricuspid  or  pulmonary  valves.  Thrombi  set  free  in  any  of  the  veins  which 
go  to  form  the  portal  trunk  are  caught  in  the  branches  of  that  channel  in 
the  liver.  Those  arising  in  the  pulmonary  veins,  left  auricle,  or  left  ven- 
tricle, vegetations  from  the  mitral  and  aortic  valves  or  thrombi  formed  on 
the  walls  of  the  aorta,  are  hurried  into  the  aorta  and  distributed  as  described 
above.  Naturally  a  thrombus  formed  in  any  smaller  artery  and  dislodged 
is  merely  pushed  further  into  the  branches  of  that  artery.  Since  emboli  are 
most  easily  traced  by  the  effects  they  produce,  the  impression  is  likely  to 
arise  that  they  lodge  most  often  in  such  organs  as  the  brain,  the  kidneys, 
or  the  spleen,  but  from  what  has  been  said  it  will  be  clear  that  even  though 
no  effects  become  visible,  the  actual  number  is  greatest  for  the  lungs,  the 
body  musculature,  and  perhaps  the  liver,  which  is  menaced  through  both 
the  portal  vein  and  the  hepatic  artery. 

With  regard  to  the  size  of  the  embolus,  a  few  more  words  may  be  said. 
The  mass  travels  until  it  comes  to  a  pass  too  narrow  to  admit  it,  and  there 
it  lodges  like  a  cork.  Naturally,  since  the  branches  are  smaller  than  the 
main  trunk  in  a  bifurcating  vessel,  the  plug  is  often  found  riding  or  balanced 
upon  the  point  of  bifurcation.  Still,  most  arteries  become  narrower  as 
they  advance,  and  the  majority  of  emboli  stick  on  this  account.  In  a  case 
of  vegetative  endocarditis  seen  at  autopsy  recently  there  were  two  masses 
of  thrombus  material  successively  lodged  in  the  common  iliac  artery,  and 
one  much  larger  mass  riding  at  the  bifurcation  of  the  aorta.  Each  was 
surrounded  by  a  propagated  clot  formed  in  the  blood  rendered  stagnant  by 
its  advent. 

The  other  things  which  can  act  as  emboli  do  so  rarely  and  are  of  far  less 
importance  as  emboli  than  are  thrombi,  although  in  their  other  effects  they 
may  be  of  great  significance.  Air-bubbles  may  act  as  emboli  of  a  rather 
temporary  character,  because  the  gas  is  so  readily  dissolved  in  the  circu- 
lating blood.  If,  however,  a  great  amount  of  gas  is  introduced  into  the 
circulation  at  any  one  time,  the  obstruction  may  be  sufficient  to  cause 
death  either  by  passing  into  the  vessels  of  the  brain,  or,  much  more  com- 
monly, by  filling  up  the  heart  and  yielding  to  its  churning  action,  so  as  to 
exclude  the  inflow  of  blood.  A  considerable  amount  of  air  or  other  gas  is 
necessary  to  produce  this  result — probably  much  more  than  is  generally 
supposed.  It  is  in  operations  and  injuries  which  involve  the  accidental 
opening  of  the  veins  of  the  neck  that  this  is  likely  to  take  place.  The 
pressure  in  these  veins  is  so  lowered  by  the  inspiratory  enlargement  of  the 


22  TEXT-BOOK   OF   PATHOLOGY 

chest  that  the  air  enters  with  a  hissing  sound,  and  the  death  of  the  in- 
dividual may  take  place  very  rapidly.  Probably  its  entrance  into  the 
coronary  arteries  is  of  great  importance. 

For  a  time  the  appearance  of  gas  in  bubbles  in  the  organs  of  the  body  was  regarded 
as  evidence  of  air  embolism,  especially  in  the  case  of  women  who  had  died  after 
childbirth  when  it  was  thought  that  the  air  had  entered  the  large  open  sinuses  in  the 
uterine  wall.  Welch  has  pointed  out  that  these  were  cases  of  infection  with  the  Bacillus 
aerogenes  capsulatus,  which  produced  after  death  bubbles  of  hydrogen  gas  everywhere 
throughout  the  organs,  so  that  they  became  distended  like  bread  that  is  rising  and  full 
of  holes.  The  liver  assumes  the  appearance  of  a  red  rubber  bath  sponge,  and  on  incision 
bubbles  of  gas  appear  which  burn  with  a  blue  flame  when  a  match  is  applied.  Similar 
cavities  may  be  formed  all  through  the  brain,  where  they  have  somewhat  the  appear- 
ance of  the  holes  in  a  Swiss  cheese.  In  the  intestine  or  stomach  the  mucosa  may  be 
lifted  up  into  blebs. 

At  other  times  emboli  may  be  constituted  of. droplets  of  fat  which  are  set 
free  into  the  blood-stream  from  the  adipose  tissue.  Such  globules  lodge, 
as  a  rule,  in  the  capillaries  of  the  lung,  and  are  pressed  into  a  sausage  shape 
by  the  blood  of  the  pulmonary  artery.  They  can  be  recognized  in  the 
frozen  section  of  such  a  lung  by  their  highly  refractive  character,  and  also 
by  the  fact  that  they  readily  stain  with  those  stains  which  are  soluble  in 
fat,  such  as  Sudan  III.  They  produce  no  obvious  change  in  the  appear- 
ance of  the  lung,  and  indeed  must  be  searched  for  in  this  way.  They  are 
commonly  introduced  by  some  mechanical  injury  to  the  bones,  such  as 
fracture;  but  even  a  severe  blow  seems  sufficient  to  cause  such  a  commo- 
tion in  the  marrow  as  to  introduce  some  of  the  abundant  fat  into  the  venous 
channels.  Fat  embolism  also  occurs  in  a  number  of  convulsive  diseases, 
and  particularly  in  such  conditions  as  delirium  tremens,  in  which  prob- 
ably the  violent  exertions  of  the  individual  play  a  part  in  the  process. 

Injury  or  crushing  of  the  tissues  of  cellular  organs  sometimes  introduces 
fragments  or  groups  of  cells  into  the  blood-stream,  where  they  act  as  emboli. 
Most  commonly  this  is  observed  in  connection  with  the  cells  of  the  bone- 
marrow  and  the  syncytial  structures  which  arise  in  pregnancy.  There  is 
little  evidence,  however,  of  their  producing  any  mechanical  effect  where 
they  lodge  in  the  capillaries. 

Bacteria  may  enter  the  blood-stream  by  growing  through  the  walls  of 
capillaries  or  by  being  discharged  from  infected  thrombi,  and  can,  as  is 
well  known,  circulate  with  the  corpuscles  of  the  blood  through  any  capil- 
laries. That  they  often  lodge  and  grow  into  colonies  which  produce  char- 
acteristic effects  on  the  surrounding  tissue  is  shown  in  cases  of  generalized 
miliary  tuberculosis  and  in  general  pyaemia,  but  they  can  be  said  to  act  as 
emboli  only  when  they  circulate  in  clumps  large  enough  to  obstruct  the 
capillaries.  Protozoan  parasites  in  the  same  way  usually  circulate  through 
the  capillaries,  but  certain  worms,  such  as  the  Schistosomum,  can  behave 
as  actual  mechanical  emboli,  plugging  and  obstructing  the  vessels. 

In  the  case  of  malignant  tumors,  the  transportation  of  cells  foreign  to  the 


EMBOLISM  23 

blood  is  of  particular  importance,  although  these  cells  rarely  act  as  gross 
emboli.  It  is  perfectly  clear,  from  a  study  of  the  gross  anatomy  of  such 
invading  tumors,  that  they  frequently  extend  their  growth  through  the 
wall  of  a  vein  and  hang  loosely  in  the  blood-stream,  so  that  fragments  can 
be  broken  off  and  swept  on  by  the  stream.  It  is,  however,  by  no  means 
always  possible  to  recognize  the  mode  of  entrance,  and  it  seems  likely  that 
in  many  cases  individual  cells  gain  entrance  into  the  thin-walled  veins 
of  the  tumor  itself,  possibly  as  a  result  of  mechanical  trauma.  The  cultiva- 
tion of  these  cells  on  the  glass  slide,  however,  has  shown  them  to  be  en- 
dowed with  a  remarkable  power  of  amoeboid  movement,  so  that  Hanes 
and  Lambert  have  advanced  the  idea  that  the  separate  cells  of  the  tumor 
may  actively  push  their  way  through  the  endothelial  lining  of  the  vein 
and  thus  enter  the  venous  blood-stream.  The  cells  appear  to  be  able  to 
pass  through  such  capillaries  as  those  of  the  lung,  and  to  set  up  their 
growth  in  more  distant  organs,  where  they  find  a  suitable  environment. 

Results  of  Embolism. — The  degree  of  anaemia  produced  by  the  occlusion 
of  any  artery  will  depend  upon  the  relation  of  its  branches  to  those  of  the 
surrounding  arteries  and  to  the  other  branches  of  its  own  trunk,  because, 
just  as  in  the  case  of  the  veins,  such  connections  dilate  to  accommodate 
blood  whenever  it  finds  its  way  blocked  through  its  ordinary  channel.  If 
these  branches  anastomose  widely  with  the  terminal  twigs  of  the  adj  acent 
artery,  a  sufficient  supply  of  blood  may  be  maintained  in  its  area  of  tissue. 
Indeed,  this  communication  between  the  end-twigs  of  the  arterial  branches 
is  so  wide  in  some  tissues,  such  as  the  muscles,  skin,  lungs,  etc.,  that  even 
a  large  artery  can  be  closed  off  without  causing  a  moment's  delay  or  dimi- 
nution in  the  supply  of  blood  to  the  tissue.  It  can  be  seen,  then,  that  the 
advent  of  an  embolus  in  one  of  these  arterial  branches  will  cause  no  par- 
ticular disturbance  in  such  tissue  as  muscle  or  lung,  or  even  in  the  stomach- 
wall. 

This  compensation  for  lost  arterial  supply  can  be  seen  most  vividly  if  one 
injects  a  quantity  of  ultramarine  blue  in  suspension  into  one  of  the  gastric 
arteries.  This  fills  the  artery,  with  all  its  branches,  with  blue  fluid,  but  the 
moment  the  stream  of  blue  fluid  is  interrupted  or  its  pressure  lowered,  the 
inflow  of  blood  from  the  neighboring  vessels  replaces  the  blue  material  in 
that  artery.  In  this  case,  however,  the  connections  are  between  the  larger 
branches  and  it  is  found  that  the  minute  twigs  of  the  gastric  artery  thus 
injected  remain  permanently  plugged  with  the  blue  granules  and  the  tissue 
which  they  supply  suffers. 

In  other  places  the  communications  are  not  nearly  so  free,  so  that  if  it 
becomes  impossible  for  the  blood  to  go  through  one  branch,  the  connections 
with  the  adjacent  branches  may  indeed  be  sufficient  to  keep  the  tissue  living 
by  furnishing  blood  to  the  terminal  twigs,  but  they  can  do  this  only  by 
actually  increasing  their  own  calibre;  so  that  in  such  a  case  the  ana- 
tomical development  of  a  collateral  circulation  is  much  more  plainly  seen. 
Sometimes  these  connections  are  so  minute  as  to  be  invisible  under  ordinary 


24 


TEXT-BOOK    OF    PATHOLOGY 


circumstances,  but  become  quite  conspicuous  after  they  are  dilated  in  this 
way. 

Extraordinary  examples  of  the  development  of  such  a  collateral  circula- 
tion are  seen  in  connection  with  the  larger  arteries  of  the  body.  So  when 
the  aorta  is  tied,  as  in  the  experiments  of  Halsted  and  Porta,  there  appears 


Fig.  8. — Collateral  circulation  after  obstruction  of  vena  cava  superior  (Osier). 


after  a  time  a  whole  brush  of  vessels  which  anastomose  with  branches 
below  the  point  at  which  the  ligature  is  applied  and  which  reestablish  the 
circulation.  I  have  recently  seen  two  cases  in  which  there  had  occurred 
obstruction  of  the  large  abdominal  arteries.  In  one  instance  it  was  the 
trunk  of  the  cceliac  axis  which  had  been  gradually  obstructed  by  an 


EMBOLISM  25 

arteriosclerotic  thickening  of  its  wall,  supplemented  finally  by  the  formation 
of  a  thrombus ;  and  in  the  other  it  was  the  superior  mesenteric  artery 
which  had  been  gradually  but  completely  pressed  together  by  the  growth 
of  a  small  aneurysm  developed  from  a  point  very  near  its  orifice  in  the  wall 
of  the  aorta.  In  neither  of  these  cases  was  there  the  slightest  disturbance 
in  the  appearance  of  the  abdominal  organs,  for  in  both  the  pancreatico- 
duodenal  artery  had  dilated  and  had  assumed  the  burden  of  transmitting 
the  whole  supply  of  blood  for  those  organs  which  would  otherwise  have 
been  deprived  of  it — in  one  case  in  one  direction  and  in  the  other  case  in  the 
other.  It  is  not  merely  in  the  case  of  the  arteries  that  such  a  collateral 
circulation  can  be  developed,  for  the  same  thing  may  be  observed  in  the 
case  of  an  obstruction  of  one  of  the  great  veins.  In  one  case  studied  not 
long  ago  the  superior  vena  cava  had  been  completely  occluded,  and  the 
venous  circulation  from  the  head  took  place  through  the  enormously  dilated 
veins  of  the  abdomen*  (Fig.  8). 

In  certain  situations  the  tissues  are  entirely  dependent  upon  receiving 
their  supply  of  blood  from  a  single  artery.  In  these  cases  there  is  prac- 
tically no  chance  for  compensation  through  the  pouring-in  of  blood  from 
adjacent  arteries,  for  there  are  no  adequate  anastomoses,  and  such  arteries 
have  been  referred  to  by  Cohnheim  as  "end  arteries,"  and  such  a  circula- 
tion as  "terminal"  circulation.  The  propulsion  of  an  embolus  into  such  an 
artery  as  this  will  inevitably  cause  complete  anaemia  of  the  portion  of  tissue 
which  had  hitherto  been  supplied  by  that  artery  (Fig.  9). 

The  effect  of  the  diminution  of  the  supply  of  blood  to  any  part  by  way  of 
the  artery  thus  depends  upon  the  degree  to  which  the  function  of  that 
artery  can  be  replaced  by  the  formation  of  channels  connecting  its  region  of 
distribution  with  other  arterial  supplies.  The  time  which  is  occupied  in 
this  reestablishment  of  the  blood-stream  is  of  the  greatest  importance,  for 
if  the  obstruction  be  gradually  produced,  it  may  reach  a  very  advanced 
degree  without  there  having  appeared  at  any  time  an  insufficiency  in  the 
blood  supply  to  the  tissues;  whereas  if  the  cut-off  be  sudden,  the  tissue  is 
likely  to  suffer. 

Finally,  there  are  some  organs,  such  as  the  liver  and  lung,  which  enjoy  a 
double  circulation,  both  arterial  and  venous  blood  being  poured  into  the 
tissues  and  escaping  by  way  of  a  common  efferent  channel.  In  both  these 
instances  the  flood  of  venous  blood  is  far  more  profuse  than  the  small 
stream  of  arterial  blood,  and  doubtless  contributes  very  largely  to  the 
nutrition  of  the  tissues,  although  that  is  perhaps  the  main  function  of  the 
arterial  supply.  In  such  cases  the  life  of  the  tissue  is  somewhat  more  se- 
cure as  far  as  its  food  supply  is  concerned  than  in  the  case  of  those  organs 
which  are  supplied  solely  from  the  artery;  and,  indeed,  it  is  actually  found 
that  a  very  much  more  extensive  disturbance  is  necessary  to  produce  ana- 
tomical changes  in  these  organs  than  in  many  others. 

*  Osier:  Johns  Hopkins  Hospital  Bulletin,  July,  1903,  xiv,  172. 


Fig.  9. — Diagram  showing  circulation  after  plugging  of  arteries:  A,  Terminal  circula- 
tion; B,  circulation  with  rich  anastomoses;  C,  double  blood  supply,  as  in  the  liver;  D, 
circulation  of  the  stomach  with  abundant  large  anastomoses. 

26 


INFARCTION  27 

Quite  aside  from  the  patency  of  the  arteries  themselves  or  of  the  veins,  a 
condition  of  local  anaemia  which  is  very  effective  in  disturbing  the  nutri- 
tion of  the  tissues  can  be  brought  about  by  muscular  contraction  in  those 
tissues  which  are  largely  made  up  of  smooth  muscle.  Welch  and  Mall  have 
pointed  out  that  this  violent  spasmodic  contraction  of  the  intestinal  wall 
which  arises  from  a  sufficient  interference  with  the  entrance  of  the  blood, 
results  in  the  complete  exclusion  of  the  blood  from  that  part  of  the  in- 
testine, and  in  that  way  takes  a  great  part  in  the  final  destruction  of  the 
tissue.  It  is  really  this  which  renders  the  circulation  of  the  mesentery  and 
of  the  intestine,  which  is,  from  an  anatomical  point  of  view,  so  rich  in  anas- 
tomoses, comparable  to  a  terminal  circulation. 

INFARCTION 

The  effect  of  local  anaemia  upon  the  tissue  is  found  to  vary  with  the  degree 
of  deprivation  to  which  the  tissue  is  subjected  and  with  the  nature  of  the 
tissue  itself.  As  has  already  been  indicated,  the  more  complex  the  struc- 
ture of  the  cell,  and  the  more  highly  developed  its  specialization  of  func- 
tion, the  more  delicate  and  susceptible  to  injury  it  becomes.  This  is  well 
seen  in  the  case  of  the  nerve-cell,  whose  function  becomes  impossible  if  its 
nutritive  supply  is  withheld  even  for  a  few  moments,  and  is  irremediably 
destroyed  in  a  very  short  time. 

On  the  other  hand,  there  is  a  long  series  of  tissues  with  gradually  de- 
creasing susceptibility  until  we  reach  the  least  highly  organized  and  con- 
sequently the  most  resistant  among  the  connective-tissue  structures  which 
can  withstand  removal  from  any  connection  with  the  circulation  for  hours 
or  even  days,  and  still  resume  their  functions  as  soon  as  they  are  placed  in 
proper  surroundings  or  grow  again  when  transplanted  into  another  animal 
of  the  same  kind. 

The  injurious  effects  of  anaemia  become  more  severe  the  more  complete 
it  is  and  the  longer  it  lasts,  and  they  reach  their  climax  in  the  death  of  the 
tissues.     Slighter  grades  of  anaemia  may  become  evident  in  their  effect 
only  when  great  effort  is  demanded  of  the  organ  involved,  as,  for  example, ' 
in  the  intermittent  claudication  spoken  of  above. 

More  complete  anaemia,  whether  caused  by  the  inability  of  the  blood  to 
reach  the  tissues  or  to  give  place  to  new  blood,  commonly  causes  the  death 
of  the  affected  part,  and  this  is  the  all-important  feature  in  the  production 
of  the  so-called  infarction.  Other  changes  subsequent  to  this  may  alter 
very  strikingly  the  appearance  of  the  tissues,  but  they  are  of  secondary 
importance.  As  in  the  clotting  of  blood  and  the  formation  of  a  thrombus, 
the  death,  or  even  the  severe  injury,  of  the  cells  is  immediately  followed  by 
the  setting  free  of  some  sort  of  ferment  which  causes  the  coagulation  of 
the  blood,  and  the  intracellular  as  well  as  the  intercellular  fluids.  The 
nuclei  either  fade  or  break  up  into  small,  deeply  staining  fragments,  and  in 
every  other  respect  the  cells  lose  the  aspect  which  they  possessed  during 
life.  They  are  dead  cells  entangled  and  held  in  a  coagulum  which  in- 


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TEXT-BOOK   OF   PATHOLOGY 


volves  the  whole  area  of  tissue,  and  the  process  is  described  by  Weigert 
and  called  by  Cohnheim  "coagulative  necrosis." 

The  area  occupied  by  these  changes  is  that  to  which  the  blood  supply 
becomes  insufficient.  It  need  not  correspond  exactly,  therefore,  with  the 
distribution  of  the  plugged  artery,  because  there  is  almost  always  some 
compensation  from  the  branches  of  adjacent  arteries.  Its  form  is  generally 
stated  to  be  pyramidal,  but  is  not  really  so  in  most  cases,  although  it  may 
approach  that  traditional  form.  This  is  because  the  vessels  in  most  organs 
really  assume  a  rather  fan-shaped  arrangement,  as  is  almost  inevitable  in 
any  vessel  which  branches  out  regularly.  Still  in  some,  such  as  the  kidney, 
there  are  blood-vessels  which  spring  up  almost  at  right  angles  from  the 
main  trunk,  and  which  reach  through  the  organ,  so  that  we  may  readily 


Fig.  10. — Anaemic  infarction  of  kidney. 

find  an  infarct  of  a  more  or  less  cubical  form  in  its  cortex  (Fig.  10).  There 
is  nothing  typical  about  the  form  of  the  infarct  in  the  intestine  which  merely 
occupies  the  whole  wall  of  a  certain  length  of  the  intestine.  So,  too,  in  the 
heart,  the  area  of  infarction  is  irregular  in  form.  The  pyramidal  form  is 
most  nearly  approached  by  the  infarct  of  the  lung,  but  even  this  is  fre- 
quently quite  irregular  in  its  shape. 

In  all  instances  the  infarcted  area  seems  at  first  swollen  and  firm,  and 
projects  above  the  surrounding  surface  of  the  tissue.  This  is  true  even 
in  the  brain  in  the  beginning,  although  after  a  short  time  has  elapsed 
the  infarcts  of  the  brain  become  soft  and  are  commonly  spoken  of  as  areas 
of  softening.  Their  resemblance  to  other  infarcts  in  the  early  stages 
was  pointed  out  by  Marchand,  who  appreciated  the  fact  that  they  too 
at  the  beginning  present  the  appearance  of  a  firm  coagulum,  although 
later  the  liquefaction  of  the  myeline  substance  proves  more  than  sufficient 


INFARCTION  29 

to  overcome  the  firmness  contributed  by  the  fibrin  and  to  make  the  whole 
area  soft.  The  swelling  and  firmness  of  an  infarct  are  due  to  the  accumu- 
lation of  a  coagulum  produced  from  the  coagulable  fluids  which  diffuse 
into  the  dead  area  from  the  surrounding  tissue.  In  a  short  time  the  mass 
becomes  dense  and  hard  and  may  be  appreciated  immediately  by  the  finger 
passed  over  the  surface  of  the  organ.  There  is  no  other  disturbance  in  the 
architecture  of  the  tissue  at  this  stage,  and  the  outlines  of  the  cells  may  still 
be  seen  quite  clearly.  Even  the  outlines  of  the  nuclei  may  still  be  seen, 
and  as  for  the  supporting  structural  framework,  it  is  usually  quite  well 
preserved,  at  least  in  its  outlines;  but  the  whole  area  is  dead  and  reminds 
one,  on  viewing  it  through  the  microscope,  of  the  appearance  of  charcoal 
as  contrasted  with  that  of  living  wood,  or  of  the  streets  of  Pompeii  as  con- 
trasted with  those  of  a  modern  town. 

The  death  with  coagulation  of  the  tissues  converts  them  into  a  white  or 
yellowish  white,  perfectly  opaque,  dull-looking  mass  so  long  as  there  is  no 
infiltration  of  red  corpuscles.  We  must  recognize,  however,  two  kinds  of 
infarcts,  in  both  of  which  the  principles  just  described  affect  the  result  in 
an  identical  manner,  but  one  is  spoken  of  as  a  hcemorrhagic  infarct  because, 
on  account  of  the  laxity  of  the  tissue  and  the  richness  of  the  adjacent  capil- 
lary circulation,  red  corpuscles  ooze  into  the  dead  area.  The  other  kind, 
which  remains  pale  and  opaque,  is  commonly  spoken  of  as  an  ancemic  in- 
farct, although  it  is  plain  enough  that  anemia  is  the  cause  of  the  death  of  the 
tissue  in  both.  The  arrangement  of  the  circulation  and  the  density  of  the 
tissue  seem  to  be  the  deciding  factors  as  to  whether  an  infarct  shall  remain 
anaemic  looking  and  white,  or,  by  being  flooded  with  stagnating  red  cor- 
puscles, assume  a  deep  red  color.  So,  in  the  kidney,  we  practically  never 
observe  a  haemorrhagic  infarction,  whereas  in  the  lung  and  in  the  intestine 
the  reverse  is  the  case,  and  it  is  only  with  the  greatest  difficulty  that  we  can 
produce  experimentally  an  infarction  which  remains  anaemic  looking.  In 
other  organs,  such  as  the  heart,  the  spleen,  the  liver,  we  may  have  some- 
times anaemic,  sometimes  haemorrhagic,  types. 

Kidney. — In  the  kidney,  infarctions  are  likely  to  be  quite  small.  They 
seem  to  arise  as  the  result  of  the  entrance  of  the  embolus  into  one  of  the 
arcuate  arteries,  or  even  into  one  of  the  branches,  passing  thence  into  the 
cortex.  One  can  nearly  always  find  this  plug  on  careful  search  and  observe 
that  the  propagated  thrombus  extends  both  ways  from  it.  The  infarcts 
commonly  occupy  especially  the  cortex,  but  they  may  sometimes  extend 
down  into  the  pyramid  of  the  kidney.  One  occasionally  sees  a  ramifying, 
anastomosing  area  of  infarction  which  occupies  a  great  portion  of  the  kid- 
ney, and  such,  indeed,  was  the  result  in  a  peculiar  instance  observed  re- 
cently. In  this  case  a  stab  wound  had  passed  through  a  branch  of  the 
renal  artery  which  happened  to  begin  its  branching  outside  of  the  kid- 
ney, and  a  haemorrhage  occurred,  which  continued  slowly  for  two  or  three 
days,  being  restrained  apparently  in  part  by  the  surrounding  tissue.  At 
the  end  of  that  time  the  kidney  was  removed  at  operation,  together 


30 


TEXT-BOOK   OF   PATHOLOGY 


with  the  mass  of  blood  which  had  been  extravasated.  It  was  found  that 
there  was  an  extensive  infarction  occupying  a  portion  of  the  kidney 
which  should  have  been  supplied  by  the  injured  artery.  This  was  an 
instance  of  local  anaemia,  but  not  caused  by  the  presence  of  a  plug  in  the 
vessel. 

On  inspection  of  such  a  kidney  containing  infarcts  it  is  possible  to  deter- 
mine readily  enough  the  position  of  the  infarct  even  through  the  capsule, 


>••?  ?!,*-.  •     •••,"•' ">v.      •'./;•,••.•:•'-.••.•.•.• 

v",,:.l-V>i:;ii  V1  •wS*.:."  V    'V 


Fig.  11. — Margin  of  renal  infarction  showing  necrosis  of  tissue  with  zones  of  haemor- 
rhage and  leucocytic  invasion. 


for  the  opaque  yellow  color  shines  through,  but  this  opacity  does  not  quite 
reach  the  surface,  being  covered  by  a  layer  of  living  and  very  hypersemic 
kidney  tissue,  which  receives  its  blood  supply  from  the  capillaries  which 
extend  to  it  from  the  capsule.  On  incision  one  finds  the  infarct  sur- 
rounded by  at  least  two  distinct  zones,  which  differ  in  color  from  the  opaque 
yellowish-white  central  portion.  These  zones  are  first  a  translucent  gray 
line  of  varying  thickness,  and  then  an  irregular  band  of  deep  red  which 
borders  the  infarct  and  marks  it  out  from  the  surrounding  normal  tissue. 


INFARCTION  31 

the  gray  zone  is  found,  on  careful  examination,  to  be  produced  by  an 
accumulation  of  the  white  cells  of  the  blood  which  have  wandered  in  there 
and  have  become  more  or  less  broken  up.  The  zone  of  haemorrhage  is 
partly  within  the  necrotic  area  and  partly  in  the  living  area,  and  although 
it  may,  like  the  accumulation  of  leucocytes,  be  explained  in  part  as  due  to 
the  inflammatory  reaction  about  the  dead  tissue,  it  seems  probable  that 
the  anaemic  changes  in  the  endothelium  of  the  capillaries  play  a  part  too  in 
allowing  the  escape  of  red  cells  (Fig.  11). 

Spleen. — Almost  the  same  descriptions  might  be  applied  to  the  anaemic 
infarctions  in  the  spleen,  except  that  they  are  usually  much  larger  and 
more  irregular  in  form  (Fig.  12) .  They,  however,  differ  from  the  infarctions 
in  the  kidney  inasmuch  as  there  is  no  capsular  circulation,  which  is  neces- 
sary to  keep  alive  any  superficial  layer  of  the  spleen,  so  that  the  death  of 
the  tissue  extends  quite  out  to  the  peritoneal  surface.  There  the  dead 
tissue  exerts  the  same  influence  upon  the  peritoneal  fluid  as  it  does  upon 


Fig.  12. — Infarction  of  spleen. 

the  passing  lymph,  and  there  is  deposited  over  the  surface  of  an  infarct  in 
the  spleen  a  layer  of  fibrin  which  roughens  the  surface.  Sometimes  one 
can  make  the  diagnosis  of  the  existence  of  an  infarct  of  the  spleen  from 
pain  which  comes  from  the  rubbing  of  this  roughened  surface  against  that 
of  the  adjacent  peritoneum  when  a  deep  breath  is  taken. 

Heart. — Exactly  the  same  thing  is  true  of  infarcts  of  the  lung,  and  even 
those  of  the  heart  wall;  but  in  the  kidney  there  is  no  opportunity  for  such 
an  occurrence.  The  infarcts  of  the  heart  are  particularly  interesting  be- 
cause of  their  great  importance  with  regard  to  the  function  of  the  heart. 
The  coronary  arteries  present  some  anastomoses  one  with  the  other,  but, 
as  has  been  pointed  out  recently  by  Spalteholz,  these  are  insufficient  to 
supply  the  really  enormously  active  circulation  which  is  necessary  for  such 
an  organ  as  the  heart.  So,  therefore,  the  arteriosclerotic  narrowing  of  the 
coronaries  often  leaves  traces  of  malnutrition  of  the  tissues  when  even  there 
is  no  actual  infarct  formed;  but  when  to  this  there  is  added  a  thrombus 
formation,  or  when  a  vegetation  from  the  valve  sweeps  into  the  mouth  of 


32  TEXT-BOOK   OF   PATHOLOGY 

the  coronary  artery,  as  has  happened  so  frequently,  the  nutrition  of  the 
heart  muscle  is  intolerably  limited  and  the  muscle  dies.  In  one  such  in- 
stance recently  observed  there  had  been  an  aortic  endocarditis  with  vege- 
tations, and  a  plug,  like  a  cork,  still  projected  from  the  mouth  of  the  left 
coronary  artery.  The  whole  of  the  septum  between  the  ventricles,  to- 
gether with  the  anterior  portion  of  the  walls  of  the  right  and  left  ventricles, 
formed  a  necrotic  mass.  The  heart  had  become  abnormally  slowed  from 
involvement  of  the  auriculoventricular  bundle,  but  still  continued  to  beat 
until  a  sudden  effort  caused  the  rupture  of  the  wall  of  the  left  ventricle  with 
a  fatal  haemorrhage. 

Other  instances,  however,  have  not  so  immediately  led  to  death,  but 
rather  to  recovery,  with  replacement  of  the  dead  tissue  by  scar.  In  that 
case  a  patch  in  the  heart  wall  may  be  markedly  thinned  and  comes  to  be 
composed  of  a  fibrous  tissue  which  has  by  no  means  the  power  of  resistance 
or  the  strength  of  the  muscular  wall,  and  one  frequently  sees  such  an  area 
bulged  out  into  a  sac  which  in  time  may  rupture.  Such  an  event  is,  how- 
ever, by  no  means  always  the  outcome  of  an  infarction,  but  may  depend  on 
the  gradual  loss  of  the  muscle  substance  from  a  partial  anaemia. 

Liver. — In  the  liver  infarcts  are  very  rare  because  of  the  extremely 
abundant  blood  supply  from  two  sources.  It  is  stated  that  complete 
closure  of  the  main  trunk  of  the  hepatic  artery  will  produce  complete  ne- 
crosis of  the  liver,  whereas  closure  of  any  of  its  branches  has  no  special 
result.  Obstruction  to  the  main  portal  vein  is  said  to  diminish  the  produc- 
tion of  bile,  as  has  been  shown  recently  by  Voegtlin  and  Bernheim,  but  it 
does  not  interfere  with  the  nutrition  of  the  tissue.  This  is  especially  well 
seen  in  the  numerous  instances  in  which  experimentally  the  whole  of  the 
blood  of  the  portal  vein  has  been  diverted  into  the  inferior  vena  cava  by  the 
so-called  Eck's  fistula.  In  that  case  undoubtedly  the  whole  of  the  tissue 
of  the  liver  must  be  supplied  by  the  hepatic  artery,  but  the  animals  live, 
and  after  a  time  show  no  very  obvious  change  in  the  tissue  of  the  liver, 
although  it  is  stated  that  sometimes  the  liver  decreases  in  bulk.  Obstruc- 
tion of  the  whole  portal  vein  is  not  very  uncommon,  arising  from  the  throm- 
bosis of  the  branches  from  some  point  of  infection  or  injury  in  the  alimen- 
tary tract,  and  extending  into  the  main  trunk;  or  as  the  result  of  compres- 
sion from  without  by  gall-stones  or  tumor  masses  in  the  vicinity  or  in  con- 
nection with  cirrhosis  of  the  liver.  Closure  of  branches  of  the  portal  vein 
may  be  followed  by  the  formation  of  haemorrhagic  infarctions  when  there 
is  some  disturbance  or  enfeeblement  of  the  general  circulation,  so  that  the 
hepatic  artery  does  not  succeed  in  making  up  the  nutrition  which  is  lost 
by  the  shutting  off  of  the  portal. 

Lung. — In  the  lung  also  there  is  a  double  vascular  supply,  the  bronchial 
arteries  really  furnishing  nutriment  only  to  the  bronchi  and  the  immedi- 
ately adjacent  lung  tissue.  It  is,  therefore,  not  to  be  wondered  at  that  if 
we  tie  a  branch  of  the  pulmonary  artery  which  has  no  connections  with 
other  branches,  as,  for  example,  in  one  of  the  isolated  lobes  of  a  dog's 
lung,  all  the  tissue  dies  except  the  bronchial  walls.  The  pulmonary  ar- 


INFARCTION  33 

teries  anastomose  with  extraordinary  freedom  in  the  lung,  probably  largely 
by  means  of  the  extremely  wide  capillaries.  On  this  account  it  proves  to 
be  impossible  to  produce  an  infarction  in  the  lung  of  a  healthy  animal  by 
throwing  emboli  into  the  pulmonary  stream,  because  the  nutrition  of  the 
obstructed  area  is  immediately  assumed  by  adjacent  branches.  Virchow 
did  succeed  in  producing  such  infarctions,  and  this  was  the  basis  of  his 
great  work  on  embolism.  But  apparently  he  succeeded  because  the  em- 
boli which  he  used  carried  bacteria,  and  he  caused,  in  that  way,  a  far  more 
extensive  injury  to  the  lung  tissue  than  could  be  produced  by  sterile  plugs. 
It  is  only  when  there  is  some  other  circumstance  which  causes  a  general 
slowing  of  the  circulation  in  the  lungs,  a  high  pressure  in  the  pulmonary 
veins,  and  such  malnutrition  of  the  lung  tissue  as  leaves  it  susceptible  to 
injury,  that  a  plug  in  a  branch  of  the  pulmonary  artery  will  cause  the 
formation  of  an  infarct.  This  is  the  condition  which  we  find  in  the  so- 
called  chronic  passive  congestion  which  results  from  the  obstruction  of  the 


Fig.  13. — Haemorrhagic  infarction  in  lung,  the  seat  of  chronic  passive  congestion. 

mitral  valve  or  from  the  regurgitation  of  blood  through  the  mitral  valve 
backward  into  the  lung.  Other  causes  may,  of  course,  produce  the  dam- 
ming back  of  blood  into  the  lungs  and  slowing  of  their  circulation,  but'the 
changes  in  the  heart,  and  especially  those  which  we  have  just  mentioned, 
are  the  most  prominent.  Under  such  circumstances,  when  emboli  are  dis- 
lodged from  some  point  on  the  venous  side  of  the  circulation  and  thrown 
into  the  branches  of  the  pulmonary  artery,  there  arise  ha3morrhagic  in- 
farctions in  the  lungs  (Fig.  13) .  Sometimes  one  can  recognize  by  symptoms 
the  beginnings  of  such  infarcts  from  the  sudden  pain  and  the  spitting-up  of 
blood,  and  possibly  even  from  the  change  in  the  percussion-note,  which 
becomes  dull  over  the  region  of  the  infarct.  When  the  lung  is  inspected,  it 
is  found  possible  to  recognize  these  infarcts  at  once  because  they  are  solid, 
hard  masses,  often  present  in  numbers  and  extending  to  the  surface  of  the 
lung.  The  pleura  over  them  is  roughened  by  a  layer  of  fibrin  which  de- 
stroys its  gloss  and  causes  the  pain  of  which  we  have  spoken  by  scratching 
4 


34  TEXT-BOOK   OF   PATHOLOGY 

against  the  opposite  pleural  surface  in  respiratory  movement.  The  in- 
farcts  vary  greatly  in  size,  from  a  diameter  of  about  1  cm.  to  such  a  size 
as  to  occupy  almost  the  whole  of  the  lobe.  They  have  a  tendency  to  a 
somewhat  triangular  or  pyramidal  form,  but  their  margins  are  usually 
round,  and  they  bulge  out  on  the  surface  of  the  lung.  They  are  very  dark 
red, — almost  black  in  color, — and  on  cutting  through  them  this  is  found 
to  be  true  also  of  their  interior  portion.  They  are  dry  and  sometimes  of 
a  remarkable  hardness. 

It  is  nearly  always  quite  easy  to  see  the  embolus  which  has  caused  their 
formation  lying  in  the  pulmonary  artery  which  forms  the  apex  of  the 
triangle.  Usually  such  a  plug  is  prolonged  both  ways  by  the  clot  which  is 
formed  about  it,  but  sometimes  this  may  not  have  happened,  and  cases  are 
even  recorded  in  which  the  embolus  lay  at  a  point  somewhat  separated 
from  the  actual  region  of  infarction  by  an  empty  stretch  of  vessel.  This  is 
important  because  there  has  been  so  much  dispute  as  to  whether  these 
infarctions  were  really  caused  by  emboli  or  whether  the  clot  in  the  vessel 
was  the  result  of  the  infarction.  It  seems  perfectly  clear,  however,  that 
the  weight  of  evidence  is  entirely  in  favor  of  the  embolic  origin  of  the  in- 
farcts.  Von  Recklinghausen  lays  a  great  deal  of  stress  upon  the  formation 
of  hyaline  thrombi  in  the  smaller  branches  of  the  pulmonary  artery,  but 
these,  it  seems  to  me,  might  be  secondary.  There  is  often  a  question  as  to 
whether  we  are  dealing  with  a  real  infarction  or  with  a  mere  hemorrhage 
into  the  lung  substance.  Such  haemorrhages  occur  frequently  from  all 
kinds  of  causes,  but  they  are  never  really  comparable  in  appearance  to  in- 
farctions— first  of  all,  because  they  are  almost  never  hard  and  dry,  but 
rather  soft  and  loose,  and  usually  very  irregular  in  outline,  occupying 
any  part  of  the  lung  without  regard  to  any  special  arrangement  and  with- 
out necessarily  approaching  the  surface  of  ,the  lung.  From  such  haemor- 
rhages absorption  of  the  blood  takes  place  with  extreme  rapidity,  and  this 
may  possibly  account  for  their  remaining  so  soft.  On  the  other  hand,  it  is 
quite  difficult  to  understand  why  the  haemorrhagic  infarction  should  be  so 
extremely  hard  unless  it  be  that  the  coagulation  of  the  red  corpuscles  is  also 
brought  about  in  the  general  coagulation  of  the  necrotic  lung  tissue. 
Close  examination  of  the  area  involved  in  the  infarction  shows  that  it  is 
overfilled  in  every  part  with  blood.  Not  only  are  the  alveoli  themselves 
full  of  red  corpuscles  in  even  greater  concentration  than  in  the  circulating 
blood,  but  these  corpuscles  are  found  also  in  the  substance  of  the  tissue. 

The  epithelial  cells  which  line  the  alveoli  disappear  rather  rapidly,  but 
the  framework  of  the  lung  is  very  resistant,  and  it  may  not  appear  to  have 
been  injured  very  markedly  by  the  local  anaemia.  There  are  those  who 
speak  of  resolution  of  infarctions  of  the  lung,  stating  that  there  is  no  real 
necrosis,  but  that  later  the  contents  of  the  alveoli  may  be  absorbed  as  in 
a  simple  haemorrhage,  and  the  lung  resume  its  function.  This,  however, 
seems  very  doubtful,  and  one  may  feel  sure  that  when  the  effect  of  the 
anaemia  is  such  as  has  been  described,  much  more  complicated  changes 


INFARCTION 


than  a  mere  resolution  or  restoration  to  normal  will  take  place.  The  dif- 
ficulty in  deciding  this  consists  chiefly  in  the  fact  that  when  haemorrhagic 
infarctions  are  formed  in  the  lungs  the  person  is  so  ill  as  to  die  before  any 
great  length  of  time  has  been  allowed  for  alterations  to  take  place  in  the 


Fig.  14. — Extensive  old  infarction  of  brain. 

infarctions,  and  so  it  is  that  we  commonly  see  at  autopsy  fresh  hsemorrhagic 
infarctions  and  only  rarely  find  areas  of  infarction  which  have  lasted  for  a 
long  time.  When  we  do  there  is  no  evidence  of  resolution,  but  rather  of  a 
great  shrinkage  of  the  tissue,  a  loss  of  the  red  color,  a  deep  yellow  pigmen- 
tation from  the  debris  of  the  red  corpuscle,  and  the  formation  of  dense, 


36  TEXT-BOOK   OF   PATHOLOGY 

hard  scar  tissue  in  the  place  once  occupied  by  the  infarct.  In  this  respect 
the  haemorrhagic  infarctions  of  the  lung  are  quite  similar  to  the  anaemic 
and  other  infarctions  in  the  spleen  and  in  the  kidney.  Even  in  the  fresh 
infarctions  of  the  lung  one  finds  always  a  good  deal  of  the  yellow  pigment 
which  comes  from  the  disintegration  of  red  corpuscles.  This  is  not  a  part 
of  the  fresh  process,  but  rather  a  result  of  the  long-continued  stagnation  of 
blood  in  the  capillaries  of  the  lung,  which  is  the  essential  feature  of  a  chronic 
passive  congestion,  and  which,  as  we  have  said,  constitutes  the  requisite 
basis  for  the  formation  of  an  infarct  there. 

Brain. — The  formation  of  infarctions  in  the  brain  is  an  extremely  com- 
mon occurrence,  and  leads  to  more  or  less  serious  results.  It  is  naturally 
most  likely  to  occur  when  thrombi  are  formed  in  the  left  side  of  the  heart 
in  such  a  way  as  to  be  dislodged  and  thrown  into  the  cerebral  circulation. 
The  mechanical  results  of  such  embolism  will  again  depend  upon  the  posi- 
tion reached  by  the  embolus,  and  if  the  obstruction  produced  is  in  the 
meninges,  it  may  happen  that  no  obvious  result  will  follow.  If,  however, 
the  plug  enters  one  of  the  arteries  actually  on  its  way  to  supply  the 
brain,  there  is  inevitably  an  infarct  formed  because  they  are  terminal 
arteries. 

The  symptoms  will  depend  upon  the  particular  tissue  thus  destroyed, 
but  if  a  large  branch  is  occluded,  there  may  be  general  symptoms  in  many 
respects  like  those  of  apoplexy;  that  is,  the  patient  becomes  unconscious. 
There  may  be  a  flaccid  paralysis  from  which,  however,  he  recovers  later 
with  the  exception  of  some  limited  paralysis,  which  corresponds  with  the 
portion  of  the  brain  destroyed. 

The  writer  has  recently  seen  an  instance  in  which  practically  a  whole 
cerebral  hemisphere  was  thus  converted  into  a  necrotic  mass  through 
rather  extensive  embolism  of  the  arteries  at  the  base  of  the  brain.  In 
other  instances  where  smaller  plugs  reached  this  circulation  there  may  be 
only  temporary  lapses  from  consciousness,  or  not  even  that.  There  may 
or  may  not  be  narrowly  localized  paralysis.  Indeed,  it  is  not  infrequent  to 
discover  at  the  autopsy,  in  a  person  who  has  long  suffered  from  a  cardiac 
affection,  very  numerous  yellowish  patches  scattered  all  over  the  surface 
of  the  brain  and  sunken  below  its  surface.  These  are  merely  the  pigmented 
scars  which  have  resulted  from  the  formation  of  the  infarcts  time  after 
time  without  any  history  of  symptoms  (Fig.  14).  When  the  infarcts  are 
perfectly  fresh  they  are,  as  stated  above,  swollen,  project  above  the  surface, 
and  are  somewhat  firm,  but  they  very  quickly  soften  into  a  semifluid  mass 
because  the  greater  portion  of  the  brain  is  composed  of  lipoid  substances 
(myelines)  which  become  converted  into  a  more  fluid  form  in  the  process 
leading  to  necrosis  of  the  tissue.  At  this  stage  of  softening  phagocytic 
cells  wander  in  to  such  an  area  and  load  themselves  with  fat-globules, 
which  they  carry  away  (Fig.  15). 

Intestine. — The  infarctions  of  the  intestine  are  usually  haemorrhagic. 
They  are  perhaps  most  commonly  produced,  as  in  strangulated  hernias, 


INFARCTION 


37 


where  the  blood  supply  is  impeded  by  the  crowding  into  the  aperture,  of 
the  mesentery  as  well  as  the  intestine  itself.  Other  instances  are  seen  in 
the  so-called  volvulus,  in  which  a  lobe  of  intestine  with  long  loose  mesen- 
tery becomes  twisted  completely  round  on  itself  so  that  the  blood-vessels 
in  the  mesentery  are  closed.  Almost  the  same  effect  can  be  produced  by 
bands  of  fibrous  tissue  such  as  arise  in  the  form  of  adhesions  between 
various  abdominal  organs  and  can  be  pulled  tight  over  the  vessels  running 
to  some  portion  of  the  intestine.  The  other  type  of  artificial  obstruction 


•*si 


'  v^;>  v :  v !:  X  :;Vi:-::>  ivVv  .-:v'.'.--p  '^:7 
%;-^vV'.:(:;/^',;W.} 

S3.:;v:  .--r^.H^-x 


•••'•:  .%'.:-.:;-/-.o>> 


Fig.  15. — Margin  of  fresher  infarct  of  brain  showing  fat-laden  phagocytes.     Several 
of  these  are  shown  enlarged  below. 

is,  as  in  the  infarction  just  described,  produced  by  an  embolus  or  thrombus. 
As  has  been  pointed  out,  the  intestines  are  peculiarly  susceptible  to  with- 
drawal of  their  blood  supply  because  they  add  to  the  anaemia  by  their  vio- 
lent contractions.  The  intestinal  wall  at  first  becomes  absolutely  pale 
with  this  contraction,  but  later  on,  with  the  death  and  relaxation  of  the 
tissue,  it  swells  enormously  and  is  infiltrated  with  blood.  The  swelling  is 
particularly  intense  in  the  submucosa,  which  may  attain  the  thickness  of 
a  centimetre,  and  the  blood  oozes  through  the  mucosa  into  the  lumen  of  the 


38  TEXT-BOOK   OF    PATHOLOGY 

intestine  and  is  passed  in  great  quantities,  giving  the  diagnostic  sign  of 
intestinal  infarction. 

The  surgeon  sometimes  meets  with  this  condition  of  swelling  and  haem- 
orrhage before  the  complete  death  of  the  cells  has  occurred,  and  occasion- 
ally he  may  replace  the  enlarged  loop  from  the  hernial  sac  or  liberate  it 
from  its  constriction  and  see  restoration  to  normal  condition  follow  his 
operation.  It  is  a  matter  for  his  judgment,  however,  to  determine  whether 
the  injury  has  passed  the  point  at  which  this  is  still  possible.  Welch  and 
Mall,  in  their  experiments,  have  found  that  there  is  relatively  little  com- 
pensation for  the  cutting-off  of  the  arterial  supply  through  the  mesenteric 


Fig.  16. — Intussusception  in  a  child's  intestine  showing    infarction    of   the  inclosed 
portion.     The  mesentery  is  seen  constricted  in  the  neck  of  the  receiving  portion. 

arteries,  so  that  if  even  such  a  short  length  of  intestine  as  5  cm.  be  sepa- 
rated from  its  blood-vessels,  it  will  undergo  necrosis  because  the  supply 
from  the  adjacent  portion  is  insufficient. 

One  of  the  commonest  causes  of  infarctions  is  the  so-called  intussusception, 
which  occurs  most  commonly  in  children  (Fig.  16).  It  may  apparently  be 
spontaneous,  and,  indeed,  it  seems  to  be  produced  by  irregular  peristalsis 
in  the  intestine,  so  that  one  portion  not  answering  to  the  peristaltic  wave  is 
dragged  by  it  into  the  next  portion,  to  which  the  wave  has  actually  leaped. 
At  any,  rate  such  intussusceptions  are  found  very  commonly  in  the  in- 
testine of  infants,  where  they  have  been  produced  postmortem,  by  the 
peristaltic  action  of  the  partially  quiescent  intestine.  The  portion  which 
is  telescoped  into  a  receiving  part  below  draws  with  it,  of  course,  its  mesen- 
teric blood  supply.  If  the  intestine  be  pulled  out  again  at  this  moment, 
no  harm  is  done;  but  if  it  remain  thus  imprisoned  for  any  considerable 
time,  there  arises  a  moderate  interference  with  the  outflow  of  the  venous 
blood  from  the  enfolded  part,  which  soon  makes  it  swell  to  such  an  extent  as 
to  cause  a  very  much  more  intense  interference  with  the  blood  supply.  This 
circle  of  events  continues  to  intensify  itself,  so  that  very  soon  the  intestine 


INFARCTION  39 

acts  as  a  constricting  band  to  prevent  the  inflow  or  outflow  of  blood,  and 
brings  about  the  hsemorrhagic  infarction  of  the  interior  portion. 

The  question  as  to  whether  an  infarct  shall  become  hsemorrhagic  or  not 
seems  to  depend  upon  a  variety  of  things.  Experimental  studies  have 
been  made  with  regard  to  the  infarction  in  the  intestine,  particularly  by 
Welch  and  Mall,  by  Niederstein  and  Marek.  The  results  of  these  experi- 
ments may  be  summed  up  in  the  following  conclusions : 

If  a  branch  of  the  mesenteric  artery  or  the  mesenteric  vein  alone  be  ob- 
structed, a  hsemorrhagic  infarction  results.  If,  however,  the  arterial  chan- 
nels leading  to  any  portion  of  the  intestine  be  absolutely  blocked  by  plug- 
ging or  tying  every  possible  anastomosis,  an  anaemic  infarction  appears, 
even  though  the  veins  be  left  widely  open.  It  is  evident,  therefore,  that 
the  hsemorrhagic  infiltration  of  the  tissue  which  forms  the  peculiar  feature 
of  hsemorrhagic  infarction  does  not  come,  as  Cohnheim  thought,  from  re- 
gurgitation  of  the  blood  from  the  veins,  but  is  the  result  of  the  oozing  of 
blood  through  the  walls  of  the  enlarged  capillaries  and  from  the  adjacent 
arterioles. 

The  laxity  of  the  tissue  which  is  found  in  the  lungs  and  in  the  intestines 
aids  in  this,  whereas  the  sudden  complete  consolidation  of  the  infarcted 
areas  of  the  kidney  and  spleen  makes  it  almost  impossible.  It  is  for  this 
reason  that  the  infarcts  in  the  last-named  places  are  commonly  pale. 
This  is  true  in  the  case  of  the  spleen,  particularly  when  the  intervascular 
and  vascular  spaces  are  densely  filled  with  foreign  cells,  as  in  the  case  of 
acute  splenic  tumor  and  leucsemic  changes  in  the  spleen. 

Infected  Emboli. — Secondary  changes  are  produced  in  infarctions  by 
the  invasion  of  bacteria.  Thus  an  embolus  may  carry  with  it  a  quan- 
tity of  bacteria  when  it  originates  from  an  already  infected  source,  and  is 
spoken  of  then  as  a  septic  embolus.  It  gives  rise  at  first  to  the  ordinary 
mechanical  effects  of  plugging  the  blood-stream,  but  later  there  become 
evident  the  effects  of  the  poisons  produced  by  the  bacteria,  and  the  infarcted 
area  becomes  the  seat  of  an  intense  acute  inflammatory  process,  with  all 
the  softening  and  disintegration  which  follow  upon  the  development  of 
liquefying  ferments  both  from  the  bacteria  and  from  the  leucocytes,  which 
hurry  to  the  spot  as  a  part  of  the  inflammatory  reaction.  The  infarct 
may  actually  assume  the  appearance  of  an  abscess,  and  it  is  sometimes 
difficult  to  say  whether  it  started  as  an  infarct  or  not.  In  most  cases, 
though  one  sees  distinctly  the  form  and  general  character  of  the  infarct, 
he  finds  that  its  central  part  is  softened  down  into  a  grayish  pulp  while  the 
periphery  still  retains  something  of  its  firmness.  This  softening  is  quite 
different  from  that  which  we  have  mentioned  in  the  case  of  the  infarcts  of 
the  brain,  and  probably  seldom  ends  in  healing  and  scar  formation. 

Healing. — Healing  of  the  uninfected  infarcts  is  by  no  means  uncommon 
in  such  organs  as  the  spleen  and  kidney,  and  it  has  been  described  already 
in  the  heart  and  brain.  It  consists  in  the  replacement  of  the  dead  tissue  by 
a  scar  tissue  which  constantly  tends  to  contract,  so  that  finally,  in  either 


40  TEXT-BOOK   OF   PATHOLOGY 

the  spleen  or  in  the  kidney,  one  finds,  as  a  sign  of  where  the  infarct  was,  a 
sunken,  hard,  scar-like  area,  usually  rather  opaque  and  colored  yellow  here 
and  there  from  the  remains  of  pigment  derived  from  the  dead  cells.  In 
such  a  scar  there  may  remain  some  traces  of  the  most  resistant  of  the 
structures  previously  occupying  that  place,  such  as  obliterated  glomeruli 
in  the  kidney;  but  usually  these  are  scarcely  recognizable,  although,  on 
account  of  the  contraction  of  the  scar,  they  may  be  concentrated  together 
in  considerable  numbers. 

GANGRENE 

All  of  these  instances  of  anaemic  necrosis  which  we  have  described  under 
the  name  of  infarcts  have  been  in  tissues  somewhere  in  the  interior  of 
the  body,  completely  surrounded  by  other  tissues  from  which  there  could 
be  derived  by  infiltration  the  ever-increasing  supply  of  fluid  which  might 
undergo  coagulation.  This  it  was  which  formed  the  basis  of  the  so-called 
coagulative  necrosis.  If,  however,  the  anaemia  affects  an  extremity  or  any 
such  tissue  as  is  not  thus  accessible  to  the  adjacent  coagulable  fluids,  a  dif- 
ferent appearance  results.  The  necrosis  of  the  tissue  is  effected  in  just  the 
same  way,  but  there  is  no  opportunity  for  it  to  assume  the  character  of  a 
coagulative  necrosis.  At  least  the  amount  of  fluid  which  undergoes  coagu- 
lation is  relatively  small,  and  the  extremity  does  not  become  rigid  and  hard 
as  the  result  of  this  process.  Such  death  of  an  extremity  is  called  gangrene, 
and  it  is  commonly  brought  about  in  the  same  way  as  is  the  death  of  the 
tissue  in  infarctions,  that  is,  by  any  one  of  the  various  processes  which  lead 
to  diminution  in  the  blood  supply  of  the  part,  often  aided  by  more  general 
disturbances  of  circulation  or  by  decreased  vitality  of  the  tissues  from  other 
causes,  as,  for  example,  in  the  case  of  diabetes,  where  gangrene  of  the  feet  is 
so  common.  It  may  assume  one  of  two  forms — the  so-called  "  moist "  gan- 
grene or  "  dry  "  gangrene.  In  the  former  case  the  tissues  remain  moist,  infil- 
trated with  blood.  They  become  opaque,  dull  looking,  and  livid  in  color. 
But  the  color  does  not  remain  as  it  is  in  the  beginning,  but  rapidly  changes 
through  a  series  of  shades  to  deep  purple  or  greenish  black  (Fig.  17).  The 
epidermis  becomes  loosened  when  rubbed,  often  leaving  a  raw,  damp  sur- 
face, which  may  readily  become  infected  and  undergo  putrefaction.  Such 
death  of  the  tissues  usually  occupies  a  portion  of  the  extremity  which  is 
sharply  demarcated  from  the  remainder  by  a  line  which  separates  the  dead 
from  the  living  tissue;  but  commonly  this  line  moves  upward  with  the 
advance  of  the  necrosis  until  it  reaches  the  point  at  which  the  blood-supply 
becomes  sufficient  to  maintain  constantly  the  life  of  the  part  above.  Unless 
the  leg  be  amputated  at  some  point  conveniently  above  this  line,  there 
may  be  a  good  deal  of  absorption  of  the  poisonous  products  of  putrefaction, 
and  the  tissue  itself  may  fall  away  so  as  to  expose  the  bone. 

The  other  kind,  the  dry  gangrene,  occurs  when  all  possible  advent  of  fluid  is 
shut  off  from  the  living  tissue  and  mummification  or  gradual  drying  up  of 
the  extremity  takes  place.  The  writer  studied  one  instance  in  an  old  man 


GANGRENE 


41 


in  whom  some  infection  of  the  axillary  glands  had  led  to  their  scarring  and 
calcification  in  such  a  way  as  to  constrict  the  axillary  artery  and  adjacent 
nerves.  The  pain  from  this  constriction  was  such  that  an  operation  was 
performed  in  which  the  artery  was  ligated  and  removed  with  the  constrict- 
ing mass.  Almost  immediately  there  began  the  evidence  of  death  of  the 


Fig.  17. — Gangrene  of  foot.     Case  of  diabetes  with  arteriosclerosis. 

fingers  and  of  the  hand  and  wrist,  which  assumed  the  dry  form,  and  resulted 
in  a  few  days  in  almost  complete  desiccation,  so  that  his  hand  came  to  look 
like  horn  or  some  such  transparent  material,  plastered  over  the  bones. 

Gangrene  of  the  extremities  occurs  in  connection  with  diabetes,  as  has 
been  mentioned,  and  also  with  certain  infectious  and  toxic  processes. 
Perhaps  the  most  striking  is  that  which  has  been  observed  in  epidemic 


42  TEXT-BOOK   OF   PATHOLOGY 

form  as  a  result  of  ergot  poisoning.  It  was  known  in  the  middle  ages  as 
St.  Anthony's  fire,  and  relief  was  sought  for  it  in  a  pilgrimage  to  Paris, 
which  at  least  acted  as  a  preventive.  The  truth  of  the  matter  was,  al- 
though it  was  by  no  means  recognized,  that  the  peasants  of  France  ate 
bread  which  was  contaminated  with  the  ergot  smut,  and  consequently 
suffered  from  that  peculiar  poisoning  which  brings  about  an  intense  con- 
striction of  the  arterioles.  Death  of  the  extremities  was  not  infrequent, 
and  in  those  pre-surgical  days,  from  the  ninth  to  the  fourteenth  century, 
it  was  no  uncommon  thing  to  have  part  of  a  hand  or  a  foot  torn  off,  after 
such  necrosis,  with  a  glove  or  boot.  At  the  church  in  Paris  the  pilgrims 
were  fed  with  bread  from  the  monks'  kitchen  and  most  of  them  recovered. 
There  is  one  other  important  instance  of  the  production  of  gangrene 
through  anemia,  which  is  extremely  common  and  which  occurs  in  those 
persons  whose  general  powers  of  resistance  have  been  lowered  and  who  have 
been  constrained  to  lie  in  one  position  in  bed  for  a  long  time.  This  is  the 
so-called  bed-sore  or  decubitus  ulcer,  to  which  we  have  referred  before. 
The  term  gangrene  is  used  most  loosely  in  referring  to  the  death  of  tissues 
produced  by  bacteria  or  by  other  means  when  associated  with  putrefaction. 
Thus  we  shall  meet  with  gangrene  of  the  lungs,  which  is  by  no  means  neces- 
sarily caused  by  mechanically  produced  anaemia,  but  is  dependent  upon  the 
destruction  of  the  pulmonary  tissue  by  various  forms  of  bacteria  associated 
later  with  the  ordinary  bacteria  of  putrefaction.  Another  instance  is  seen 
in  the  so-called  noma,  or  cancrum  oris,  and  in  the  hospital  gangrene,  which 
used  to  cause  such  mortality  in  the  wards  of  the  larger  hospitals.  In  all 
these  cases  it  appears,  from  recent  studies,  that  a  combination  of  fusiform 
bacilli  and  spirilla  plays  an  important  part. 

LITERATURE. 

Karsner:   Jour.  Med.  Research,  1912,  xxvii,  205.     (Literature.)     Jour.  Amer.  Med. 

Assoc.,  1911,  Ivii,  951.     (Infarctions.) 
Welch:  Allbutt's  System  of   Medicine,  1899,  vi,  228.      (Literature.)     Trans.  Assoc. 

Amer.  Phys.,  1887,  ii,  211. 

Winternitz:  Johns  Hopkins  Hospital  Bulletin,  1911,  xxii,  396. 
Voegtlin  and  Bernheim:  Jour.  Pharm.  and  Exp.  Therap.,  1910,  ii,  455. 
Whipple  and  Hooper:  Jour.  Exp.  Med.,  1913,  xvii,  593. 
Niederstein:  Deutsch.  Zeitschr.  f.  Chir.,  1909,  xcviii,  188. 
J.  Marek:  Arch.  f.  wiss.  u.  prakt.  Tierheilk.,  1907,  xxxiii,  225. 


CHAPTER  III 
DISTURBANCES  OF  INTERCELLULAR  FLUIDS  AND  LYMPH 

Their  movement,  character,  and  excessive  accumulation.     (Edema,  ascites,  etc. 

(EDEMA,  ASCITES,  ETC. 

IT  is  apparent  from  what  has  been  said  that  the  well-being  of  the  tissues 
is  dependent  upon  the  continuous  and  unobstructed  circulation  of  the 
blood  through  them  from  the  arteries  and  the  veins;  but  the  conditions 
are  even  more  complicated,  for  there  is  a  constant  circulation  of  fluids  with 
dissolved  materials  from  the  blood,  from  the  arterioles  and  capillaries,  out 
into  the  crevices  of  the  tissue  and  into  a  position  where  they  can  come  into 
immediate  contact  with  the  cells.  In  this  process  almost  all  the  cells  are 
left  behind,  but  a  certain  number  of  them  undoubtedly  take  part  in  this 
wandering-out  from  the  blood-vessels.  This  type  of  circulation  is  com- 
pleted by  the  reentrance  of  the  transuded  fluid  into  the  veins  or  into  the 
lymphatic  channels,  and  in  every  case  the  fluid  must  pass  again  a  complete, 
continuous,  and  semipermeable  membrane  composed  of  endothelial  cells. 

The  idea  formerly  held  that  these  tissue  spaces  are  in  open  communica- 
tion with  the  lumen  of  the  lymphatics  must  be  abandoned  in  the  light  of 
recent  anatomical  work  (MacCallum,  Sabin),  and  it  becomes  necessary 
to  regard  the  tissue  fluid  as  having  its  own  peculiar  characteristics.  It  is 
with  the  tissue  fluid  that  the  cells  have  immediate  relations,  and  this  cir- 
culation must  be  quite  active.  Up  to  the  present  no  method  has  been  found 
by  which  this  particular  fluid  can  be  drained  away  and  studied,  so  that  the 
statements  are,  to  a  certain  extent,  based  on  hypothesis. 

The  distribution  of  the  fluids  of  the  blood  into  the  tissues,  and  the  drain- 
age of  these  tissues,  proceed  in  such  a  way  that  no  matter  how  rapid  the 
circulation  may  be,  there  is  at  no  time  an  excessive  quantity  of  fluid  among 
the  cells.  There  are  conditions,  though,  in  which  a  disproportion  in  the 
rate  of  inflow  and  outflow  occurs,  and  there  arises  an  accumulation  in  the 
crevices  of  the  tissue  (oedema)  or  in  the  body  cavities  which  are  in  a  sense 
analogous  to  the  tissue  spaces.  When  this  concerns  the  peritoneal  cavity, 
we  speak  of  it  as  ascites;  collections  of  fluid  in  the  pleural  cavity  constitute 
hydrothorax;  in  the  pericardial  cavity,  hydropericardium. 

(Edematous  tissues  are  swollen,  ooze  fluid  on  incision,  and  are  inelastic 
on  account  of  the  spreading  apart  of  the  cells  so  that  they  retain  the  im- 
press of  one's  fingers  on  pressure.  Any  organ  may  become  so,  but  the  most 
striking  examples  are  seen  in  the  subcutaneous  tissues,  especially  in  the 
extremities,  and  in  such  places  as  the  external  genitalia  or  in  the  soft  parts 
below  the  eyes,  where  the  tissues  are  loose.  When  the  water-logged 

43 


44  TEXT-BOOK   OF   PATHOLOGY 

condition  of  the  subcutaneous  tissue  is  very  general,  it  is  spoken  of  as 
anasarca. 

In  those  cases  which  generally  result  from  diseases  of  the  heart  or  kid- 
neys the  accumulation  of  fluid  is  often  such  that  the  skin  becomes  tense 
and  shiny,  and  may  even  crack  and  allow  the  escape  of  some  of  the  fluid. 
The  tissues  lose  much  of  their  opacity,  and  become  almost  agate-like  in  ap- 
pearance, because  the  opaque  cells  are  widely  separated  by  the  clear  yel- 
lowish fluid.  This  is  especially  true  of  the  lungs,  and  of  such  fibrous  and 
muscular  tissues  as  make  up  the  wall  of  the  intestine  and  gall-bladder. 

Causes. — There  are  many  things  which  seem  capable  of  causing  such 
damming-up  in  tissues,  and,  indeed,  in  spite  of  long  study  and  experi- 
mentation we  are  not  yet  precisely  informed  as  to  the  part  played  by  each. 
Pathologists  have  proposed  a  great  many  widely  different  theories  to  ex- 
plain this  occurrence,  and  probably  all  of  them  contain  some  part  of  the 
truth.  Ludwig's  school  contented  itself  chiefly  with  the  mechanical  in- 
crease in  infiltrative  pressure  which  seemed  to  them  sufficient  explanation, 
although  it  is  obvious  that  there  are  many  instances  of  oedema  which  can 
by  no  means  be  explained  in  this  way.  For  that  reason  Heidenhain,  Ham- 
burger, and  others  introduced  the  conception  of  the  vital  secretory  activi- 
ties of  the  endothelial  cells  which  were  thought  to  pour  the  fluid  from  the 
vessels  into  the  tissues.  This  idea  involves  a  mystery  which  may,  of  course, 
be  unavoidable,  but  which  does  not  seem  to  help  us  further  toward  a 
satisfactory  understanding  of  the  condition.  This  is  true,  in  fact,  of  all 
the  theories  which  attempt  to  bridge  over  the  difficult  places  by  resorting 
to  such  vague  terms  as  "vital  activity,"  which,  while  they  may  express  a 
present  conception  of  the  process,  shed  no  new  light  upon  it.  In  general, 
stress  is  laid  upon  the  mechanical  obstruction  to  the  outflow  of  fluids, 
malnutrition,  and  poisoning  of  the  tissues  and  endothelial  cells  which  in- 
crease their  permeability,  disturbances  of  trophic,  vasomotor,  and  motor 
nerves,  and,  more  recently,  alterations  in  the  metabolism  and  in  the  state 
of  nutrition  of  the  tissues  themselves,  which  may  change  their  power  of 
actively  attracting  and  retaining  water  within  themselves. 

The  first  of  these  four  general  factors,  the  obstruction  to  the  outflow  of 
fluids,  concerns  both  lymphatic  and  venous  outflow,  which  are  apparently 
in  a  sense  compensatory  to  each  other,  for  it  has  been  observed  that  if  the 
veins  of  an  extremity  are  tied,  the  flow  of  lymph  from  the  lymphatic  trunk 
becomes  greatly  increased.  No  such  observations  appear  to  have  been 
made  upon  the  venous  outflow  when  the  lymphatics  are  obstructed. 
Mechanical  obstruction  of  the  flow  in  both  veins  and  lymphatics  arises  when 
the  heart  fails  in  its  duty  of  propelling  the  blood,  and  it  becomes  difficult 
for  more  blood  to  enter  it.  But  such  venous  stagnation  is  felt  by  all  the 
tissues,  not  only  through  the  obstruction  to  the  escape  of  fluids,  but  through 
the  consequent  obstruction  to  the  entrance  of  new  nutritive  arterial  blood. 
Consequently  there  arise  at  once  several  factors  which  might  favor  cedema. 
Filtration  pressure,  increased  permeability  of  the  endothelium  from  mal- 


(EDEMA,    ASCITES,    ETC.  45 

nutrition,  and,  for  the  same  reason,  heightened  osmotic  pressure  on  the 
part  of  the  tissues  occur,  and  it  is  difficult  to  determine  which  of  these  is 
the  most  important.  All  are  removed  if  the  heart  is  supported  to  increased 
activity,  when,  with  the  improved  circulation,  the  oedema  disappears. 

Local  venous  obstruction  may  bring  about  the  same  chain  of  events  as 
in  the  so-called  milk-leg,  which  is  an  oedema  produced  by  the  obstruction 
of  the  femoral  vein  by  a  clot.  This  kind  of  local  oedema  seems-  to  be  based 
on  precisely  the  same  principles  as  exist  in  the  case  of  the  general  disable- 
ment of  the  circulation.  It  depends,  to  a  certain  extent,  upon  the  sudden- 
ness with  which  the  obstruction  has  been  produced,  and  in  any  case  dis- 
appears later  if  there  be  established  a  collateral  circulation  which  allows 
the  proper  drainage. 

Those  types  of  oedema  which  are  ascribed  to  alterations  in  nervous  activity 
rest  on  a  very  vague  and  indefinite  foundation,  and  even  such  so-called 
angioneurotic  cedemas  as  have  been  long  known  and  quite  helplessly  as- 
cribed to  nervous  interferences  are  gradually  revealing  themselves  as  effects 
of  chemical  disturbances  of  a  complicated  character.  Naturally,  those 
diseases  of  the  nervous  system  which  are  followed  by  prolonged  inactivity 
of  the  limbs  result  in  cedema  of  these  immovable  extremities  in  just  the 
same  way  as  ankylosis  of  the  joint  or  contractures  of  the  tendons  might 
produce  it.  In  all  such  cases  the  circulation  is  impaired,  the  kneading 
action  of  the  muscles  which  ordinarily  propels  the  fluids  in  the  limb  is 
lost,  and  the  tissues  are  badly  nourished.  Almost  exactly  the  same  factors 
exist  in  the  various  forms  of  anaemia  and  cachexia  with  cedema. 

The  deterioration  in  the  nutritive  qualities  of  the  blood  in  general 
anaemias,  and  the  absorption  of  some  indefinite  poisonous  material  in  the 
so-called  cachexias,  bring  about  the  important  factor  of  tissue  malnutri- 
tion regardless  of  pressure  relations.  Poisonous  substances,  indeed,  are 
very  commonly  responsible  for  the  appearance  of  oedema,  and  certain  things 
seem  especially  capable  of  producing  it.  Such  substances  as  morphine, 
the  juice  of  grapes  and  of  various  fruits,  etc.,  are  always  spoken  of  in  the 
text-books  as  capable  of  producing  such  cedema,  possibly  by  injuring  the 
endothelial  wall  of  the  vessel,  and  the  same  explanation  is  offered  for  the 
cedema  which  arises  as  a  response  to  all  the  manifold  effects  of  injury  which 
give  rise  to  the  complex  inflammation.  In  every  case  we  probably  do 
have  just  such  an  injury  to  the  vessel-walls,  but  we  can  never  exclude  an 
injury  of  the  surrounding  tissues,  which  may  be  an  equally  important 
factor. 

It  is  only  because  the  fluid  which  exudes  in  the  course  of  an  inflammation 
differs  quite  markedly  in  its  chemical  composition  from  that  which  we  find 
in  other  instances  of  cedema  that  we  seem  to  have  especially  good  proof  of 
the  existence  of  an  injury  to  the  endothelial  walls  which  makes  them  more 
permeable  for  the  albuminous  material  of  the  blood. 

(Edema  of  the  Lungs. — In  spite  of  much  study  the  mechanism  of  cedema 
of  the  lungs  is  not  yet  clear.  Welch,  who  produced  it  experimentally  by 


46  TEXT-BOOK   OF   PATHOLOGY 

compressing  the  left  ventricle  and  thus  producing  an  enormous  dispropor- 
tion in  the  work  of  the  two  sides  of  the  heart,  thought  that  it  might  result 
from  such  a  disproportion  arising  spontaneously.  It  can  be  produced  by 
adrenalin  injections,  and  some  have  thought  it  of  toxic  origin.  The  fluid 
of  the  blood  exudes  into  the  alveolar  walls,  and  especially  into  the  alveoli, 
so  that  the  air  is  expelled  by  the  coagulable  liquid.  In  the  extreme  exam- 
ples of  this  agonal  condition  frothy  fluid  may  run  away  from  the  nostrils 
and  the  patient  die  practically  drowned  (Fig.  18). 


Fig.  18. — (Edema  of  the  lung.     Alveoli  filled  with  fluid  coagulated  by  fixing  agent. 

The  oedema  which  so  frequently  accompanies  nephritis  of  various  types 
is  apparently  clearly  shown  to  be  due  to  the  inability  of  the  kidney  to  ex- 
crete water  and  salt.  It  appears  that  in  most  instances  the  power  to  ex- 
crete salt  is  at  fault,  its  retention  causing  the  retention  of  water  in  order 
to  maintain  the  normal  tonicity  of  the  tissue  fluids.  Withdrawal  of  salt 
from  the  diet  has  generally  the  remarkable  effect  of  increasing  for  a  time  the 
excretion  of  salt,  and  consequently  the  excretion  of  water,  so  that  the 
oedema  disappears  as  though  by  magic,  and  the  swollen  patient  shrinks 


(EDEMA,    ASCITES,    ETC.  47 

visibly  day  by  day.  At  a  certain  point  the  relations  of  salt  and  water  ex- 
cretion approach  the  normal  in  proportion  to  the  intake  and  the  patient 
remains  cedema-free,  but  an  indiscretion  in  the  consumption  of  salt  may 
again  suddenly  close  the  exit,  so  that  with  its  retention  water  again  accumu- 
lates in  the  tissues. 

LITERATURE 

Cohnheim  and  Lichtheim:     Virchow's  Arch.,  1876,  Ixix,  106. 
Meltzer:  "(Edema,"  American  Medicine,  1904,  viii,  19,  59,  151,  191. 
Muller,  F.:  Verb.  Dtsch.  Path.  Gesellsch.,  1906,  ix,  75. 
Welch:  Virchow's  Archiv,  1878,  Ixxii,  375. 


CHAPTER  IV 
THE  STRUCTURE  AND  METABOLISM  OF  CELLS 

Cellular  doctrine;  ultimate  unit  of  life.  Nucleus  and  cytoplasm.  Mitochondria,  plas- 
mosomes,  paraplasmic  substances,  intercellular  substances.  Tissues  and  motile  cells. 
Variations  in  the  appearance  of  cell.  Necrosis,  coagulation,  and  autolysis.  Death. 

WITH  the  establishment  of  the  cellular  nature  of  the  tissues,  and  Virchow's 
epochal  revelation  that  disease  may  be  referred  to  alterations  in  the  cell, 
it  may  well  have  seemed  that  the  ultimate  unit  of  life  had  been  reached 
and  that  no  minuter  element  need  be  considered.  Indeed,  our  doctrine 
of  pathology  is  essentially  a  cellular  one,  although  we  realize  that  the 
cell  is  in  all  cases  a  vastly  complicated  structure,  within  which  there  are 
elaborate  mechanisms  developed  in  almost  infinite  variety,  and  within 
which,  too,  we  can  discern  evidences  of  the  accomplishment  of  chemical 
processes  which,  in  complexity  and  ingenuity  of  combination,  surpass  any- 
thing which  can  be  carried  out  in  the  best  of  chemical  laboratories.  Within 
one  cell  there  may  occur  at  once  and  side  by  side  synthetic  processes  and 
decompositions  which,  in  the  laboratory,  would  require,  if  they  were  pos- 
sible at  all,  the  most  elaborate  apparatus  and  the  most  extravagant  ex- 
penditure of  energy.  Therefore  it  is  not  surprising  that  many  have  sought 
for  a  still  simpler  unit  of  living  matter. 

But  even  though  we  can  recognize  minuter  organ-like  structures  within 
the  cells,  we  realize  that  they  are  merely  coordinate  parts  in  building  up  the 
cell,  which  is  the  ultimate  mechanism  which  seems  complete  enough  to  live 
independently.  The  smaller  parts  may  be  specialized  instruments  for 
some  particular  function,  but  they  cannot  exist  or  carry  on  this  work  apart 
from  the  cell.  Indeed,  it  seems  that  it  is  upon  the  nice  adjustment  and  co- 
ordination of  all  the  parts  of  the  mechanism  in  the  cell  that  life  depends; 
when  food  and  temperature  conditions  are  favorable,  the  precisely  adjusted 
mechanism  begins  to  move  as  though  by  spontaneous  combustion  under  the 
boiler  of  an  engine  all  prepared. 

While  the  modern  studies  of  immunity  seem  to  ascribe  wonderful  proper- 
ties to  the  fluids  of  the  body,  and  changes  almost  intelligent  in  their  pur- 
posefulness  in  these  fluids  in  response  to  noxious  substances,  all  the  chem- 
ical characters  are  controlled  by  the  cells  and  there  is  little  prospect  of  a 
return  to  the  humoral  theories  of  long  ago. 

It  would  serve  no  good  purpose  here  to  enter  into  the  details  of  the  va- 
rious conflicting  theories  as  to  the  nature  of  the  substances  which  make  up 
the  body  of  the  cell  and  its  nucleus — all  this  may  be  read  in  the  work  of 
M.  Heidenhain,  the  recent  review  of  Benda  and  Ernst,  and  in  other  places. 

48 


THE    STRUCTURE    OF   CELLS  49 

So  little  is  firmly  established  that  it  will  suffice  here  to  mention  those  points 
which  we  seem  to  know  most  surely. 


THE  STRUCTURE  OF  CELLS 

In  spite  of  the  great  variety  in  form  and  size  and  in  special  modifications 
of  the  cell-body  for  different  functions,  we  may  recognize  the  following 
parts: 

(1)  The  nucleus. 

(2)  The  centrioles  or  centrosomes. 

(3)  Golgi's  reticular  apparatus. 

(4)  The  cytoplasm,  in  which  are  found — 

(5)  The  mitochondria. 

(6)  The  plasmosomes. 

(7)  Various  paraplasmic  substances. 

(1)  The  nucleus  differs  from  the  general  protoplasm  in  its  density,  its 
chemical  nature,  and  its  inner  structure. 

How  it  is  separated  from  the  rest  of  the  cell  is  a  matter  still  disputed,  but 
it  is  clear  than  an  active  interchange  of  materials  goes  on  between  the  nu- 
cleus and  the  protoplasm,  and  that  the  nucleus  presides  over  the  activities 
of  the  cell,  and  especially  over  its  reproduction  by  division,  in  which  it  is 
itself  so  intimately  concerned.  In  the  absence  of  a  nucleus  the  protoplasm 
can  remain  alive  a  short  time  and  carry  on  sluggish  assimilation,  but  it 
soon  dies.  The  minute  structure  of  the  nucleus  is  as  much  disputed  as 
that  of  the  cytoplasm.  In  most  cases  there  is  a  homogeneous  nucleolus, 
and  in  our  fixed  preparations  there  are  various  condensations  of  deeply 
staining  chromatin  material.  Kite  states  that,  from  dissection  of  the  liv- 
ing nucleus,  he  can  show  that  the  chromatin  is  not  in  definite  masses  in 
the  resting  cell,  and  that  only  the  nucleolus  is  recognizable  as  a  colloid 
material  of  different  density  from  the  rest.  In  the  process  of  mitosis, 
however,  the  clumping  of  the  chromatin  into  tangible  masses,  the  chro- 
mosomes, is  familiar  to  every  one.  Their  longitudinal  division  into  equal 
parts,  and  the  separation  of  these  parts  by  the  action  of  the  fibrils  of  the 
achromatic  spindle  into  the  so-called  daughter  stars,  which  later  form  two 
separate  nuclei,  is  abundantly  described  in  all  books  on  histology.* 

(2)  The  centrioles  or  centrosomes  are  minute  bodies,  occurring  in  pairs 
outside  the  nucleus,  and  surrounded  by  modified  protoplasm.     They  oc- 
cupy varying  positions  in  the  resting  cell,  being  often  at  the  roots  of  the 
cilia  in  ciliated  epithelium,  in  other  cells  often  embedded  in  a  dell  in  the 
nucleus.     In  mitosis  they  become  active,  separating  to  opposite  poles  of  the 
cell  and  surrounding  themselves  with  radiating,  contractile  fibrillse  (achro- 
matic spindle),  which  exercise  a  mechanical  influence  upon  the  chromosomes. 

*  For  a  discussion  of  the  peculiar  extra  chromosomes  which  have  to  do  with  the  de- 
termination of  sex  the  reader  is  referred  to  Morgan's  book,  Heredity  and  Sex,  1913. 

5 


50  TEXT-BOOK   OF   PATHOLOGY 

(3)  Golgi's  reticular  apparatus  appears  to  be  a  network  or  basket-like 
arrangement  of  canaliculi  filled  with  a  peculiar  lipoid  material  which  is  invis- 
ible by  ordinary  methods  of  observation,  and  only  brought  to  view  by  im- 
pregnation with  silver  or  by  the  blackening  effect  of  osmic  acid.    The  net- 
work is  usually  close  to  the  centrioles,  although  it  sometimes  surrounds  the 
nucleus.    It  varies  greatly  in  the  details  of  its  form  and  arrangement  in  the 
cells  of  different  tissues.    During  mitosis  it  disintegrates  and  the  fragments 
separate  to  the  two  halves  of  the  cell,  arranging  themselves  roughly  in 
relation  to  the  radiations  of  the  achromatic  substance.     Its  function  is 
quite  unknown  and  its  relation  to  pathological  changes  in  the  cells  has  been 
very  little  studied.     It  is  present  in  what  appears  to  be  the  usual  form 
in  tumor  cells,  it  becomes  multiple  in  relation  to  the  numerous  centrioles 
in  multinucleated  giant  cells,  and  it  is  suggested  that  its  lipoid  constituents 
may  furnish  the  material  for  the  hyaline  globules  in  the  degenerating  epi- 
thelial cells  of  the  kidney  in  acute  nephritis.     But  it  is  clear  from  such 
fragmentary  information  that  the  matter  demands  much  further  study. 

(4)  The  Cytoplasm. — The  divergent  theories  as  to  the  nature  of  the  pro- 
toplasm may  be  read  elsewhere.    It  seems  that  the  more  recent  study  of 
the  granular  structures  which  are  embedded  in  it  has  removed  much  of  the 
support  for  the  earlier  theories,  and  the  outcome  seems  to  be  that  the  cyto- 
plasm is  essentially  colloid  in  its  composition,  obeying  the  physical  laws 
which  govern  colloids  in  their  various  phases.    Possibly  a  mixture  of  col- 
loids of  various  densities,  it  has  varying  powers  of  water  absorption  and 
swelling.     The  admixture  of  fat-like  substances  alters  its  physical  char- 
acter somewhat.    With  regard  to  the  surface  of  the  cell,  it  has  been  sug- 
gested that  some  such  condensation  through  the  aid  of  cholesterin  or  leci- 
thin admixture  may  exist.    Overton's  theory  that  there  is  an  actual  thin 
lipoid  membrane  which  acts  as  a  semipermeable  sheath  to  each  cell  is 
well  known,  and  has  served  in  the  explanation  of  the  action  of  anaesthetics, 
but  it  still  admits  of  criticism,  as  pointed  out  by  Bayliss  (Principles  of 
General  Physiology,  1918,  page  138). 

(5)  The  Mitochondria. — Altmann,  in  1894,  devised  staining  methods 
which  made  visible  certain  granules  in  the  cell  protoplasm  which  he  re- 
garded as  elementary  organisms,  or  the  only  living  constituents  of  the  cyto- 
plasm.    While  this  view  cannot  be  maintained,  there  is  much  that  is  exact 
in  his  observations.     Benda  recognized  by  other  stains  granules,  rods,  and 
threads  in  the  protoplasm  which  he  called  mitochondria,  and  which  have 
been  shown  by  many  workers  (Meves,  Duesberg,  and  others)  to  be  a  very 
constant  constituent  of  the  cell-body. 

Many  names  have  been  proposed  indicating  differences  in  form,  such  as 
chondriocont  for  the  longer  filamentous  forms,  chondriomita  for  those  re- 
sembling a  string  of  beads,  etc.,  but  the  original  term,  mitochondria,  may 
well  be  used  in  a  collective  sense.  The  greatest  variety  of  functions  has 
been  ascribed  to  them  by  different  writers.  Meves  claims  that  they  fur- 
nish the  connective-tissue  fibrillae,  that  they  transmit  the  hereditary  char- 


THE    STRUCTURE    OF   CELLS  51 

acters  of  the  cell-body,  etc.  Champy,  in  studying  absorption  and  secre- 
tion in  the  intestinal  epithelium,  states  that  they  accumulate  at  both  poles 
of  the  cell  and  are  converted  into  secretory  granules. 

It  is  clear  that  we  must  as  yet  be  careful  in  interpreting  their  function, 
and  while  it  seems  probable  that  they  play  some  important  role,  it  is  possible 
that  already  too  many  different  duties  have  been  assigned  to  them. 

(6)  The  Plasmosomes. — Benda  distinguishes  sharply  from  the  mito- 
chondria these  granules,  which  he  speaks  of  as  concerned  with  the  house- 
keeping of  the  cell,  with  the  assimilation  of  nutritive  materials,  with  the 
formation  of  secretory  products  as  the  result  of  their  specific  metabolism, 
and  with  the  excretion  of  waste. 

They  are  not  to  be  recognized  in  themselves  by  any  of  the  staining  meth- 
ods which  we  know  now,  but  are  readily  enough  made  visible  by  the  sub- 
stances which  they  store  or  secrete  or  by  their  power  to  store  vital  stains. 
That  they  are  really  distinct  from  the  mitochondria  is  shown  by  their 
different  position  in  the  cell,  by  the  fact  that  the  mitochondria  are  recog- 
nizable as  thin  filaments  in  a  cell  in  which,  side  by  side  with  them,  the  plas- 
mosomes  are  swollen  with  some  absorbed  material,  or  with  a  stainable  se- 
cretion, and  by  the  fact  that  in  mitosis,  mitochondria,  and  plasmosomes 
separately  divide  and  continue  their  existence  in  the  daughter-cells. 

It  is  in  connection  with  these  that  fats  and  carbohydrates  are  stored  in 
the  cell.  It  is  probably  they  that  swell  and  become  conspicuous  in  "  cloudy 
swelling"  or  " parenchymatous  degeneration."  They  in  their  varieties 
constitute  the  specific  granulations  of  the  leucocytes  and  other  cells.  To 
this  class  too  belong,  no  doubt,  the  zymogen  granules  in  many  glands,  even 
though  in  such  a  gland  as  the  pancreas  we  can  distinguish  so  easily  the 
coarse,  deeply  staining  zymogen  granules  in  the  acinar  cells  from  the 
very  minute  granules  of  two  types  in  the  cells  of  the  islands  of  Lan- 
gerhans. 

Lewis  has  shown  recently  that  in  young  connective-tissue  cells 
cultivated  in  vitro  granules  appear  in  vacuoles,  especially  about  the 
centriole  when  the  culture  grows  old  and  becomes  ill-nourished.  These 
stain  with  neutral  red,  while  the  mitochondria  stain  with  Janus  black. 
He  regards  them  as  degeneration  products  composed  of  non-living 
material. 

It  is  clear  that  the  construction  of  the  cell  is  highly  specialized  in  most 
cases  for  the  function  which  it  is  to  carry  out,  and  that  it  is  supplied  with 
the  most  perfect  mechanisms  for  these  purposes.  Some  of  these  are  evi- 
dent in  the  form  of  contractile  bands  in  the  protoplasm,  or  in  long  nerve 
processes  like  electric  wires  carefully  insulated  by  sheaths  of  fatty  ma- 
terial, or  in  mobile  cilia  which  mechanically  perform  duties  in  the  trans- 
portation of  foreign  particles,,  In  others  the  tools  of  their  trade  are  recog- 
nizable in  the  form  of  the  granules  which  seem  to  prepare  ferments  by  which 
the  chemical  processes  which  the  cells  effect  are  carried  out.  While  these 
are  visible  in  many  cases,  there  are  others  in  which,  even  when  we  know 


52 


TEXT-BOOK    OF    PATHOLOGY 


that  the  most  multifarious  chemical  reactions  are  being  carried  on,  nothing 
of  the  mechanism  is  recognizable  to  our  eyes. 

(7)  Paraplasmic  Substances. — While  the  actual  instruments  of  metab- 
olism are  thus  often  invisible,  the  materials  which  are  being  worked  up  by 
the  cells,  and  more  especially  those  which  the  cell  is  unable  to  dispose  of, 
often  remain  conspicuous  in  the  cell-body.  Such  "paraplasmic"  particles, 
which  may  consist  of  fat-globules  (Fig.  19),  glycogen  granules  (Fig.  20), 
vacuoles  filled  with  fluid,  granules  of  pigment  or  calcium,  often  form  an  in- 
dex of  the  activity  of  the  metabolism  of  the  cell,  and  are  useful  in  determin- 


Fig.  19. — Fat-globules  in  the  epithelium  of  the  renal  tubules.     Sudan  stain. 

ing  its  condition,  although  it  must  be  remembered  that  there  are  doubtless 
many  other  substances  equally  burdensome  to  the  cell,  and  accumulated  in 
its  protoplasm,  because  its  metabolism  is  so  sluggish  as  to  make  it  unable 
to  dispose  of  them,  and  these,  because  of  their  solubility  or  because  they 
are  inaccessible  to  our  stains,  are  invisible.  Certainly  these  substances 
are  not  to  be  thought  of  as  alive,  at  any  rate  until  they  become,  through 
assimilation,  integral  constituents  of  the  chemical  structure  of  the  proto- 
plasm. 


TISSUES    AND    MOTILE    CELLS 
TISSUES  AND  MOTILE  CELLS 


53 


It  is,  of  course,  clear  in  connection  with  this  that  the  higher  animals,  at 
least,  exist  as  communities  of  cells  in  which  each  district  is  made  up  of 
individuals  which  have  specialized  in  some  form  of  activity  which  is  con- 
tributed to  the  good  of  the  whole,  and  that  in  such  a  community  there  are 
many  things  in  common,  such  as  the  blood-supply,  the  gaseous  interchange, 
and  the  removal  of  waste.  Just  as  in  a  town  the  water-supply/  the  air, 
and  the  sewerage  are  of  common  interest,  so  we  have  seen  that  in  the  body 


Fig.  20. — Liver  of  a  normal  well-fed  dog  showing  glycogen  in  cells.     Best's  carmine  stain. 

whole  districts  may  suffer  from  the  failure  of  one  of  these  common  necessi- 
ties. 

Communities  of  this  character,  inasmuch  as  they  hold  together  in  a 
coherent  grouping,  we  easily  recognize  as  "tissues."  It  is  not  so  easy  to 
think  of  a  constantly  moving  and  changing  group  of  cells  like  the  blood  as  a 
tissue,  although  in  every  other  respect  it  deserves  the  same  dignity  as  the 
community  of  liver-cells  or  kidney-cells.  And  so  it  is  with  those  free  lances, 
the  wandering  phagocytic  cells,  which  straggle  about  in  the  tissues  every- 
where, but  are  ready  on  call  to  assemble  at  a  point  where  they  are  needed. 


54  TEXT-BOOK   OF   PATHOLOGY 

Intimately  related  to  the  mobile  cells  of  the  blood,  they  have  the  same  claim 
to  the  honors  of  a  community,  although  it  must  be  remembered  that  they 
differ  from  the  "fixed  tissue"  elements  in  refusing  to  hold  together  into  a 
solid  structure  or  to  adopt  any  particular  place  as  a  permanent  site. 

The  whole  body  is  not  composed  of  cells.  Were  the  cells  all  removed, 
there  would  still  remain  a  framework  so  complete  that  although  we  might 
see  through  it  as  through  a  basket,  the  whole  form  of  the  body  in  all  its 
parts  would  be  represented  and  much  of  its  solidity  would  remain.  This 
is  the  intercellular  substance,  which  varies  greatly  in  character  in  different 
places,  being  almost  the  whole  of  the  skeleton  and  the  bulkier  part  of  all 
the  connective  tissues  which  permeate  all  tissues  and  organs.  Whether 
this  material  is  alive  has  been  long  discussed.  Certainly  the  fibres  of 
connective  tissue,  the  matrix  of  cartilage,  and  the  calcified  substance  of 
bone  could  not  remain  alive  alone;  but  in  the  body  all  these  things 
undergo  constant  change,  being  broken  down  and  reconstructed,  and  there 
seems  no  doubt  that  they  carry  on  a  sluggish  interchange  of  chemical  mate- 
rials— a  slow  metabolism. 

VARIATIONS  IN  APPEARANCE  OF  CELLS 

Alterations  in  the  appearance  of  the  cell  arise  constantly  from  variations  in 
its  activity,  and  one  must  be  familiar  with  such  physiological  transforma- 
tion in  order  to  interpret  correctly  what  might  otherwise  be  looked  upon 
as  the  effects  of  pathological  processes.  This  presupposes  that  we  are  able 
to  view  the  cells  as  they  are  in  the  height  of  their  activity,  but  in  truth  this 
is  seldom  the  case,  since  most  studies  of  human  tissue  are  made  after  the 
individual  has  been  dead  for  some  time,  or  after  the  tissue  has  been  re- 
moved from  the  body  at  operation.  Naturally,  changes  must  be  expected 
to  occur  in  this  interval,  and  it  is  easily  realized  that  the  more  quickly  the 
cells  can  be  studied  after  their  removal  from  the  living  body,  the  more 
nearly  they  will  approach  to  their  living  condition.  Naturally,  too,  there 
are  great  advantages  to  be  gained  by  studying  such  cells  at  once  without  the 
application  of  any  chemical  reagent,  a  method  once  universal,  but  now  far 
too  little  used.  But  it  is  realized  that  while  much  may  be  learned  in  this 
way,  such  tissues  change  rapidly,  and  we,  therefore,  preserve  them  by  sud- 
denly stopping  all  ferment  action  and  coagulating  the  protein  substances 
by  the  application  of  some  fluid,  such  as  alcohol  or  formalin.  Advantage 
is  taken  of  the  fact  that  nuclei,  protoplasm,  etc.,  react  differently  to  various 
stains,  and  in  the  end  our  microscopical  preparations  show  us  the  cells 
sharply  brought  into  relief  by  being  coagulated,  and  by  having  each  of  its 
elements  differently  colored.  We  are  accustomed  to  the  appearance  in  the 
stained  preparations  of  what  was  a  normal  cell  and  interpret  diseased  con- 
ditions of  the  cell  by  its  divergence  from  this  standard,  but  at  the  same 
time  we  know  that  the  cell  is  really  greatly  changed  from  its  appearance 
while  alive.  It  resembles  the  living  cell  about  as  a  boiled  egg  resembles  a 
fresh  laid  one.  In  an  autopsy  upon  a  man  who  had  swallowed  a  large 


NECROSIS   AND    NECROBIOTIC    CHANGES 


55 


amount  of  pure  carbolic  acid,  which  is  an  excellent  "fixing  fluid,"  the  gas- 
tric mucosa  was  obviously  dead  and  coagulated  into  a  white  layer  long 
before  the  man  died,  but  although  it  looked  so  abnormal,  the  microscopical 
section  showed  the  most  perfectly  preserved  normal  gastric  mucosa. 

If,  then,  these  are  all  dead  cells  which  constitute  our  standard  of  the 
appearance  of  live  cells,  how  shall  we  recognize  injured  or  dead  cells  among 
living  ones?  It  is  very  easy,  because  what  we  recognize  is  not  the  death  of 
the  cell,  but  the  changes  to  which  it  is  exposed,  after  death,  while  still  sur- 
rounded by  living  tissues  and  their  fluids,  and  which  result  partly  from  the 
action  of  ferments  and  partly  from  the  formation  of  a  clot  in  the  sub- 
stance of  the  dead  cell  and  the  coagulable  fluids  which  may  permeate  it. 


Fig.  21. — Renal  epithelium  showing  pyknosis  in  several  nuclei,  with  disappearance  of 

others. 

If  only  a  portion  of  the  gastric  mucosa  had  been  killed,  so  that  the  man 
remained  alive  for  a  time,  it  would  soon  have  been  liquefied  by  the  gastric 
juice.  Exactly  so  a  dead  cell  in  the  substance  of  the  liver  becomes  the  seat 
of  clotting,  and  then  is  liquefied  by  the  ferments  of  the  passing  fluids  and 
mobile  cells,  and  it  is  in  some  stage  of  this  process  that  we  recognize  the 
necrotic  cell.  A  cell  which  had  just  died  would  look  quite  like  its  living 
neighbor. 

NECROSIS  AND  NECROBIOTIC  CHANGES 

It  is  important,  then,  to  consider  briefly  these  evidences  of  the  effects  of 
necrobiotic  changes,  a  matter  which  is  simplified  since  they  are  the  same 


56 


TEXT-BOOK    OF    PATHOLOGY 


throughout,  whether  the  injury  be  caused  by  a  poison,  by  starvation,  or 
in  any  other  way,  unless,  of  course,  the  poison  or  mechanical  injury  should 
in  itself  produce  some  peculiar  change  in  the  cell.  With  the  cessation  of 
life  in  the  cell  there  is  a  short  pause,  during  which  the  dead  cell  has  every 
appearance  of  being  alive,  and  then  its  protoplasm  sets  in  a  clot.  The 
thromboplastic  substance,  or  thrombokinase,  which  the  dead  cell  radiates 
causes  the  coagulation  of  the  fibrinogen  in  the  blood  plasma  which  filters 
into  it,  and  in  the  end  the  body  of  the  dead  cell  becomes  a  swollen  mass, 
much  denser  and  heavier  than  the  body  of  the  original  live  cell.  All  this  is 
riot  done  without  changes  in  the  appearance  of  the  cell — changes  which 
probably  begin  before  the  actual  death  and  continue  after  clotting  has 


Fig.  22. — Karyorrhexis.     Edge  of  infarct  of  kidney. 


occurred.  The  most  conspicuous  are  alterations  in  the  nucleus  which  may 
cause  it  to  shrink  and  stain  more  deeply  (pyknosis)  (Fig.  21).  Portions  of 
its  substance  may  be  extruded  beyond  its  original  outline  in  bizarre  forms, 
or  it  may  break  up  into  several  irregular,  solid-looking,  and  deeply  stained 
fragments,  or  even  into  a  fine  dust  of  black  grains  (karyorrhexis)  (Fig.  22). 
On  the  other  hand,  it  sometimes  retains  its  form  for  a  long  time,  but  gradu- 
ally fades  until  only  the  faintest  rim  takes  the  stain  and  in  turn  finally  dis- 
appears (karyolysis)  (Figs.  23  and  24).  At  the  same  time  the  structural 


NECROSIS   AND   NECROBIOTIC    CHANGES 


57 


Fig.  23. — Karyolysis  in  renal  epithelium. 


jig 


Fig.  24. — Death  of  renal  epithelium  with  fading  nuclei. 


58  TEXT-BOOK    OF    PATHOLOGY 

details  of  the  cytoplasm  are  lost,  and  merge  into  a  dense,  granular  or  vitre- 
ous mass,  which  assumes  a  deep  pink  stain  with  eosin.  Later  changes 
caused  by  proteolytic  ferments  lead  to  the  erosion,  disintegration,  and  final 
liquefaction  and  disappearance  of  the  whole  cell  remnant.  Frequently 
the  boundaries  of  many  adjacent  necrotic  cells  are  lost  before  liquefaction 
occurs,  and  a  granular  mass  remains  in  which  nuclear  fragments  or  the  fine 
dust  of  them  is  scattered,  but  even  then  it  is  often  possible  to  make  out  the 
positions  of  the  original  cells  because  the  more  resistant  connective-tissue 
framework  of  the  tissue  persists. 

Much  of  the  disintegration  and  removal  of  the  debris  of  such  dead  cells 
is  effected  mechanically  by  phagocytic  cells,  usually  of  the  mononuclear 
type,  which  engulf  particles  in  their  protoplasm  in  addition  to  their  activ- 
ity in  furnishing  the  proteolytic  ferment.  They  in  the  end  wander  away 
with  these  partly  digested  fragments,  the  liquefied  material  is  absorbed, 
and  the  area  of  cell  death  collapses  or  is  partly  filled  by  a  growth  of  scar 
tissue.  Sometimes,  as  in  large  infarctions  or  in  tuberculous  foci,  the  dead 
material  may  remain  undissolved  for  a  long  time,  and  is  walled  off  by  a 
capsule  of  fibrous  tissue. 

Autolysis. — This  liquefaction  by  means  of  a  proteolytic  ferment  is 
exactly  the  process  known  as  autolysis,  except  that  it  is  recognized  in  that 
process  that  all  tissues  can  liberate  in  varying  degrees  of  intensity  the  pro- 
teolytic ferment  necessary  to  dissolve  their  own  cell-bodies.  Even  a  piece 
of  lung  or  liver  kept  sterile  in  a  warm  place  will  soften  and  finally  liquefy, 
while  tissues,  such  as  spleen,  which  contain  large  numbers  of  specialized 
phagocytic  cells  which  are  particularly  active  in  producing  such  ferments 
will  dissolve  into  a  turbid  fluid  rich  in  amino-acids  far  more  quicky. 
Bradley  and  Morse  emphasize  the  importance  of  a  slightly  acid  reaction 
in  accelerating  this  process.  Dernby  shows  that  in  all  tissues  studied 
there  are  both  pepsin-like  and  trypsin-like  enzymes,  so  that  autolysis 
would  proceed  most  rapidly  if  the  reaction  were  first  slightly  acid  and 
then  alkaline.  Undoubtedly  this  mechanism  is  well  adapted  to  rid  the 
body  of  useless  dead  and  crippled  cell  material,  and  it  will  be  seen  that  it 
plays  a  great  part  in  the  restoration,  to  an  untrammeled  working  condition, 
of  all  injured  organs,  and  throughout  life  is  the  constantly  active  method 
of  housecleaning  which  keeps  the  machinery  in  order. 

Death. — Death  of  cells  is  thus  a  relatively  complicated  matter,  but  the 
whole  body  is  a  community  of  tissues  which  is  not  entirely  disabled,  even 
by  the  loss  of  many  cells.  As  in  the  cell  where  the  controlling  nucleus  is 
destroyed  the  protoplasm  also  dies,  so  in  the  body  life  is  the  expression 
of  the  working  of  a  delicate  machine  which  works  because  it  is  marvelously 
attuned  to  the  environment.  Because  it  has  elaborate  regulators,  control- 
lers, and  safety-valves,  it  can  compensate  for  many  injuries,  but  when  the 
limit  of  the  influence  of  these  is  passed,  the  machine  stops.  Therefore  there 
are  many  ways  in  which  the  balance  can  be  made  impossible  at  one  point 
or  another — points  important  enough  to  involve  finally  the  all-important 


NECROSIS   AND   NECROBIOTIC    CHANGES  59 

circulation  and  respiration.  When  they  cease,  all  the  tissues  soon  die, 
although  for  some  time  after  the  main  machine  has  stopped  working  the 
various  accessory  machines  are  still  in  good  working  order,  and  need  only 
the  current  of  clean  blood  through  their  vessels  to  make  them  begin  once 
more  to  work.  Of  course,  the  central  nervous  system  is  the  great  regulator, 
and  one  might  say  the  master  engineer,  but  life  can  go  on  without  it  if 
only  some  one  will  assume  its  role  and  arrange  that  the  circulation  should 
continue  properly.  So,  though  it  is  so  familiar,  it  is  difficult  to  define 
precisely  what  a  person's  death  means  or  to  say  at  just  what  moment  the 
most  important  part  of  death  occurred. 

LITERATURE 

Benda:  Ergebn.  d.  Anat.  u.  Entwickl.,  1903,  xii,  743.     Verb.  Dtsch.  Path.  Gesell,  1914, 

xvii,  5. 

Bradley,  Morse:  Jour.  Biol.  Chemistry,  1915,  xxi,  113;  1916,  xxiv,  27. 
Champy:  Arch,  d'anat.  Microsc.,  1911,  xiii,  55. 
Cowdry:  Amer.  Jour,  of  Anat.,  1916,  xix,  423,  and  other  papers. 
Dernby:  Jour.  Biol.  Chemistry,  1918,  xxxv,  179. 
Duesberg:  Biological  Bulletin,  1919,  xxxvi,  71,  and  other  papers. 
Ernst:  Verh.  Dtsch.  Path.  Gesell.,  1914,  xvii,  43. 
Heidenhain,  M.:  Plasma  u.  Zelle,  1907,  i. 
Lewis:  Johns  Hopkins  Hospital  Bulletin,  1919,  xxx,  81. 

Meves:  Arch.  f.  mikr.  Anat.,  Ixxi,  Ixxii,  Ixxv,  Ixxvi,  etc.    Anat.  Anzeiger,  xxxi,  xxxiv. 
Morgan,  T.  H. :  Heredity  and  Sex,  Columbia  University  Press,  1913. 
Pappenheimer :  Anatomical  Record,  1916,  xi,  107. 


CHAPTER  V 

DISTURBANCES    IN    THE    NUTRITION    AND    METABOLISM    OF 

CELLS 

Nature  of  metabolism.  Disturbances  resulting  from  slight  injuries.  Degenerations. 
Atrophy:  its  causes. 

ORDINARILY  the  normal  and  abnormal  metabolism  of  animals  is  studied 
by  chemical  investigation  of  the  materials  taken  into  the  body  in  compari- 
son with  those  excreted,  taking  into  account  the  energy  liberated  in  the 
form  of  heat,  and  the  changes  in  the  weight  of  the  body.  This  gives  a 
fairly  accurate  idea  of  the  whole  material  interchange  in  the  body,  and  when 
the  normal  balance  is  much  disturbed,  it  is  usually  easy  to  recognize  the 
effects  anatomically. 

It  is  known  to  every  one  that  in  early  life  the  anabolic,  or  building-up, 
processes  should  be  in  excess  of  the  katabolic,  or  destructive,  processes, 
so  that  growth  proceeds  through  the  assimilation  and  permanent  retention 
of  much  of  the  food  materials  in  the  form  of  body  tissue.  In  mature  life 
such  an  exquisite  balance  is  maintained  that  little  change  in  the  body  weight 
occurs,  while  in  the  declining  years  the  organs  waste  and  the  body  shrinks 
because  the  katabolic  outstrip  the  anabolic  processes. 

Substances  taken  in  as  food  may  be  used  directly  for  the  building  up  of 
tissue,  whereupon  they  become  a  relatively  stable  part  of  the  body  struc- 
ture, or  they  may  be  burnt  to  produce  energy,  or  stored  for  future  burning. 
Such  stores  are  essentially  labile  constituents  of  the  body,  ready  at  any 
time  to  be  moved  about  or  to  undergo  rapid  chemical  change.  They  thus 
constitute  the  ready  fuel,  and  it  is  only  after  they  are  exhausted  that  the 
actual  cell  substance  is  consumed.  It  is  like  Palissy's  furnace,  into  which, 
when  the  supreme  effort  was  being  made  and  fuel  was  finally  exhausted,  he 
cast  his  furniture. 

Naturally,  if  the  activities  of  the  cells  are  restricted,  the  fuel  will  tend  to 
accumulate — even  if  the  cell  is  slightly  injured,  so  that  it  can  no  longer 
make  use  of  all  the  materials  brought  to  it,  we  may  expect  them  to  collect 
in  its  body. 

Under  these  circumstances  we  can  often  see  the  accumulated  materials; 
although  .we  can  detect  no  evidence  of  injury  to  the  structure  of  the  cell, 
and  it  must  be  a  matter  of  long  experience  to  ascertain  how  much  real  in- 
jury corresponds  with  the  heaping-up  of  such  materials. 

This  is  the  basis  of  the  so-called  "  degenerations,"'  'of  which  so  much  has 
been  written.  When  it  was  thought  that  the  globules  of  fat  in  a  cell  were 
the  direct  product  of  the  decomposition  of  its  protoplasm,  this  naturally 

60 


DISTURBANCES    IN    THE    NUTRITION    AND    METABOLISM    OF    CELLS      61 

indicated  a  great  injury,  but  now  if  we  think  the  fat  merely  a  part  of  that 
which  is  transported  from  place  to  place,  finally  sidetracked  in  these  cells, 
we  cannot  be  so  readily  convinced  of  the  injury  to  the  cell,  especially  since 
we  know  that  the  same  appearances  can  arise  in  perfectly  normal  persons. 
It  is  almost  as  though  we  were  to  attempt  to  tell  the  condition  of  a  flour 
mill  which  we  suspect  of  being  out  of  order  by  estimating  the  amount  of 
wheat  in  its  hopper  at  any  given  moment.  It  might  be  better  to  estimate 
the  flour  it  has  ground  or  to  look  for  broken  wheels  in  its  machinery. 

The  situation  is  difficult  for  the  following  reasons :  Of  all  the  substances 
which  enter  into  the  material  interchange  of  the  cells,  we  can  see  only  a  few, 
such  as  fat.  As  shown  by  chemical  studies,  great  disturbances  of  metabolic 
activity  may  occur  without  our  being  able  to  see  the  substances  concerned, 
and,  on  the  other  hand,  great  variations  in  the  quantity  of  the  visible 
materials  in  the  cell  need  not  indicate  an  injury  to  the  cell.  Functional 
disability  of  the  cell  may  exist  without  any  obvious  anatomical  alteration, 
and  yet  cause  this  stagnation  of  food  materials,  while  perfectly  obvious 
anatomical  demolition  of  the  cell  machinery  may  occur  in  such  a  way  that 
no  heap  of  fuel  material  collects  to  indicate  the  change.  So  we  must  in- 
terpret what  we  find  with  extreme  care. 

It  is  the  aim  of  this  chapter  to  discuss  the  anatomical  changes  in  the 
tissues  produced  by  injuries,  which  are  accompanied  by  disturbances  of 
metabolism.  These  changes  may  be  so  slight  as  to  be  invisible,  and  indi- 
cated only  by  the  accumulation  of  materials  which  should  have  been  used 
up,  or  they  may  be  so  intense  as  to  have  destroyed  the  structure  of  the  cell. 

The  term  degeneration  is  usually  employed  to  indicate  the  effect  of  an 
injury  sufficient  not  to  cause  the  death  of  the  cell,  but  to  disturb  its  metab- 
olism to  such  a  degree  that  the  raw  materials  or  the  products  of  its  activi- 
ties accumulate  in  it.  It  is  loosely  used  in  other  senses,  as  in  the  case  of 
hyaline  degeneration,  in  which  the  cells  die  and  are  merged  into  a  homo- 
geneous mass,  or  amyloid  degeneration,  in  which  an  abnormal  substance 
is  deposited  in  the  crevices  of  the  tissue. 

It  would  seem  desirable,  if  possible,  to  abandon  the  term  degeneration 
entirely  and  to  use  others  which  refer  more  accurately  to  the  disturbances 
of  metabolism  or  to  the  actual  injury  of  the  cell.  But  even  if  we  at- 
tempted this,  it  would  probably  be  unsuccessful,  for  the  words  are  so 
deeply  rooted  and  express  so  concisely  a  complex  and  obscure  idea. 

It  must  be  observed  that  a  rather  limited  number  of  raw  materials 
are  normally  concerned  in  the  chemical  processes  of  the  body,  although 
they  are  presented  in  an  almost  infinite  number  of  combinations,  and  pass 
through  many  further  changes  in  the  cells,  but  the  body  can  deal  with  other 
things  which  are  not  good  food  or  drink  or  air  to  breathe,  in  ways  which 
are  sometimes  surprising  and  always  more  or  less  definitely  adapted  to  its 
protection. 

Normally  we  take  in  water,  air,  protein,  carbohydrates,  and  fats,  to- 
gether with  smaller  but  continuous  supplies  of  the  salts  of  sodium,  potas- 


62  TEXT-BOOK    OF   PATHOLOGY 

slum,  magnesium,  and  calcium,  combinations  of  iron,  phosphorus,  sulphur, 
iodine,  chlorine,  and  minimal  amounts  of  various  other  substances.  The 
lack  of  any  one  of  these  will  be  severely  felt,  and  may  produce  an  astound- 
ing upset  of  the  whole  machinery  of  the  body. 

At  other  times,  when  the  facilities  for  dealing  with  one  or  other  of  these 
substances  are  disarranged,  it  may  become  necessary  to  eliminate  them 
from  the  food  if  life  is  to  be  prolonged — carbohydrates  are  withheld  from 
the  diabetic  and  salt  from  the  waterlogged  sufferer  from  Bright's  disease. 

ATROPHY 

In  order  that  growth  should  occur,  or  even  that  the  tissue  should  maintain 
its  status,  the  machinery  of  the  cell  must  be  in  working  order.  We  may 
imagine  that,  by  reason  of  age,  this  machinery  might  deteriorate  or  that 
in  other  ways  it  might  be  incapacitated. 

Evidently  when  this  deterioration  appears,  the  oxidizing  or  katabolic 
processes  go  on,  although  the  more  difficult  building  up  proceeds  but 
haltingly  until  the  cell  is  hopelessly  in  arrears  and  wastes  away. 

The  cell  laboratory  does  not  start  up  into  activity  merely  because  food  is 
presented — rather  it  is  controlled  in  its  synthetic  and  analytic  processes 
by  influences  from  without — from  the  nervous  system,  perhaps  indirectly 
through  the  organs  of  internal  secretion.  They  set  the  pace  and  determine 
the  rate  of  work.  Without  them  tissue-cells  will  grow  a  little  in  such  a 
culture  as  has  lately  become  possible,  but  this  growth  is  so  meagre  that 
their  importance  has  become  more  than  ever  clear.  When  the  cell  does 
nothing,  we  might  perhaps,  at  first  thought,  expect  it  to  remain  unchanged, 
and  so  it  would  if  we  assured  its  complete  inactivity  by  putting  it  in  forma- 
lin, but  the  inactivity  of  a  cell  is  more  like  a  household  in  which  the  bread- 
winner stops  work. 

Of  course,  grosser  influences  may  have  the  same  effect — hunger  may  de- 
prive the  tissues  of  nutrition,  pressure  may  so  constrict  the  cell  that 
nourishment  is  impeded,  or  poisons  may  wreck  the  machinery.  The 
atrophy  of  tissues  is,  therefore,  not  a  simple  matter,  and  perhaps  were  the 
effects  as  different  in  appearance  as  the  causes,  we  might  have  many  words 
to  describe  it.  And  even  though  we  may  discover  the  primary  reason  for 
the  great  change,  we  cannot  always  be  sure  of  the  immediate  cause  because 
a  vicious  circle  is  started  each  time,  any  part  of  which  may  be  responsible 
for  the  end  result.  Can  we  be  sure,  when  the  muscles  of  a  limb  atrophy 
from  disuse,  whether  the  inactivity  of  the  muscle-cell  directly  halts  its 
metabolism,  or  whether  the  cell  wastes  because  but  little  blood  comes  to  it 
now,  either  because  it  fails  to  assist  the  circulation,  or  because  the  vaso- 
motors  adjust  the  supply  to  its  needs  as  an  inactive  rather  than  an  active 
cell? 

Wasting  of  the  tissue  may  be  caused  by  starvation,  by  old  age,  by  mental 
disease,  by  derangement  of  the  internal  secretions,  by  infections  and  in- 
toxications, especially  when  associated  with  fever,  by  inactivity,  especially 
when  caused  by  paralysis,  by  mechanical  pressure,  and  by  various  other 
causes. 


ATROPHY  63 

Hunger. — According  to  the  state  of  nourishment  with  which  it  starts, 
the  animal  body  can  survive  the  complete  withdrawal  of  food  for  varying 
periods.  If  water  is  available,  the  length  of  time  that  elapses  before  serious 
symptoms  or  death  results  may  be  several  weeks,  especially  in  certain  per- 
sons who  have  trained  themselves  to  fast.  It  is  even  longer  in  dogs. 
Aside  from  the  sensations  of  hunger  (which  soon  decrease)  and  weakness, 
there  are  usually  no  particular  symptoms  until  rather  late,  when  phenomena 
of  intoxication  with  nervous  symptoms  arise  on  account  of  the  irregular 
decomposition  of  fats  into  /3-oxybutyric  acid  and  acetone,  with  related 
substances.  This  acid  intoxication,  which  may  bring  on  coma,  is  not,  as 
a  rule,  seen  in  fasting  dogs. 

In  a  starving  person  the  absorption  of  oxygen  and  exhalation  of  carbon 
dioxide  continue,  the  excretion  of  urine  goes  on,  although  the  faces  disap- 
pear. Wasting  occurs  first  in  the  stored  substances,  such  as  fat,  glycogen, 
etc.,  then  in  the  tissues  themselves,  beginning  with  those  which  are  least 
called  into  use.  Of  the  muscles,  the  active  ones  retain  their  bulk  longer 
than  the  idle  ones.  The  liver  shrinks,  and  the  parts  which  retain  their  full 
size  for  a  long  time  are  the  central  nervous  system,  the  heart,  and  the 
bones,  although  the  last  probably  become  rarefied. 

While  complete  deprivation  in  this  way  brings  about  the  rapid  wasting 
of  the  body,  there  are  many  mechanical  and  other  conditions  which  lead 
to  the  same  result  more  slowly.  Any  obstruction  to  the  passage  of  food 
through  the  mouth  and  oesophagus  to  the  stomach  may  gradually  starve 
the  sufferer,  and  so  may  an  obstruction  at  the  pylorus,  since  nourishment 
is  not  sufficiently  absorbed  from  the  stomach  and  is  usually  vomited  after 
a  long  stay  there.  Beside  this,  there  are  various  nervous  disturbances, 
which  result  in  inability  to  take  food  (anorexia  nervosa)  or  to  retain  and 
digest  it,  and  lead  to  extreme  emaciation. 

Senility. — With  the  advance  of  age,  wasting  becomes  evident  in  many 
organs,  if  not  in  all,  although  the  inconstancy  with  which  it  appears  leads 
one  to  wonder  whether  other  factors  do  not  also  play  a  part.  The  skin  be- 
comes thin  and  satiny,  and  the  disappearance  of  fat  and  muscle  tissue 
beneath  it  throws  it  into  wrinkles.  The  hair,  after  becoming  white,  falls 
out,  the  teeth  loosen  and  decay  and  fall  out.  The  muscles  waste  away  and 
grow  weak,  and  the  ligaments  which  bind  together  the  bones  stretch  and 
weaken.  Deprived  of  its  strong  muscular  and  ligamentous  support,  the 
back  bends  forward.  The  bones  become  rarefied,  so  that  they  break  more 
easily  and  heal  with  greater  difficulty  than  in  a  young  person. 

The  internal  organs  decrease  in  size  and  turn  brown,  and  every  cell, 
through  its  shrinkage  and  the  accumulation  of  pigment,  can  be  recognized 
as  that  of  a  senile  organ.  The  liver  becomes  a  flabby,  shrunken  organ,  of  a 
dark-brown  color,  made  up  of  lobules  far  smaller  than  the  normal;  often 
whole  layers  of  liver  tissue  disappear,  so  that  on  the  surface  of  the  organ 
blood-vessels,  bile-ducts,  and  the  fibrous  skeleton  of  the  liver  lie  exposed 
(Fig.  25).  The  heart  becomes  small  and  brown,  with  tortuous  coronary 


64 


TEXT-BOOK   OF   PATHOLOGY 


arteries  showing  through  the  watery,  brownish  fat.  The  fat  of  the  epi- 
cardium  has  disappeared,  and  its  cells  are  separated  by  fluid  which  gives  the 
gelatinous  appearance  to  the  tissue.  The  heart  decreasing  in  size  is  too 
small  for  the  coronary  vessels,  which  must  take  a  tortuous  course.  Each 
heart  muscle  cell  greatly  reduced  in  thickness  shows  at  the  poles  of  its  nu- 
cleus great  quantities  of  a  yellowish 
brown,  granular  pigment,  which  stains 
a  little  with  Sudan  III  (brown  atrophy) 
(Fig.  26).  This  is  one  of  the  little 
known  group  of  lipochrome  pigments 
which  seem  to  arise  everywhere  with 
the  wasting  of  the  cell-body.  The 
formation  of  a  pigmented  ring  about 
the  margin  of  the  cornea  (arcus  senilis) 


Fig.  25. — Superficial  atrophy  in  a 
senile  liver,  exposing  the  vessels  and 
the  framework  of  the  organ. 


Fig.  26. — Brown  atrophy  of  the  heart.  Pig- 
ment-granules at  the  poles  of  the  nuclei  of  the 
wasted  fibres. 


is  another  analogous  process — there,  too,  the  pigment  is  probably  of  the 
group  of  lipochromes.  The  brain  withstands  this  shrinkage  for  a  long  time — 
at  least  so  far  as  its  external  appearance  goes,  though  in  the  end  the  con- 
volutions become  narrower  and  separated  by  wide  sulci  in  which  fluid  col- 
lects. Long  before  this  the  mental  deterioration  may  have  given  an  index 
of  the  disappearance  of  association-tracts  and  the  disabling  of  the  cells. 


ATROPHY  65 

In  the  skeleton,  aside  from  the  general  rarefaction  of  bony  tissue,  con- 
spicuous deformities  may  occur,  such  as  the  gradual  erosion  or  hollowing 
away  of  the  outer  table  of  the  skull  over  the  parietal  regions  until  deep 
grooves  are  formed  over  these  regions — sometimes  so  deep  as  to  penetrate 
the  inner  table  and  leave  the  brain  covered  only  by  a  soft  tissue. 

Mental  Disease. — We  know  very  little  about  the  control  of  metabolism 
from  the  central  nervous  system,  but  every  one  is  familiar  enough  with  the 
lean  and  hungry  looks  of  the  fanatic  and  the  sleek  plumpness  of  such  as 
are  content  and  sleep  "o'nights."  Possibly  it  is  the  constant  activity  of 
the  one  and  the  folding  of  the  hands  of  the  other  that  cause  these  differ- 
ences, but  mere  muscular  activity  seems  not  quite  sufficient  to  account  for 
it  all. 

In  some  mental  diseases  the  influence  of  excitation  or  apathy  is  very 
striking — in  the  manic  depressive  insanity,  or  folie  circulaire,  the  patients 
pass  through  periods  of  the  wildest  maniacal  excitement,  which  alternate 
with  others  of  apathy  and  depression.  In  the  maniacal  periods  they  be- 
come emaciated  in  the  extreme,  only  to  grow  fat  when  they  pass  into  the 
state  of  depression. 

Deranged  Internal  Secretions. — These  are  intimately  related  with  the 
mental  condition,  and  it  is  possible  that  it  is  in  some  way  through  them  that 
the  mental  disturbance  acts  to  affect  metabolism.  Psychic  disturbances 
change  the  secretion  of  the  adrenal  (Cannon),  and  possibly  they  do  the 
same  with  the  thyroid  in  such  a  disease  as  exophthalmic-  goitre.  Wast- 
ing characterizes  that  disease,  while  in  the  absence  of  the  thyroid,  in  de- 
ficiency of  the  hypophysis  or  of  the  ovary  or  testis,  fat  accumulates. 
Evidently  these  organs  have  the  most  intimate  relations  with  the  general 
metabolism,  and  are  in  most  direct  control  of  it,  for  their  integrity  affects 
not  only  the  disposition  that  is  made  of  the  labile  substances,  but  also  the 
growth  of  the  tissues. 

Febrile  Disease  and  Tumors. — In  infections  and  intoxications  accom- 
panied by  fever  the  whole  metabolism  is  so  adjusted  that  the  katabolic 
processes  are  in  excess,  and  it  is  thought  that  in  time  the  tissues  themselves 
are  attacked  and  oxidized.  It  is,  therefore,  not  surprising  that  extreme 
degrees  of  emaciation  are  found  in  cases  of  protracted  infections  with 
fever — the  long-standing  cases  of  pulmonary  and  bone  tuberculosis  or 
typhoid  fever  are  examples. 

But  the  same  appearances  sometimes  accompany  the  ravages  of  certain 
tumors,  even  when  there  is  no  bacterial  infection,  no  ulceration,  and  no 
fever.  Not  all  tumors  can  do  it,  nor  are  the  emaciation  and  evidence  of 
poisoning  dependent  altogether  upon  the  size  of  the  new-growth — instead, 
such  symptoms  as  weakness,  pallor,  loss  of  weight,  lowered  resistance  to 
infection,  and  all  the  other  signs  of  what  has  long  been  called  "cachexia," 
may  be  the  first  indication  of  the  existence  of  any  tumor.  For  this  reason, 
although  one  might  imagine  that  much  food  and  body  substance  would  be 
used  up  or  diverted  to  the  formation  of  a  large  new-growth,  it  is  necessary 
6 


66 


TEXT-BOOK   OF   PATHOLOGY 


to  believe,  when  the  tumor  is  very  small,  that  it  disturbs  metabolism 
through  some  poison  which  it  distils  or  whose  formation  it  favors. 

In  such  emaciated  people  the  fat  from  the  wasted  subcutaneous  tissue 
seems  to  be  lodged  in  the  liver  and  other  internal  organs  whose  cells  are 
unable  to  dispose  of  it. 

Inactivity. — More  local  in  its  effects,  and  scarcely  capable  of  causing 
anything  resembling  the  general  emaciation  which  is  seen  under  the  fore- 
going conditions,  inactivity  may  stop  the  growth  of  the  tissues  of  the  young 
and  lead  to  the  wasting  of  those  of  adults.  In  such  organs  as  muscles  the 
forced  repose  which  follows  the  rigid  splinting  of  an  extremity  or  the  un- 
bending fixation  of  a  joint  is  quickly  followed  by  a  decrease  in  the  size  of 
the  muscle  which  can  be  seen  to  be  the  effect  of  wasting  of  the  separate 


ggiisr--;  - 1 '  n;pfe  j$"  g  •  p .... . 

*    /v      -:••    •  '•••-   ,:   S^^;^     ""*  •-;'.•••    '„    -•"  •    -^.!    ..-,:^^v 


5^S>'-;-*'-^r-  -*t   -J^;  *^.r  -  '  »^<K£^< 


Fig.  27. — Atrophy  of  muscle  with  pigmentation  and  concentration  of  sarcolemma 

nuclei. 

fibres  until,  with  the  loss  of  fibril  after  fibril,  they  are  reduced  to  remnants 
of  thread-like  thinness  or  disappear  entirely  (Fig.  27).  Generally,  the 
sarcolemma  nuclei  remain  and  collect  together  until  they  form  long  beaded 
rows  in  the  collapsed  sheath.  But  they  disappear  also  in  time,  and  their 
place  is  taken  by  a  little  fat  or  by  fibrous  tissue  which  contracts  so  as  to 
pull  the  joint  into  a  fixed  position. 

When  the  inaction  follows  the  cutting  of  the  nerves  or  destruction  of  the 
motor  nerve-cell  in  the  anterior  horn  of  the  spinal  cord  (as  in  the  so-called 
progressive  muscular  atrophy),  the  wasting  is  even  more  rapid  and  com- 
plete. It  seems  that  even  when  the  normal  muscle  is  perfectly  quiescent 
there  are  impulses  reaching  it  constantly  through  the  nerve  which  main- 
tain its  tension  or  tone.  A  kind  of  tremulous,  tuned-up  state  is  kept  up 


ATROPHY 


67 


which  prevents  its  complete  inertness,  and  this  involves  a  certain  metabolic 
activity. 

When  the  nerve  is  cut,  all  these  impulses  cease  and  the  muscle  sags  down 
quite  flaccid — compared  with  the  oxygen  and  carbon  dioxide  exchange  of 
the  intact  resting  muscle  the  metabolism  of  this  paralyzed  muscle  is  almost 
nothing,  and  hence,  no  doubt,  its  rapid  wasting.  Doubtless,  as  was  sug- 
gested before,  the  decreased  blood  supply  to  a  paralyzed  limb  adds  to  the 
tendency  to  waste,  although  it  cannot  be  regarded  as  the  most  important 
factor. 


Fig.  27A. — Atrophy  of  muscle-fibres.     Juvenile  muscular  dystrophy. 


Other  things  than  muscle  waste  in  these  same  circumstances— the  bone, 
the  ligaments,  even  the  skin,  become  atrophic  in  a  paralyzed  extremity. 

We  have  little  experience  with  changes  that  might  occur  in  internal 
organs  deprived  of  their  nerve  supply,  but  they  are  rendered  inactive  in 
other  ways,  and  chiefly,  perhaps,  by  the  occlusion  of  their  ducts  or  by  com- 
pression. Examples  of  the  former  are  discussed  elsewhere  (hydronephrosis, 
pancreatic  duct  occlusion,  etc.). 

The  secretion  accumulates  and  distends  the  duct,  finally  compressing 
the  gland  tissue  so  that  the  nutrition  of  the  cells  is  interfered  with.  The 


68  TEXT-BOOK    OF    PATHOLOGY 

whole  gland  may  be  converted  into  a  thin-walled  sac  containing  the  secre- 
tion under  high  tension.  The  other  factors  which  play  a  part  in  completing 
the  destruction  of  the  tissue  are  no  doubt  the  compression  of  the  blood- 
vessels, which  now  run  in  the  tense  wall  of  the  sac,  and  the  stoppage  of  the 
function  of  the  secreting  cells. 

We  know  little  about  the  actual  mechanism  of  secretion,  but  it  seems  probable  that 
if  the  concentration  of  any  element  of  the  secretion  in  the  sac  becomes  very  high,  it  will 
be  impossible  for  the  cell  to  continue  to  pour  more  of  that  substance  into  the  solution. 
That  part  of  the  cell's  metabolism  will  come  to  a  standstill,  although  it  is  shown  that  if 
the  sac  be  emptied,  secretion  will  begin  again  at  once.  It  is  possibly  somewhat  as  though 
two  salts  were  in  solution.  If  from  these  a  new  salt  can  be  formed  which  alone  of  the 
four  possible  combinations  is  capable  of  escaping  by  osmosis  from  the  solution,  that  salt 
will  be  formed  and  escape  until  all  its  constituents  are  gone.  Not  so  if  it  cannot  be  re- 
moved— it  will  be  formed  until  a  balance  is  reached  and  then  all  interaction  will  cease. 

This  is  different  from  the  cessation  of  metabolism  which  follows  section  of  the  nerve, 
but  it  is  equally  capable  of  exposing  the  cell  to  continued,  if  gradual,  breaking-down 
processes. 

Pressure. — Continuous  pressure,  if  applied  to  sensitive  tissues  firmly 
enough,  may  cut  off  the  entrance  of  blood  completely  so  that  the  tissue 
dies.  This  is  the  fate  of  the  skin  and  underlying  tissues  in  the  formation 
of  bedsores  or  "decubitus  ulcers"  in  bedridden  and  emaciated  persons 
whose  tissues  are  already  poorly  nourished.  Where  their  prominent  bones 
touch  the  bed,  the  skin  is  kept  pressed  bloodless  and  quickly  dies.  But 
if  the  pressure  is  less  violent,  the  cells  of  the  tissue  dwindle  away  slowly. 
This  is  once  more  a  question  of  inadequate  nourishment,  for  not  only  are 
the  blood-vessels  partly  closed,  but  the  cells  themselves  are  compressed, 
so  that  absorption  of  nutriment  and  the  carrying  on  of  their  functions  sink 
to  a  low  ebb. 

This  is  seen  particularly  well  about  a  tumor-nodule  growing  in  such  an 
organ  as  the  liver — all  the  surrounding  cells  and  capillaries  are  flattened 
and  gradually  disappear. 

One  might  expect  the  accumulated  food-stuffs,  such  as  fat-globules,  to  disappear  first, 
and  after  that  the  cell-body  itself,  but  it  appears  that  if  the  cell  is  caught  with  fat- 
globules  in  it,  it  may  be  unable  to  use  them  up  before  it  itself  is  quite  disabled,  perhaps 
by  lack  of  oxygen.  Therefore  the  liver-cells  immediately  next  to  the  advancing  tumor- 
nodule  may  be  loaded  with  fat,  though  most  exposed  to  pressure  (Fig.  28). 

The  effect  of  pressure  in  distorting  and  perverting  the  growth  of  tissue 
is  seen  in  the  misshapen  heads  of  some  French  peasants  and  certain  In- 
dians, in  the  crippled  feet  of  the  Chinese  women,  and  the  constricted  livers 
of  the  fashionable  white  women  of  past  generations.  Numerous  other 
instances  are  found  in  the  compressed  and  distorted  organs,  and  limbs 
found  in  malformed  infants  as  the  result  of  amniotic  adhesions  in  intra- 
uterine  life. 

Another  example  commonly  adduced  is  the  effect  of  aneurysms  upon 
the  tissues  upon  which  they  impinge.  Soft  tissues  yield  in  front  of  them — 


ATROPHY 


69 


hard  tissues,  like  bone,  are  hollowed  out  before  them.  But  I  cannot  be- 
lieve that  this  is  merely  a  pressure  atrophy,  for  one  finds  the  bone  actually 
comminuted,  as  though  with  a  hammer,  and  the  fragments  bathed  in  blood 
and  attacked  by  great  phagocytic  giant-cells  (osteoclasts) .  In  the  ver- 
tebral column  the  centra  of  the  vertebra  are  thus  excavated,  while  the 
inter  vertebral  discs  project  unchanged  (Fig.  29). 

Decreased  blood  supply  is  commonly  held  to  be  a  prominent  cause  of 


Fig.  28. — Compression  of  liver-cells  about  a  metastatic  tumor-nodule. 


atrophy  without  questioning  more  closely  the  nature  of  the  examples  that 
are  always  presented.  Decreased  blood  supply  does  occur  in  regions  or 
organs  which  we  find  in  a  state  of  atrophy,  but  it  must  be  asked  whether 
it  is  cause  or  effect.  The  blood  supply  may  be  decreased  by  pressure  on 
the  supplying  artery,  or  by  contraction  of  the  vessel  or  the  narrowing  of 
its  lumen  by  abnormal  thickening  of  its  wall. 

If  effective  occlusion  of  the  vessels  occurs  rapidly,  the  tissue  dies — if 


70 


TEXT-BOOK   OF   PATHOLOGY 


gradually,   a  collateral  or  roundabout  circulation  is  developed  and  no 
effect  is  produced. 

Probably  such  a  situation  as  is  found  in  the  kidney  in  which  arterio- 
sclerotic  narrowing  of  the  blood-vessels  limits  the  blood  supply  without 
recourse,  could  be  most  satisfactorily  given  as  an  example  of  atrophy  of 


Fig.  29. — Destruction  of  vertebrae  by  aneurysm. 

in  situ. 


Dried  specimen  with  aneurysmal  sac 


the  tissue  from  this  cause,  although,  as  in  the  senile  ovary  or  uterus,  in 
which  the  arteries  become  gradually  obliterated,  the  wasting  of  the  kidney 
might  be  explained  otherwise. 

In  a  kidney  recently  observed  there  were  two  supplying  arteries,  one  of 
which  had  long  been  occluded  by  a  thrombus.  That  half  of  the  kidney 
was  shrunken,  in  sharp  contrast  with  the  other  half. 

Hypertrophy  and  Hyperplasia. — Both  terms  imply  an  increase  in  the 
bulk  of  a  tissue,  but  hypertrophy  is  used  to  indicate  an  enlargement  and 
strengthening  of  an  organ  brought  about  by  increase  in  the  size  of  its  ele- 
ments. Hyperplasia,  on  the  contrary,  is  the  result  of  an  increase  in  the  num- 
ber of  these  elements  or  cells.  Nevertheless  it  is  sometimes  difficult  to 
determine  except  by  exact  enumeration  of  the  cells,  as  in  the  case  of  hyper- 
trophy of  the  heart  wall,  whether  the  increase  in  the  bulk  does  not  represent 
both  processes. 

Hypertrophy  has  often  the  character  of  physiological  growth  in  response 


ATROPHY  71 

to  the  free  functioning  of  an  organ  and  its  consequently  improved  metab- 
olism. One  might  look  in  this  way  upon  the  muscles  of  the  practised 
athlete.  In  a  different  sense  there  is  hypertrophy  in  the  uterine  wall  in 
the  course  of  pregnancy. 

But  from  the  point  of  view  of  the  pathologist,  hypertrophy  is  usually 
the  response  to  some  abnormal  strain,  as  in  the  case  of  the  great  thickening 
of  the  heart  wall  when  its  function  is  made  difficult  by  obstruction  or  by 
whatever  causes  heightening  of  the  blood-pressure.  In  all  these  cases  it 
seems  to  be  a  work  hypertrophy.  No  sharp  distinction  should  be  drawn  be- 
tween hypertrophy  and  hyperplasia,  because  the  same  causes,  usually  the 
demand  for  extra  work,  give  rise  to  the  enlargement  of  organs  through 
the  increase  in  the  number  of  their  constituent  cells.  The  distinction  is  a 
futile  one  at  any  rate,  since,  as  a  rule,  both  are  involved.  A  compensatory 
enlargement  of  the  kidney  when  the  other  is  destroyed  is  due  to  an  enlarge- 
ment of  the  tubules  and  glomeruli,  but  that  is  only  possible  through  an  in- 
crease in  the  number  of  lining  cells. 

Numerous  instances  will  be  given  later  in  which  the  destruction  or  dis- 
abling of  portions  of  the  tissue  of  organs  is  followed  by  a  new  formation  of 
equivalent  tissue  somewhere  else  in  the  organ.  This  is  compensatory 
hyperplasia;  it  is  also  regeneration.  The  organ  in  a  broad  sense  under- 
goes, as  far  as  its  units  go,  a  compensatory  hypertrophy,  and  becomes  once 
more  able  to  perform  its  full  function.  It  is  seen  from  this  that  the  terms 
must  continue  to  be  used  rather  loosely,  and  it  must  be  realized  that  in  at- 
tempting to  understand  the  processes  themselves  we  are  brought  face  to 
face  with  the  problems  of  the  causation  of  tissue  growth  in  general. 

Whether  other  impulses  than  the  demand  for  functional  activity  can  initi- 
ate growth  is  still  unknown.  The  long-standing  dispute  between  the  fol- 
lowers of  Weigert,  who  declared  that  the  new  formation  of  tissue  might 
occur  only  when  injury  or  the  production  of  some  defect  had  disturbed  the 
normal  equilibrium,  and  those  who  maintained  that  external  stimuli  of  the 
most  various  sorts  could  occasion  new  growth  of  tissue,  still  persists.  In 
practically  every  case  arguments  can  be  brought  to  prove  one  side  or  the 
other,  and,  indeed,  it  seems  that  it  is  chiefly  owing  to  our  lack  of  precision  in 
defining  the  nature  of  the  stimuli  that  we  find  difficulty  in  arriving  at  a  con- 
clusion. To  say  that  disturbance  of  equilibrium  is  a  cause  of  new  growth 
is  to  employ  a  vague  expression  which  may  indicate  a  condition  many 
steps  removed  from  that  which  is  actually  at  work.  So,  too,  the  analysis 
of  the  action  of  chemical  or  physical  stimuli  is  generally  incomplete  and 
stops  far  short  of  the  point  at  which  they  actually  influence  the  cell.  When, 
for  example,  we  say  that  an  extensive  haemorrhage  stirs  the  bone-marrow 
cells  to  reproduction  of  red  corpuscles,  it  is  easy  to  say  that  equilibrium  be- 
tween the  blood  and  blood-forming  tissue  is  disturbed,  but  it  is  quite  as 
possible  that  chemical  substances  formed  somewhere  because  of  inadequate 
transportation  of  oxygen  or  disturbances  in  the  relation  of  acids  and  bases 
from  incomplete  removal  of  carbon  dioxide  directly  affect  the  bone-marrow 
and  stimulate  it  to  new  formation  of  cells. 


CHAPTER  VI 
DISTURBANCES  OF  FAT  METABOLISM 

Neutral  fats  and  lipoids.  Their  source,  absorption,  distribution,  and  functions.  Patho- 
logical disturbances. 

IF  WE  attempt  to  discuss  the  disturbances  of  metabolism  in  their  relation 
to  pathology,  we  must  remember  that  the  methods  of  pathological  anatomy 
which  show  alterations  in  the  tissues  consisting  of  destructive  changes  of 
the  cell  structure,  on  the  one  hand,  and  accumulation  of  the  materials 
concerned  in  metabolism,  on  the  other,  must  give  us  only  the  most  in- 
complete and  even  misleading  idea  of  what  is  taking  place.  Many  of  the 
protein  or  albuminous  materials  are  in  solution  and  invisible,  and  even  when 
we  make  them  visible  by  coagulation,  it  is  impossible  to  recognize  them 
definitely.  The  same  thing  is  true  of  the  carbohydrates,  since  glycogen 
is  the  only  form  that  we  can  demonstrate  histologically.  Sometimes  we 
can  see  fats  and  lipoid  substances,  but  rarely  when  they  are  in  the  form  in 
which  they  take  part  in  the  actual  function  of  the  cell — rather  it  is  when 
they  are  stored  and  inactive,  or  when  they  are  thrown  out  of  the  current 
of  the  life  of  the  cell  as  stagnant  material,  that  they  can  be  seen.  Indeed, 
we  are  doubtless  wrong  even  in  trying  to  consider  proteins,  fats,  and  car- 
bohydrates separately,  for  in  their  relation  to  the  processes  of  life  they 
seem  to  combine  into  the  really  important  substances  with  which  we  are 
only  indirectly  acquainted.  Fat  we  know  as  it  appears  in  adipose  tissue 
or  in  globules  in  other  cells,  but  fat  in  what  may  be  a  lipoid  proteid  com- 
bination as  it  exists  invisible  in  the  cell  and  recoverable  from  it  only  after 
the  cell  is  reduced  to  debris  by  digestion,  we  scarcely  know,  although  it  is 
probably  in  that  form  that  it  is  most  important. 

It  seems  that  in  these  combinations,  varied  as  they  are,  we  may  find 
the  agents  of  many  of  the  extraordinarily  efficient  chemical  processes  that 
go  on  in  the  body.  This  should  be  the  ground  for  discussion  in  pathology. 
It  should  form  one  of  the  principal  chapters,  if  we  only  knew  enough  to 
bring  it  into  the  field;  on  the  other  hand,  it  seems  hardly  worth  while  to 
describe  in  detail  the  various  places  where  abnormal  accumulations  of  some 
of  the  inert  separated  constituents  of  these  specialized  expert  bodies  are 
laid  up  so  that  we  can  see  them. 

If  we  could  do  more  than  guess  at  the  nature  of  most  of  the  disturbances 
that  wreck  the  machinery  and  heap  up  the  raw  material  or  the  slag,  it 
would  be  something,  but  even  that  is  commonly  obscure.  Nevertheless, 
we  must  tell  what  we  can  with  our  surmises  about  the  true  inwardness  of 
the  actions  which  have  left  these  traces. 

72 


FATS   AND    LIPOID    SUBSTANCES  73 

Of  all  these  substances,  as  long  as  we  have  been  in  the  habit  of  separating 
them  into  three  great  classes  it  has  been  the  custom  to  regard  the  proteins 
as  the  most  important,  the  real  basis  of  life,  the  substance  of  protoplasm, 
while  the  fats  and  lipoids  or  fat-like  materials  were  looked  upon  as  fuel  and 
as  useful  in  other  vaguely  understood  ways,  possibly  as  insulating  materials 
in  the  nervous  system  or  even  as  padding  underneath  the  skin  to  keep  the 
body  warm.  Carbohydrates  seemed  essentially  fuel  for  rapid  burning; 
now,  however,  in  Ivar  Bang's  phrase,  the  lipoids  are  beginning  to  be  recog- 
nized as  actors  of  extreme  importance,  with  roles  of  unsuspected  delicacy 
and  complexity.  Even  yet  the  carbohydrates  have  not  met  with  what 
may  be  a  deserved  recognition,  but  it  is  becoming  clearer  that  it  is  the 
ensemble  action,  and  not  the  part  played  by  the  isolated  fragments, 
which  we  salt  out  or  extract  with  ether,  that  brings  about  the  wonders  of 
life. 

FATS  AND  LIPOID  SUBSTANCES 

The  fat-like  bodies  soluble  in  organic  solvents,  such  as  ether,  alcohol,  chloroform,  or 
benzol,  are  denned  by  Bang  as  lipoids.  It  is  perhaps  common,  however,  to  speak  of  the 
neutral  fats  as  fats,  and  of  the  rest  as  lipoids,  since  that  must  have  been  the  origin  of  the 
word. 

Of  this  great  group  there  are  almost  innumerable  examples,  and  the  series  may  per- 
haps be  extended  to  forms  as  yet  unsuspected,  but  in  human  physiology  and  pathology 
comparatively  few  concern  us. 

These  are  as  follows,  according  to  Bang: 

1.  Fats — lipoids  of  the  aliphatic  series  containing- only  C,  H,  and  0,  without  N  or 

P. 

2.  Cholesterines — lipoids  of  the  aromatic  series  containing  only  C,  H,  and  O, 

without  N  or  P. 

3.  Phosphatides — lipoids  containing  N  and  P  in  addition  to  C,  H,  and  O. 

4.  Cerebrosides — lipoids  containing  N  but  not  P,  together  with  C,  H,  and  O. 

5.  Other  important  but  little  understood  lipoid  substances,  which  include  the 

lipochromes. 

The  details  of  what  is  known  chemically  of  these  substances  must  be  read  in  such  works 
as  those  of  Leathes,  Bang,  Jolles,  and  others,  and  only  the  barest  outline  can  be  given 
here. 

Fats. — These,  which  form  the  great  bulk  of  the  subcutaneous  and  other  depot  fat, 
are  esters  of  glycerin  with  fatty  acids.  For  the  most  part  those  which  occur  in  the  animal 
body  are  triglycerides  of  stearic,  palmitic,  and  oleic  acids,  but  in  certain  secretions, 
as  in  milk,  butyric,  caproic,  and  other  fatty  acids  occur. 

A  typical  formula  is  as  follows: 


CH2— O— OC— C17H33 
H  — O— OC— C17H33 
2— O— OC— Ci7H33 


d 

CH2 


which  is  triolein. 

The  difference  in  their  melting-points  and  other  characters,  and  in  the  proportions  in 
which  they  occur  in  the  fat  of  different  animals,  are  all  well  known,  and  one  realizes  that 
if  sheep-fat  is  more  solid  at  room  temperature  than  human  or  dog  fat,  it  is  because  it 
contains  more  tristearin  and  tripalmitin  and  less  triolein. 

Such  fats  may  be  saponified  or  broken  up  by  the  action  of  alkalies  into  glycerol  and 


74  TEXT-BOOK   OF   PATHOLOGY 

soaps,  or  combinations  of  the  alkalies  with  the  fatty  acids.  In  another  way  they  may 
be  separated  into  their  constituents,  glycerol  and  fatty  acid,  by  the  action  of  a  ferment 
(lipase),  and  this  action  is  reversible. 

The  cholesterines  occur  in  wide  distribution  throughout  the  body  as  constant  con- 
stituents of  the  cells  and  body  fluid,  either  free  or  in  combination  with  fatty  acids  (cho- 
lesterine  esters),  often  in  solution,  but  sometimes,  as  in  the  adrenal  cortex,  in  the  form  of 
globules.  Crystals  of  free  cholesterine  are  found  under  pathological  conditions.  The 
formula  for  the  cholesterine  found  in  the  human  body  is  given  as  C27H46O.  It  is  a  com- 
plex terpene,  bearing  no  relation  to  fats,  carbohydrates,  or  proteins,  but  consisting 
probably  of  a  saturated  cyclic  system  with  the  character  of  a  secondary  alcohol,  since  it 
can  form  ketones,  and  also  with  fatty  acids,  esters.  It  crystallizes  in  flat,  rhombic 
plates  which  often  show  broken  or  reentrant  angles. 

The  phosphatides  are  of  the  very  greatest  biological  importance,  and  enter  extensively 
into  the  structure  and  function  of  many  organs.  They  fall  into  the  following  groups 
(Bang,  Thudichum,  Aschoff): 

1.  Monoaminomonophosphatides  (lecithines,  kephaline)  (glycerophosphoric  acid 

esters  of  two  fatty  acids  and  choline). 

2.  Monoaminodiphosphatides  (cuorine,  etc.). 

3.  Triaminodiphosphatides  (sahidine,  etc.). 

All  of  these  contain  unsaturated  acids.  Of  the  phosphatides  containing  saturated  fatty 
acids  we  have: 

4.  Diaminomonophosphatides  (sphingomyeline,  etc.). 

5.  Triaminomonophosphatides. 

Of  these  substances,  the  Imowledge  is  essentially  vague,  since  practically  none  of  them 
can  be  obtained  in  a  pure  state,  partly  on  account  of  their  labile  character.  The  best 
known  are  probably  the  lecithines  and  kephalines,  although  they  too  are  enveloped  in  a 
haze  of  uncertainty,  and  one  cannot  say  whether  these  fragile  substances  which  are 
strained  out  of  the  brain  and  other  organs  ever  existed  there  in  the  form  in  which  they 
come  to  light. 

Ledthine,  which  forms  sticky,  waxy  white  or  orange  masses,  is  given  the  formula: 

OH 

CH20—  PO—  O—  C2H4 


CH2OR 

That  is  a  glycerophosphoric  acid  ester  of  two  fatty  acid  radicles  (one  of  which  is  unsat- 
urated) hi  combination  with  choline.  It  is  soluble  in  alcohol  and  other  lipoid  solvents 
except  cold  acetone;  it  unites  with  acids  and  bases,  with  carbohydrates  and  with  pro- 
teins (vitelline,  lecithoalbumin). 

Kephaline  is  a  resin-like,  crumbling,  hygroscopic  substance,  soluble  in  ether,  etc.,  but 
not  in  alcohol  or  acetone.  It  is  the  chief  phosphatide  of  the  brain,  and  is  otherwise 
widely  distributed.  Bang  gives  the  following  probable  constitution: 


OH 

CH20— PO— O— C2H4 
CHO— Ci8H35O     CH3— N 


CH2O— CisHsiO      OH 

which  is  a  glycerophosphoric  ester  of  stearic  and  linoleic  acids  with  a  monomethyl- 
choline. 


METABOLISM   OF   FATS  75 

The  Cerebrosides. — These  are  glucosides,  and  being  disintegrated,  yield  a  sugar,  galac- 
tose,  fatty  acids,  and  a  nitrogenous  substance,  but  no  phosphoric  acid.  They  occur  in 
the  white  substance  of  the  brain,  the  blood,  spermatozoa,  etc.  The  most  important 
are  perhaps  the  phrenosin  and  kerasin  of  Thudichum. 

The  other  little  understood  lipoid  substances,  which  include  the  pigmented  fatty 
granules  found  in  wasting  cells  (lipochromes),  and  probably  various  substances  con- 
cerned in  immunity,  remain  to  be  investigated. 

It  has  been  said  that  these  substances  are  sometimes  recognizable  as 
such  (neutral  fats,  cholesterine  esters,  etc.),  but  most  of  them  are  extracted 
from  the  organs  by  the  aid  of  various  solvents,  and  freed  from  impurities 
by  different  chemical  manoeuvres.  It  is,  therefore,  hard  to  feel  sure  that 
in  the  living  organs  they  exist  in  the  form  in  which  they  are  finally  studied 
and  not  rather  in  some  easily  disturbed  combination  with  proteins  or  other 
substances.  Some  of  them  are  readily  dissolved  out  of  the  cells,  in  which 
they  can  be  seen  as  globules  of  pure  fat;  others  appear  to  be  loosely  ad- 
herent or  adsorbed  in  fine,  invisible  layers  about  other  substances  in  the 
cells.  They  can  be  extracted  too  without  great  difficulty,  although  they 
cannot  be  seen  with  the  microscope  in  the  cell.  Still  others  are  so  firmly 
held  that  they  seem  to  be  in  chemical  combination  with  the  materials  of 
the  cell,  and  these,  naturally  invisible  in  the  cell,  can  be  extracted  only 
after  the  tissue  is  digested  or  hydrolyzed  so  that  its  chemical  compounds 
are  disintegrated.  That  there  is  constant  change  in  their  relations  is  in- 
dicated by  the  way  in  which  the  simpler  fats  undergo  lipolytic  decomposi- 
tion into  glycerin  and  fatty  acids,  followed  by  the  formation  of  soaps, 
their  decomposition,  and  the  reconstruction  of  fats. 

As  Aschoff  says,  the  pathological  anatomist  is  most  interested  in  determin- 
ing in  what  form  these  lipoid  substances  become  morphologically  visible,  and 
by  what  means  their  specific  composition  can  be  recognized.  The  chemist,  on 
the  contrary,  must  be  content  with  analyzing  the  lipoids  which  remain  to  him 
after  his  tortuous  methods  of  extraction,  separated  thus  by  a  gulf  from  their 
original  relations,  and  perhaps  even  entirely  changed  in  their  characters. 
It  is  the  biologist  who  must  try  to  combine  these  two  sets  of  information 
and  attempt  to  learn  the  functional  role  which  the  lipoids  play  in  the  body. 

The  anatomist  applies  with  success  certain  methods  to  the  study  of  fats 
in  the  tissues.  There  are  stains  which  color  all  lipoids,  such  as  sudan, 
others  which  stain  neutral  fats  red,  phosphatides  blue,  such  as  Nile-blue 
sulphate;  osmic  acid  is  blackened  by  fats  of  unsaturated  acids;  cholesterine 
esters  are  doubly  refractive.  Phosphatides  and  soaps  form  bizarre  myeline 
figures,  and  so  on.  Great  ingenuity  has  been  applied  to  the  recognition 
and  distinction  of  fatty  bodies  by  these  methods  (which  must  be  read  in  the 
works  of  Aschoff,  Kawamura,  Verse,  and  others),  but  they  are  still  very 
imperfect  and  unreliable,  except  in  the  simplest  situations. 

SOURCE,  ABSORPTION,  TRANSFORMATION,  AND  DEPOSITION  OF  FATS 

Since  similar  substances  occur  in  the  tissues  of  other  animals,  it  is  probable 
that  a  great  source  of  the  fats  in  the  human  body  is  to  be  found  in  animal 


76  TEXT-BOOK   OF   PATHOLOGY 

food.  Some  are  derived  from  vegetable  foods,  and  others  are  produced  in 
the  body  from  carbohydrates,  and  since  carbohydrates  can  be  formed 
from  the  decomposition  products  (amino-acids)  of  proteins,  no  doubt  fats 
are  thus  indirectly  derived  from  proteins.  Cholesterine  comes  to  us  in 
animal  food — how  it  is  produced  in  the  bodies  of  herbivorous  animals  is 
not  perfectly  clear,  but  it  probably  arises  from  the  phytosterines  which  are 
found  in  plants. 

Taken  into  the  intestine,  the  absorption  of  fats  occurs  by  the  action  of 
lipolytic  ferments,  which  produce  glycerin  and  soluble  soaps,  which  are 
reconstituted  into  fats  in  the  intestinal  wall,  or  by  direct  passage  of  un- 
changed fats,  perhaps  with  the  aid  of  the  bile.  Whether  in  the  reconstitu- 
tion  in  the  intestinal  wall  the  foreign  fats  are  remoulded  into  human  fats 
is  uncertain.  Undoubtedly,  some  foreign  fats  go  through  unchanged  to 
the  tissues,  but  since  the  fats  of  animals  are  characteristic,  the  remoulding 
must  take  place  somewhere,  possibly  in  the  course  of  numerous  decomposi- 
tions and  reconstitutions  which  accompany  the  wanderings  of  fat  in  the 
body.  How  cholesterine  and  its  esters  enter  is  not  investigated.  Choles- 
terine fed  to  rabbits  is  lodged  in  the  tissues  largely  in  the  form  of  choles- 
terine esters,  and  a  great  deal  of  work  has  been  done  upon  the  distribution 
of  such  esters.  They  are  stored  in  the  cortex  of  the  adrenal,  the  corpus 
luteum,  etc.,  and  are  found  abundantly  present  in  the  endothelial  cells  of 
the  spleen,  liver,  etc.  Aschoff  and  Landau  assume  that  there  is  thus  a 
"reticulo-endothelial  apparatus"  controlling  their  intermediary  metab- 
olism. The  advent  and  transformation  of  phosphatides  and  cerebrosides 
are  even  more  obscure. 

Distribution  in  the  Body. — Neutral  fats  are,  as  every  one  knows,  lodged, 
sometimes  in  enormous  quantities,  in  what  are  roughly  known  as  fat  de- 
pots, among  which  the  subcutaneous  and  intermuscular  tissues,  the  bone- 
marrow,  the  mesentery,  omentum,  and  retroperitoneal  tissues,  the  epi- 
cardium,  the  tissue  about  the  kidneys,  and  the  tissues  of  the  orbit  furnish 
examples.  In  very  obese  persons  the  fat,  after  filling  these  places  to  their 
utmost,  seems  to  overflow  into  the  most  unexpected  localities — adipose 
tissue  extends  through  the  wall  of  the  heart  and  appears  under  the  endo- 
cardium; it  pushes  apart  the  lobules  of  the  pancreas,  and  even  spreads 
round  to  the  free  surface  of  the  intestines.  In  every  case  the  fat  is  inclosed 
in  cells.  In  the  infant  one  may  readily  observe  that  the  adipose  tissue 
falls  into  lobules  which  are  easily  separated.  These  are  seen  to  be  sharply 
outlined,  gland-like  structures,  provided  with  an  extremely  rich  capillary 
circulation,  and  composed  of  polygonal  cells  with  very  granular  protoplasm 
which  contains  only  the  beginnings  of  the  accumulation  of  oil-globules 
which  will  ultimately  distend  them  (Fig.  30).  Such  lobules  are  quite  dis- 
tinct from  the  surrounding  loose  connective  tissue,  which  contains  no  fat, 
and  are  very  conspicuous  in  any  section  which  passes  through  adrenal  or 
thyroid  since  a  comparison  with  those  glands  is  at  once  suggested.  They 
have  even  been  described  by  Pende  as  organs  of  internal  secretion,  and 
perhaps  the  specificity  of  the  adipose  tissue  is  almost  sufficient  to  justify 


DISTRIBUTION    OF    FAT  77 

him  in  such  an  idea.  In  later  life  they  disappear  because  so  much  fat 
gathers  in  their  cells  that  the  protoplasm  becomes  a  mere  film  about  the 
great  oil-globule — the  separate  lobules  of  this  tissue  swell  until  they  touch 
one  another,  the  intervening  fibrous  tissue  is  lost  to  view,  and  we  seem  to 
have  a  homogeneous  adipose  tissue. 

It  would  be  interesting  to  be  able  to  show  that  all  adipose  tissue  is  of  this 
nature,  but  probably  in  obesity  fat  accumulates  in  other  connective-tissue 
cells  which  have  no  specific  relation  to  its  metabolism. 


Fig.  30. — Adipose  tissue  of  foetus.     Lobule  of  specialized  connective  tissue  in  which 

fat  accumulates. 

Neutral  fat  occurs  in  the  blood  plasma  and  in  the  lymph  and  chyle,  and 
thus  indicates  the  mode  of  transport  from  one  part  of  the  body  to  another, 
and  from  the  digestive  tract  to  the  tissues.  It  is  found  in  the  cells  of  many 
parenchymatous  organs,  such  as  the  liver,  adrenals,  and  others,  where  it 
may  be  merely  stored,  or  where  its  presence  may  be  explained  in  other 
ways  which  shall  be  discussed  later. 


78  TEXT-BOOK   OF   PATHOLOGY 

There  seems  to  be  little  evidence  to  show  that  such  neutral  fats,  aside 
from  being  foods  and  the  source  of  energy,  play  any  very  complex  part  in 
the  life  of  the  cell.  On  the  contrary,  although  we  do  not  know  exactly 
how  they  are  distributed  in  the  tissues,  we  cannot  escape  the  impression 
that  the  phosphatides,  the  cholesterine  compounds,  and  cerebrosides  are 
absolutely  essential  elements  in  most  of  the  important  functions  of  the 
cells.  Each  new  investigation  reveals  their  silent  and  unsuspected  par- 
ticipation in  the  most  fundamental  processes. 

It  is  known  that  even  when  the  microscope,  aided  by  the  most  effective 
staining  methods,  reveals  no  trace  of  fat  in  the  tissues,  a  large  quantity 
can  be  extracted  by  chemical  methods.  A  perfectly  normal  human  kidney 
which  shows  no  recognizable  fat  yields  10  to  20  per  cent,  of  its  weight  upon 
digestion  and  extraction.  This  fat  must  have  been  in  some  extremely 
fine  state  of  division,  or  else  in  chemical  combination,  such  that  it  failed  to 
give  the  usual  staining  reactions. 

None  of  the  hypotheses  about  this  disposition  of  lipoids  in  the  cell  has 
up  to  now  been  satisfactorily  proved,  and  they  are  the  subject  of  much 
dispute.  It  is  Overton's  idea  that  each  cell  is  bounded  by  a  very  thin 
lipoid  membrane  which  controls  the  entrance  and  exit  of  the  substances 
which  reach  the  cell.  According  to  this  idea,  drugs  like  narcotics,  which 
are  usually  soluble  in  fats,  gain  easy  access  to  the  cell,  although  it  does  not 
appear  quite  easy  to  understand  how  these  substances  leave  the  lipoid 
membrane  to  enter  the  watery  cell-body.  On  the  other  hand,  the  passage 
of  salts  in  and  out  becomes  difficult,  and  the  theory  is  forced  to  resort  to 
the  vital  activity  of  the  cell  to  explain  these  things.  Nevertheless,  the  idea 
of  a  lipoid  enveloping  membrane  for  cell  and  nucleus  is  very  generally  held. 

Within  the  cell  similar  lipoid  membranes  are  supposed  to  line  vacuoles 
and  perhaps  to  cover  some  of  the  specific  granules  —  at  any  rate,  there 
is  much  to  show  that  the  fine  globules  of  fat  which  appear  in  the  cell  pro- 
toplasm do  so  in  relation  with  mitochondria,  or,  as  Benda  claims,  rather 
with  the  vegetative  granules,  the  plasmosomes.  These  granules  accumu- 
lating fat  about  them  finally  take  on  the  form  of  globules.  But  even  with 
these  explanations  it  is  evident  that  there  must  be  much  lipoid  material 
in  the  cell  in  an  invisible  form. 

FUNCTIONS  OF  FATS  AND  LIPOIDS 

The  most  obvious  and  best  known  function  of  the  fats  lies  in  their  acting 
as  food-stuffs.  In  their  oxidation  to  set  free  energy  in  the  form  of  heat  or 
work,  they  require  more  oxygen  than  do  carbohydrates,  so  that  the  res- 


piratory  quotient  or  ratio,  —  ~A  is  about  .795.     They  form,  of  course,  since 

they  can  be  conveniently  stored,  the  ideal  material  for  the  accumulation  of 
a  source  of  energy.  Nevertheless,  we  must  suppose  that  they  also  take 
part  in  aiding  the  growth  of  the  tissues  through  furnishing  material  for 
their  constructive  processes. 

If  it  be  true  that  they  form  lipoid  membranes  about  each  cell,  each  nu- 


FUNCTIONS   OF   FATS   AND    LIPOIDS  79 

cleus,  and  each  vacuole,  it  must  be  agreed  that  they  are  primarily  instru- 
mental in  regulating  the  assimilation  of  the  cell  and  in  permitting  it  to 
control  in  a  way  the  substances  which  present  themselves  for  absorption. 

The  part  played  by  lipoid  substances,  especially  the  phosphatides  and 
cerebrosides,  in  the  construction  of  the  nervous  system,  must  be  of  prime 
importance,  although  we  approach  its  contemplation  so  awkwardly  by 
extracting  them  from  the  ground-up  brain.  From  their  arrangement  in 
the  myeline  sheaths  of  the  nerve-fibres  it  would  appear  that  they  may  act 
as  insulating  substances  which  insure  the  passage  of  the  nervous  impulse 
to  the  correct  end-organ;  in  other  words,  that  they  serve  a  purpose  analo- 
gous to  that  of  the  rubber  and  shellac  in  a  complex  electric  cable,  or  even 
in  the  brain,  to  that  of  the  more  elaborate  insulation  in  the  interior  of 
the  dynamo. 

In  their  relation  to  enzyme  action  the  neutral  fats  are  played  upon  by 
lipases  which  occur  everywhere  in  the  organs  and  fluids  of  the  body,  as 
well  as  in  the  digestive  juices.  Anti-lipases  which  inhibit  this  reversible 
action  exist  also.  The  lipases  which  must  exist  to  control  the  decomposi- 
tion of  cholesterine  esters  and  of  the  phosphatides  (lecithinase,  choles- 
terase,  etc.)  are  not  yet  even  certainly  demonstrated.  Bang  objects  that 
experiments  carried  out  to  show  that  such  lipoid  substances  may  influence 
the  action  of  other  ferments  are  inconclusive,  but  Jobling  has  shown  that 
the  decomposition  products  of  some  fats — unsaturated  fatty  acids  and 
their  soaps — have  the  most  decisive  inhibiting  action  upon  proteolytic 
ferments,  their  power  being  in  a  sense  porportional  to  the  degree  of  un- 
saturation  of  the  fatty  acid.  So  universally  is  it  true  that  such  unsatu- 
rated fatty  acids  can  impede  the  action  of  proteolytic  ferments  that  many 
pathological  conditions  (such  as  the  persistence  of  caseous  tuberculous 
material  in  its  solid  form)  can  be  shown  to  be  due  to  their  presence.  If 
they  are  rendered  impotent  by  saturation  of  their  unsaturated  group  with 
iodine,  the  proteolysis  goes  on  rapidly  and  the  caseous  tubercle  or  gumma 
rapidly  softens. 

In  the  complex  process  which  occurs  in  the  clotting  of  blood  Howell 
has  shown  that  the  thromboplastic  substance  derived  from  the  tissue  is  a 
lipoid,  kephaline.  It  has  been  shown  that  certain  lipoid  substances, 
especially  cholesterine,  can  act  as  inhibiting  or  neutralizing  agents  toward 
such  hsemolytic  poisons  as  saponin,  cobra  poison,  etc.,  through  forming 
with  them  an  innocuous  compound.  Hanes  showed  that  the  relative 
immunity  of  puppies  from  chloroform  poisoning  is  due  to  the  large  amount 
of  cholesterin  esters  in  their  tissues.  When  artificially  introduced  into  the 
tissues  of  adult  animals  a  similar  protection  is  conferred.  By  some  (Takaki) 
it  was  thought  that  lipoids  of  the  nervous  system,  phrenosin,  cerebron,  etc., 
could  neutralize  the  tetanus  toxin,  but  this  is  contradicted  by  others  and 
is  uncertain.  In  the  so-called  "Wassermann  reaction"  lipoid  substances 
act  in  a  somewhat  similar  way  to  combine  with  or  absorb  the  complement 
and  withdraw  it  from  combination  with  the  blood-corpuscles. 

Our  knowledge  in  this  direction  is  very  slight;  nevertheless  it  is  enough 


80  TEXT-BOOK   OF    PATHOLOGY 

to  suggest  the  possibility  that  lipoid  substances  may  sometimes  accumulate 
in  an  organ  for  the  protection  of  the  cells  of  that  organ  from  toxic  injury. 
On  the  other  hand,  lipoids  may  act  as  toxic  substances  or  as  activators  of 
toxins.  Of  these,  the  toxic  ones  are  foreign  lipoids,  such  as  may  be  ex- 
tracted from  bacteria.  The  fats  from  the  tubercle  bacillus  may  produce 
lesions  somewhat  resembling  those  caused  by  the  organisms  themselves. 
It  is  in  connection  with  hsemolytic  poisons,  such  as  cobra  venom,  that 
lipoids  (lecithin)  are  found  to  behave  as  activators.  Regarded  at  first  as 
representing  the  complement  according  to  Ehrlich's  theory  (Kyes) ,  it  now 
seems  more  probable  that  the  lipoids  may  aid  in  transferring  the  poison  to 
the  cell,  since  the  "lecithid"  is  apparently  only  a  solution  of  the  venom  in 
lecithin  (Bang).  The  direct  production  of  immunity  against  lipoid  sub- 
stances used  as  antigens  has  given  some  vague  results,  but  the  matter  still 
remains  to  be  investigated. 

Undoubtedly  the  lipoids  fill  an  important  position  in  many  ways,  in  re- 
lation to  the  processes  of  immunity,  but  for  the  further  discussion  of  the 
matter  reference  must  be  made  to  works  upon  that  subject  (Jobling). 

Cholesterine  compounds  are  known  to  exist  in  the  circulating  blood  and 
in  the  adrenal  cortex,  as  well  as  in  other  tissues.  What  must  be  a  significant 
index  of  their  importance  is  found  in  the  course  of  pregnancy,  when  there 
comes  a  gradual  but  great  increase  in  the  quantity  found  in  the  blood,  a 
great  storing  in  the  corpora  lutea,  and,  with  the  end  of  pregnancy  and  be- 
ginning of  lactation,  an  outpouring  of  cholesterine  esters  with  the  first 
milk.  After  that  the  proportion  decreases  in  the  milk,  and  in  the  blood 
sinks  back  to  normal.  Why  this  should  be  is  not  known,  but  the  flooding 
with  cholesterine  esters  seems  to  have  a  protective  influence  of  some  kind, 
since  under  those  circumstances  animals  will  survive  the  loss  of  the  adrenal 
gland  far  longer  than  non-pregnant  controls,  and,  indeed,  the  injection  of 
cholesterine  esters  seems  to  have  the  same  influence  (Stewart). 

PATHOLOGICAL  DISTURBANCES  OF  FAT 

So  far  we  have  attempted  to  review  the  normal  relations  of  the  lipoid  sub- 
stances in  the  body,  and  finding  our  knowledge  so  woefully  incomplete 
there,  we  turn  not  very  hopefully  to  their  study  under  pathological  con- 
ditions. 

Obesity. — From  what  was  said  of  the  normal  use  of  fats  as  food  we  may 
judge  that  a  certain  balance  is  maintained  in  the  storehouse  of  the  body. 
Nevertheless,  the  consumption  of  a  great  excess,  especially  an  excess  of 
fats  and  oils  and  of  carbohydrates,  tends,  in  persons  who  lead  an  inactive, 
sedentary  life,  to  cause  the  accumulation  of  excessive  fat  in  all  possible 
depots  in  the  body.  Even  the  secreting  cells  of  parenchymatous  organs, 
such  as  the  liver,  become  somewhat  richer  in  fat  than  normal,  although  it 
is  by  no  means  in  obese  people  that  one  finds  the  great  collection  of  fat  in 
the  liver-cells.  The  storing-up  of  fat  can  be  prevented  and  the  fat  made 
to  disappear  by  active  exercise,  massage,  etc.,  or  even  by  hot  baths,  which 
seem  to  hasten  its  consumption.  But  every  one  has  noticed  that  the 


PATHOLOGICAL   DISTURBANCES   OF   FAT  81 

obesity  which  comes  from  mere  sedentary  habits  and  overeating  is  in  most 
persons  a  mild  kind  of  disability;  other  people,  even  with  the  greatest 
abuse  of  these  things,  remain  quite  thin,  while  there  are  certain  unfortu- 
nates who,  in  spite  of  efforts  to  limit  their  diet  strictly  and  to  take  abundant 
exercise,  grow  enormously  fat.  It  seems  possible  that  in  these  cases  there 
may  exist  some  defect  in  such  organs  of  internal  secretion  as  the  thyroid 
or  the  hypophysis,  whose  secretion  appears  to  enhance  the  activity  of 
metabolism  in  general.  In  known  cases  of  hypophysis  defect  in  young 
persons  great  obesity  arises  with  retardation  of  sexual  development,  and  in 
cases  in  which  the  thyroid  has  been  destroyed  a  similar,  if  less  extreme, 
obesity  may  arise. 

Diabetes. — In  pancreatic  diabetes  another  disturbance  of  internal 
secretion  in  which  the  consumption  of  carbohydrates  is  made  difficult,  an 
abnormal^  violent  attack  is  made  upon  the  fats,  which  are  turned  into  the 
blood-stream  for  transportation  in  such  a  way  as  to  give  the  serum  a  milky 
appearance  (diabetic  lipaemia).  The  irregular  consumption  of  these  fats 
leads  to  the  production  of  the  poisonous  acetone  bodies.  (See  Diabetes.) 

Degeneration  of  Nerves. — It  has  been  pointed  out  that  lipoid  bodies 
form  the  coatings  of  nerve-fibres,  as' though  to  insulate  the  axis-cylinders 
within  these  myeline  sheaths.  When  the  nerve  dies  through  being  cut 
through  or  from  the  destruction  of  its  cell-body,  the  lipoids  of  the  myeline 
sheath  about  the  dead  axis-cylinder  disintegrate,  leaving  globules  of  the 
decomposition  products  which  now  blacken  with  osmic  acid  in  a  way  foreign 
to  the  myeline  itself  (Figs.  31 A  and  31B).  Saponine  attacks  and  combines 
with  the  lipoid  sheath  of  the  nerve  and  causes  paralysis.  Many  other  sub- 
stances, most  of  which  have  certain  affinities  for  lipoid  materials,  cause  in- 
juries to  the  nerves,  followed  by  inflammation  or  by  paralysis.  Lead  palsy, 
arsenical  and  alcoholic  neuritis,  the  neuritis  occurring  in  the  intoxication 
associated  with  pregnancy  and  in  diabetes,  are  examples  of  this  vague  con- 
nection. Beriberi,  a  form  of  multiple  neuritis,  is  supposed  to  result  from 
the  lack  of  a  lipoid  constituent  belonging  to  the  covering  of  the  rice  grain, 
since  it  occurs  in  persons  fed  on  polished  rice.  This  is  not  yet  satisfactorily 
proven,  but  all  these  things  point  to  the  possibility  of  a  common  character 
in  the  affection  of  nerves  due  to  disturbances  in  their  medullary  sheaths. 

Anaemias. — The  same  vagueness  and  uncertainty  prevail  with  regard  to 
the  part  played  by  the  lipoids  in  the  production  of  some  forms  of  anaemia. 
Faust  and  Tallquist  thought  that  the  pernicious  type  of  anaemia  caused  by 
the  bothriocephalus  was  due  to  a  lipoid  which  they  later  stated  to  be  oleic 
acid,  but  this  is  scarcely  probable.  On  the  other  hand,  many  of  the  toxic 
materials  which  produce  anaemia,  such  as  benzole,  are  solvents  of  lipoids  or 
soluble  in  them,  and  it  may  be  through  this  relation  that  the  lipoid  constitu- 
ents of  the  red  cells  are  attacked.  The  whole  question  of  haemolysis  has 
intimate  dependence  upon  the  lipoid  content  of  the  cells. 

Abnormal  Accumulations  of  Fats  and  Lipoids  in  Organ  Cells.— One  type 
of  evidence  as  to  the  role  of  the  lipoids  in  pathological  conditions  which  has 
scarcely  been  touched  upon  is  found  in  the  anatomical  recognition  of  ab- 
7 


82 


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normal  accumulations  of  these  bodies  in  the  cells  of  the  organs.  This, 
which  has  always  formed  the  chief  interest  of  pathological  anatomists,  is, 
after  all,  at  most  only  an  indication  of  the  disability  or  injury  of  those  cells, 
and  has  relatively  little  bearing  upon  those  functions  of  the  lipoids  which 
are  beginning  to  show  themselves  as  of  fundamental  importance. 

Both  neutral  fats  and  globules  or  granules  of  other  lipoids,  especially  the 


Fig.  31  A. — Normal  nerve.     Osmic  acid  (Marchi)  tinges  the  myeline  sheaths  gray. 


0S"+'S5? 


Fig.  3 IB. — Degenerated  nerve  (Marchi).     Lipoid  medullary  sheath  reduced  to  fat-like 
globules  which  stain  black  with  osmic  acid. 

cholesterine  esters,  and  probably  also  the  phosphatides,  may  appear  in  ab- 
normal situations.  Since  they  are  normally  present  in  some  organs,  we 
recognize  their  abnormal  character  by  their  unwonted  situation  or  some- 
times by  their  quantity. 

The  source  of  these  fats  has  long  been  the  subject  of  dispute,  the  main 


PATHOLOGICAL   DISTURBANCES    OF   FAT 


83 


question  being  whether  they  are  derived  from  the  substance  of  the  cell  in 
which  they  are  found,  or  transported  thither  from  some  depot  of  fat  or 
other  source.  This  problem  has  lost  much  of  its  interest,  since  we  have 
learned  that  much  of  the  fat  is  transported,  while  some  is  made  visible  (fat 
phanerosis)  by  being  liberated  from  its  invisible  combinations  in  the  cell. 
The  old  question  as  to  the  production  of  the  fat-globules  at  the  expense  of 
the  protoplasm  of  the  cell  is  now  hardly  discussed  in  that  form. 

A  few  examples  of  such  fat  accumulation  may  be  mentioned  before  con- 
sidering further  the  nature  of  the  process. 

In  the  heart  one  may  find,  in  cases  of  long-standing  anemia,  or  chronic 
infection,  or  intoxication,  or  in  dis- 
turbances of  the  coronary  circula- 
tion, especially  in  the  inner  layers 
of  its  muscle,  a  yellowish  pallor 
which,  on  close  inspection,  is  found 
to  be  due  to  innumerable  minute 
streaks  and  patches  of  opaque  yel- 
low which  shine  through  the  endo- 
cardium and  give  the  checkered  ap- 
pearance which  has  long  been  called 
tigering  or  the  faded-leaf  appearance 
(Fig.  32).  Ribbert  thinks  that  the 
patches  correspond  with  minute  ir- 
regularities in  the  distribution  of  the 
capillary  blood  supply,  and  that 
local  anaemia  produces  them.  Mi- 
croscopically it  is  found  that  the 
yellow  patches  show  heart  muscle- 
fibres  in  which  myriads  of  minute 
globules,  ranged  in  transverse  and 
longitudinal  rows,  lie  in  the  sarco- 
plasmic  discs  (Fig.  33). 

In  the  liver,  where  there  is  nor- 
mally some  fat  in  the  cells,  various 
conditions  can  arise.  The  whole  or- 
gan may  be  enormously  enlarged,  yel- 
lowish white,  with  swollen  round  edges,  and  on  section  greasy  to  the  touch, 
rigid,  and  inelastic.  In  such  a  liver  almost  every  cell  is  found  stretched  with 
one  or  more  globules  of  fat,  so  that  the  nucleus  is  flattened  to  one  side  and 
only  a  thin  film  of  protoplasm  remains.  In  others  fat  is  found  about  the 
efferent  vein,  in  the  middle  zone,  or  about  the  portal  veins,  but  not  with 
such  sharp  consistency  that  one  can  well  associate  these  forms  of  distribu- 
tion with  different  setiological  factors.  Whenever  there  is  a  destructive 
lesion  of  the  liver-cell,  as  in  chronic  passive  congestion  or  focal  necrosis 
involving  part  of  each  lobule,  fat  generally  accumulates  in  the  cells  just 


Fig.  32. — Fatty  heart,  showing  mottling 
of  myocardium. 


84 


TEXT-BOOK   OF   PATHOLOGY 


adjacent  to  the  injured  cell,  and  therefore  usually  between  them  and  the 
portal  vein  radicle.  Sometimes  the  fat  is  in  large  droplets,  sometimes  in 
small  ones  or  granule-like  particles.  Probably  these  arise  differently,  but 
they  can  surely  not  be  made  the  basis  for  declaring,  as  Virchow  did,  that 
the  first  indicate  a  physiological  infiltration,  the  second  a  "  fatty  degenera- 
tion," in  which  the  fat  is  produced  at  the  expense  of  the  cell-body. 

In  the  kidney  fat-globules  collect  in  the  epithelium  of  the  tubules,  most 
often  in  the  convoluted  portions  and  in  the  glomerular  epithelium,  but 


%/*$ 

"•    *V'i 


.»,-//  «j>"^»y   r  •*/•.•' 

•%$5gf  /5'"/?' 

*»^  jsr 


*<>>" 

^ 


'  '  '" 


Fig.  33.  —  Fatty  heart  muscle.     Fat-globules  in  fibres  stained  with  osmic  acid. 


appearing  also  in  the  conducting  tubules  (cf.  Fig.  19).  They  lie  usually 
near  the  base  of  the  epithelial  cells  at  first,  but  later,  when  the  quantity  is 
greater,  they  may  occupy  most  of  the  protoplasm.  Such  fat  is  sufficient 
to  give  a  very  opaque  yellow  color  to  the  labyrinthine  portions  of  the  renal 
cortex,  and  in  much  scarred  and  distorted  kidneys  it  is  seen  in  patches  where 
the  tubular  tissue  is  best  preserved. 

In  the  aorta  and  smaller  arteries  which  are  the  seat  of  arteriosclerotic 
processes  fats  accumulate  in  the  intimal  thickenings  and  give  them  their 
opaque  yellow  color. 


PATHOLOGICAL   DISTURBANCES   OF   FAT  85 

But  it  is  impossible  to  refer  to  all  the  situations  in  which  the  cells  may 
thus  be  the  lodging-place  of  abnormal  fats.  Somewhat  different  in  prin- 
ciple are  those  collections  of  fat  which  form  in  the  living  tissues  around  foci 
of  necrosis  in  the  brain,  in  which  multitudes  of  phagocytic  cells  are  found 
loaded  with  globules  of  fat  derived  from  the  disintegrating  brain  substance. 
These  are  analogous  to  the  fat-laden  zones  of  tissue  about  infarctions  or 
abscesses  or  in  the  neighborhood  of  tuberculous  lesions  which  have  de- 
stroyed much  tissue.  The  cells  bordering  upon  a  growing  tumor  are  laden 
with  fat,  and  so  are  those  whose  nutrition  is  affected  in  any  other  mechan- 
ical way  by  the  cutting  off  of  the  blood  supply.  Even  the  malnutrition 
which  comes  in  company  with  general  anaemia,  such  as  pernicious  anaemia, 
brings  with  it  extensive  stagnation  of  fat  in  all  the  organs. 

Not  all  this  fat  is  alike  chemically  or  physically.  Nearly  always  there 
are  globules  of  neutral  fats,  but  in  the  kidney  the  sclerotic  plaques  of  the 
aorta,  in  the  desquamated  epithelial  cells  of  the  alveoli  adjoining  tubercu- 
lous lesions  in  the  lungs,  in  the  phagocytic  cells  about  infarcts  of  the  brain, 
and  in  a  thousand  other  places,  many  of  the  globules  have  a  different  na- 
ture. They  shine  dully;  under  the  polarizing  microscope  they  show  a 
brilliant  outline;  on  heating  they  disappear;  on  cooling  again  they  start 
back  into  view  suddenly  as  brilliant,  round,  doubly  refractive  globules, 
showing  a  Maltese  cross  of  light.  These  are  cholesterine  esters  and  have 
the  characters  of  the  myeline  bodies  described  by  Virchow  (Adami).  Cho- 
lesterine crystals  are  often  associated  with  them,  and  probably  various 
soaps,  although  these  must  be  of  a  rather  evanescent  character.  Whether 
combinations  of  phosphatides  and  cerebrosides  occur  in  these  places  too, 
our  present  technical  methods  do  not  reveal  clearly,  but  it  seems  inevitable 
that  they  should  be  there  especially  when  the  lesion  affects  nervous  tissue. 
But  without  paying  too  much  attention  to  that  probability,  Aschoff  and 
others  emphasize  the  occurrence  of  degenerative  changes  in  the  cells, 
accompanied  by  the  lodgment  of  two  distinct  types  of  fatty  substances, 
glycerin  esters  and  cholesterine  esters. 

What  explanation  can  we  offer  for  the  accumulation  of  these  fatty  bodies 
in  the  cells?  Briefly,  the  results  of  the  long  discussion  are  about  as  fol- 
lows :  Virchow's  idea  that  the  fat  might  reach  the  cell  from  elsewhere  and 
appear  there  as  an  infiltration  in  the  case  of  normal  cells,  or  be  produced  at 
the  expense  of  the  protoplasm,  when  it  was  to  be  spoken  of  as  a  fatty  de- 
generation, held  sway  for  long  years.  These  two  types  were  distinguished 
by  the  large  size  of  the  globules  of  fat  in  the  infiltration,  their  very  small 
size  in  degeneration.  But  Rosenfeld  showed,  in  a  long  series  of  investiga- 
tions, that  the  cells  of  the  liver  received  fat  from  distant  depots  when  the 
animal  was  poisoned  with  phosphorus.  He  starved  dogs  and  then  fed 
them  on  mutton  fat  until  it  was  stored  in  quantities  in  their  subcutaneous 
tissues — phosphorus  poisoning  then  loaded  the  liver  with  mutton  fat.  If 
the  dog  was  so  starved  as  to  have  no  subcutaneous  fat,  none  appeared  in 
the  liver  after  phosphorus.  It  seemed  to  Rosenfeld  that  all  the  fat  came 


,86  TEXT-BOOK   OF   PATHOLOGY 

from  outside.  But  an  organ  with  abundant  fat-globules  in  the  cells  need 
contain  no  more  fat  on  chemical  analysis  than  one  which  shows  none  mi- 
croscopically— the  production  of  a  fatty  degeneration  need  not  increase  the 
total  quantity  of  fat  in  the  organ.  Beside  the  fats  found,  there  are  often 
cholesterine  esters  which  are  not  to  be  obtained  from  the  subcutaneous 
tissue,  although  they  may  well  be  transported  from  other  sources,  such 
as  the  adrenal,  where  they  have  been  stored. 

In  view  of  these  and  other  facts  the  following  explanations  of  the  appear- 
ance of  fat  in  the  tissue-cell  seem  possible : 

1.  An  excess  of  fat  may  be  brought  to  the  normal  cell. 

2.  A  normal  amount  of  fat  may  be  brought  to  a  cell  which  is  injured,  and 
therefore  incapable  of  using  up  its  fat  with  normal  rapidity.     Such  injury 
may  or  may  not  be  anatomically  obvious.     Impaired  circulation,  impaired 
oxygen  supply  from  general  anemia,  or  toxic  injury  to  the  cell  in  the  course 
of  infection  are  among  the  causes  which  might  give  occasion  for  the  con- 
dition.    Fat  would  accumulate  because  it  was  not  properly  consumed. 

3.  Injury  of  many  types  might  disintegrate  the  physical  or  chemical 
combinations  of  lipoids  which  are  known  to  exist  in  invisible  form  in  the 
cells,  and  thus  make  the  lipoids  visible  as  such  in  the  cell-body  (fat  phanero- 
sis). 

4.  Tissues  in  the  neighborhood  of  areas  of  cell  destruction  may  absorb 
or  engulf  by  phagocytic  activity  the  fats  set  free  from  those  disintegrating 
tissues,  as  in  the  case  of  an  infarct  of  the  brain  or  other  organ. 

That  fats  are  redistributed  in  the  body  in  cases  of -infection  and  intoxica- 
tion is  shown  not  only  by  the  demonstration  of  the  fats  in  transit  in  the 
blood,  but  by  the  enormous  accumulation  of  fat  in  the  liver  in  certain  cases 
in  which  the  rest  of  the  body  is  greatly  emaciated. 

LITERATURE 

Anitschkow:   Ziegler's  Beitrage,  1913,  Ivi,  379;    1914,  Mi,  201. 
Aschoff:   Ziegler's  Beitrage,  1910,  xlvii,  1. 

Bang,  Ivar:    Ergebn.  d.  innere  Med.,  1909,  iii,  447.     Chemie  u.  Biochemie  der  Lipoide 
Wiesbaden,  1911.     XVII.  Internal;.  Cong,  of  Med.,  London,  1913,  Sect.  Ill,  i,  151 
Jobling:  Jour,  of  Immunology,  1916,  i,  491, 

Kraus,  Ribbert,  Albrecht,  Rosenfeld:  Verb.  Dtsch.  Path.  GeseUsch.,  1904,  vi,  37-73. 
Kawamura:  Cholesterinesterverfettung,  Jena,  1911. 
Landau:  Ber.  Naturf.  Gesellsch.,  Freiburg,  1913,  xx,  69. 
Leathes:  The  Fats,  Monographs  on  Biochemistry,  1910. 
Lubarsch:  Ergebn.  d.  allg.  Path.,  1897,  iiii,  631. 
Rothschild:  Ziegler's  Beitrage,  1914,  Ix.  39,  66,  Lit. 
Stewart:  XVII.  Internat.  Cong.,  London,  1913,  iii2,  173. 


CHAPTER  VII 

DISTURBANCES    OF   PROTEIN   AND    CARBOHYDRATE   METAB- 
OLISM 

General  character  of  protein  metabolism.  The  purine  bodies.  Gout.  Cloudy  swelling. 
Hyaline  metamorphosis.  Amyloid  infiltration.  Carbohydrate  metabolism.  Glycogen. 

Protein  Metabolism. — It  is  somewhat  surprising,  in  view  of  the  great  im- 
portance of  protein  materials  in  the  constitution  of  the  body  and  in  the 
composition  of  our  food,  to  find  ourselves  able  to  say  so  little  with  regard  to 
the  pathological  anatomy  of  alterations  of  the  metabolism  of  these  sub- 
stances. 

Doubtless  it  is  altogether  the  result  of  our  inability  to  see  or  make  recog- 
nizable the  abnormalities  that  may  arise.  We  cannot  tell,  as  we  can  in  the 
case  of  fats  and  carbohydrates,  whether  a  tissue  is  loaded  with  an  excess  of 
protein  material.  Indeed,  we  know  rather  little  about  the  relation  of 
labile  or  food  protein  to  tissue  protein.  But  one  may  recognize  the  ab- 
normal loss  of  protein  in  the  urine  in  renal  disease,  the  passage  of  albumoses 
into  the  urine  in  disease  of  the  bones  (myeloma,  etc.),  and  the  occurrence 
of  various  amino-acids  there  when  the  liver  has  been  extensively  destroyed 
(leucine  and  tyrosine  in  acute  yellow  atrophy  of  the  liver).  Under  other 
circumstances  there  occur  cystinuria  and  alkaptonuria,  both  resulting  from 
disturbances  of  protein  metabolism,  and  producing,  in  the  one  case,  urinary 
concretions  of  yellow  crystals,  in  the  other,  a  pigmentation  of  the  cartilage. 

Disturbances  in  Purine  Metabolism. — Variations  occur  also  in  the  quan- 
tities of  urea,  uric  acid,  ammonia  compounds,  etc.,  in  the  urine,  and  these 
naturally  have  a  direct  relation  to  the  protein  metabolism.  Nevertheless, 
it  is  rarely  possible  to  gather  any  real  clue  as  to  the  protein  metabolism 
from  their  variations.  The  disproportion  in  this  regard  is  seen  especially 
well  in  the  case  of  uric  acid,. a  substance  playing  an  important  role  in  gout. 
From  the  variations  in  its  reaction  it  would  never  be  possible  to  diagnose 
gout,  because  even  greater  variations  occur  in  a  healthy  person. 

GOUT 

This  is  a  disease  the  cause  of  which  is  unknown.  It  may  even  be  said  that 
the  essential  nature  of  the  disease  is  quite  unknown,  since  the  disturbance 
of  a  part  of  the  protein  metabolism,  which  is  accompanied  by  striking  symp- 
toms, is  evidently  only  the  effect  of  some  underlying  disarrangement  of 
the  machinery  of  intermediary  metabolism,  which  is  obscure. 

Profound  alterations  arise  in  the  metabolism  of  the  purine  substances, 
such  that  uric  acid,  the  common  end-product  of  fermentative  decomposi- 
tions and  oxidations  of  these  complex  bodies,  is  retained  in  the  tissues  in 
the  form  of  salts  of  soda  and  calcium,  and  lodges  itself  in  cartilages  and 
elsewhere,  causing  great  pain  to  the  sufferer. 

Chemistry  of  Purine  Bodies. — The  investigation  of  the  chemical  nature  of  the  complex 
bodies  which  finally  yield  uric  acid  has  been  made  by  Kossel,  Fischer,  Brugsch  and  Schitt- 

87 


88  TEXT-BOOK   OF   PATHOLOGY 

enhelm,  Burian,  Jones,  Levene,  and  others,  and  may  be  read  in  Jones'  monograph 
(Nucleic  Acids). 

It  appears  that  compounds  containing  nitrogen  and  phosphorus,  which  have  long  been 
known  as  nucleins  or  nucleoproteins,  can  be  extracted  from  the  tissues,  and  in  special 
abundance  from  those  such  as  thymus,  lymph-glands,  or  materials  like  pus  or  sperma- 
tozoa, in  which  cell  nuclei  form  a  large  proportion  of  the  mass.  These  names  are 
being  abandoned  since  it  has  been  shown  that  they  mean  nothing  definite,  and  that  the 
characteristic  constituent  is  a  nucleic  acid.  It  is  from  the  nucleic  acids  that  the  peculiar 
and  important  alloxuric  bodies  are  derived  by  the  action  of  ferments.  These,  in  so  far 
as  they  interest  us,  are  guanine,  adenine,  hypoxanthine,  xanthine,  and  uric  acid.  All 

are  chemical  derivatives  of  purine. 

N  =  CH  (6) 
/          I 
(2)  HC  C  —  NHX 

^         II  >CH  (8) 

N—  C  —  N^ 

Representing  the  purine  ring,  with  its  three  replaceable  hydrogen  atoms,  by  the  abbre- 

/H  (2) 
viated  expression,  P^-H  (6),  the  relation  of  the  five  purine  compounds  to  one  another  is 

seen  in  the  following  diagram  (Jones): 

NH2  /H 

P(-NH2 


H 

Guanine  Adenine 

(2-amino-6-oxy-purine)  (6-amino-purine) 

/OH  /OH  /H 

P^OH  P^OH  PA)H 

X)H  \E  \H 

Uric  acid  Xanthine  Hypoxanthine 

(2-6-8-  trioxy-purine)  (2-6-dioxy-purine)  (6-oxy-purine) 

Uric  acid  can  be  formed  from  the  amino-purine  by  deaminization  and  subsequent 
oxidation  —  from  the  oxypurines  by  oxidation.  The  deaminization  is  brought  about  by 
special  ferments,  guanase  and  adenase,  which  are  distinct  and  vary  greatly  in  their 
localization  with  animal  species.  The  lack  of  guanase  in  the  pig's  tissue  seems  to  be  the 
explanation  of  the  deposition  of  guanine  which  sometimes  occurs  there  (guanine  gout). 

As  a  brief  indication  of  what  precedes  this,  the  following  may  be  quoted  from  Jones' 
monograph  : 

Thymus  nucleic  acid,  according  to  Levene,  is  a  combination  of  four  mononucleotides, 
each  of  which  is  a  nucleoside  united  with  phosphoric  acid.  Hexose,  joined  to  the  nitro- 
genous ring  compound  or  purine  group,  is  a  nucleoside.  From  this  point  of  view  the 
nucleic  acid  is  a  tetranucleoside,  made  up  of  four  mononucleotides.  Levene  and  Jacobs 
give  the  following  formula  for  animal  nucleic  acid: 

HO\ 

0=PO—  C6H1004- 


Guanine  group 
HO\ 

O=PO— C6H8O2— C5H5N2O2 
HO/          | 

O  Thymine  group 

0=PO-C6H802— C4H4N30 
HO/ 

Cytosine  group 


\ 

O=PO-C6H10O4—  C6H4N5 
HO/ 


Adenine  group 


GOUT  89 

The  disruption  of  this  complex  takes  place  by  the  action  of  two  ferments,  which  first 
split  the  tetranucleotide  into  two  dinucleotides,  after  which  they  in  turn  are  split  into 
mononucleotides.  These  ferments  are  phosphonuclease  and  purine  nuclease.  Levene 
and  Medigreceanu  find  that  nucleotidases  split  the  nucleotides  to  nucleosides,  which 
further  separate  into  carbohydrate  and  purine  base  under  the  action  of  a  nucleosidase. 

The  liberation  of  the  guanine  and  adenine  is  well  in  the  line  of  uric-acid  formation; 
the  fate  of  the  pyrimidine  groups,  thymine  and  cytosine,  is  still  uncertain.  Dr.  Levene 
tells  me  that  he  has  been  unable  to  find  an  enzyme  which  will  decompose  the  nucleoside 
in  which  they  occur,  and  that  since  they  cannot  form  uric  acid,  they  are  possibly  excreted 
as  urea  or  in  other  forms.  Only  50  per  cent,  of  the  nucleic  acid  nitrogen  can  be  counted 
on  for  the  production  of  uric  acid,  namely,  that  in  the  guanine  and  adenine  groups. 

The  tissues  of  the  lower  animals  contain  a  ferment,  uricase,  which  can  decompose 
uric  acid,  but  no  such  ferment  exists  in  human  tissues,  and  uric  acid  is  excreted  as  such. 

Uric  acid  is  derived  from  the  food  or  from  the  waste  of  the  tissues.  It  occurs  in  the 
blood  in  small  amounts,  and  is  excreted  in  the  urine  in  quantities  up  to  one  gram  daily. 
The  amount  excreted  is  increased  by  the  feeding  of  substances  rich  in  nucleic  acid.  The 
solubilities  of  uric  acid  are  interesting  and  important,  since  it  has  been  stated  by  Gudzent 
that  the  monosodium  urate  exists  in  the  blood  in  two  forms — one,  the  easily  soluble, 
unstable  lactam  form,  the  other  the  isomeric,  stable,  relatively  insoluble  lactim  urate. 
The  change  from  one  of  these  forms  to  the  other  may,  according  to  him,  account  for  the 
precipitation  of  the  urates  in  the  tissues.  More  important  seems  the  more  recent  work 
of  Schade,  who  shows  that  uric  acid  or  its  salts  may,  through  the  influence  of  alkalies 
(hydrates),  pass  into  a  condition  in  which  it  is  far  more  soluble  than  usual,  and  that,  in 
reaching  the  crystalline  form  from  this  oversaturated  solution,  it  passes  through  a  colloid 
stage  in  which  it  is  relatively  stable.  Materials  which  protect  this  colloid  stage  and 
antagonize  precipitation  occur,  such  as  glycerin,  urea,  albumen  of  the  serum,  nucleic 
acids,  etc.  The  application  of  this  knowledge  has  not  yet  been  made. 

Gout  is  a  hereditary  affection  most  common  in  men,  often  transmitted 
by  women  who  have  themselves  shown  no  symptoms.  It  is  common  in 
those  who  overeat,  and  yet  it  occurs  as  well  in  the  poor.  It  is  often  as- 
sociated with  lead-poisoning,  on  which  account  a  type,  "saturnine  gout," 
has  been  spoken  of.  Renal  disease  is  a  frequent  but  not  constant  accom- 
paniment or  sequel,  and  some  writers,  thinking  that  the  gout  might  depend 
on  renal  disease,  have  specified  another  form,  " renal  gout."  But  for  these 
separate  forms  there  is  little  good  evidence. 

There  seems  to  be  an  underlying  hereditary  tendency  to  develop  the 
actual  disease  in  these  persons,  although  much  may  be  done  to  ward  off 
its  appearance  by  careful  avoidance  of  foods  rich  in  purine.  Whether  it 
can  be  prevented  in  this  way  remains  uncertain.  Alcohol  has  always 
been  thought  an  important  cause  of  gout,  although  its  actual  influence  is 
not  clearly  denned. 

Acute  attacks  are  characteristic,  with  remissions  in  which  the  condition 
is  fairly  good.  Chronic  forms  also  occur  in  which  acute  attacks  appear  as 
exacerbations  of  the  more  continuous  process.  The  acute  attack  begins 
with  violent  nocturnal  pain  in  a  joint,  followed  by  fever  and  chills  and 
evidences  of  inflammation  in  the  joint. 

Before  the  attack  the  excretion  of  uric  acid  in  the  urine  is  diminished; 
during  the  attack  it  is  much  increased.  It  is  clear  from  this  that  there  is 
no  real  inability  on  the  part  of  the  kidneys  to  excrete  uric  acid.  Between 
attacks  it  is  about  normal,  although  it  may  be  diminished  (Garrod). 


90  TEXT-BOOK   OF   PATHOLOGY 

. 

There  is  generally  an  increased  amount  of  uric  acid  in  the  circulating 
blood,  both  in  the  intervals  and  during  the  attacks.  The  average  amount 
in  Pratt 's  cases  was  3.7  mg.  per  100  grams  of  blood  contrasted  with  1.7  mg. 
in  the  non-gouty  cases  studied  by  Adler  and  Ragle. 

Although  Garrod  and  others  held  that  the  decreased  excretion  was  due 
to  the  disability  of  the  kidneys,  Umber  puts  forward  the  more  plausible 
suggestion  that  the  uric  acid  is  actively  retained  by  the  tissues. 

Anatomically,  the  most  prominent  feature  of  the  disease  is  the  extra- 
ordinary deposition  of  needle-shaped  crystals  of  monosodium  urate  in  the 
substance  of  the  cartilages.  Such  opaque,  white,  chalky  deposits  are  very 
conspicuous  when  an  affected  toe-joint  or  knee-joint  is  opened  (Fig.  34); 
they  lie  a  little  beneath  the  free  surface,  and  extend  only  about  one-third 
of  the  way  through  the  cartilage,  rarely  entering  the  bone.  Microscopic- 
ally in  sections  of  the  joint,  sheaves  of  these  fine  crystals  are  found  em- 


Fig.  34. — Knee-joint  with  white  deposits  of  urates.    Gout. 

bedded  in  the  matrix  of  the  cartilage,  often  surrounded  by  an  area  of  hya- 
line, pink-staining  altered  cartilage.  Ebstein  thinks  that  necrosis  of  the 
cartilage  is  the  necessary  forerunner  of  their  deposit,  but  in  this  he  is  not 
supported  by  the  other  writers,  who  feel  that  the  changes  in  the  cartilage 
may  be  secondary  to  the  crystalline  deposit. 

Besides  the  joint  cartilages,  the  neighboring  ligaments,  tendons,  and 
synovial  membranes  may  occasionally  be  subjected  to  the  precipitation. 
Olecranon,  prepatellar,  and  other  bursae  are  especially  likely  to  be  affected. 
Other  sites  are  the  edges  of  the  cartilages  of  the  ear,  the  eyelids,  the  larynx, 
the  kidneys,  especially  the  pyramidal  portion,  where  masses  of  crystals 
may  form  in  or  between  the  tubules,  and  many  other  situations.  But 
the  cartilages  of  the  joints,  especially  of  the  great  toe,  the  fingers,  and  the 
knees,  form  the  site  of  predilection.  Such  accumulations  of  crystals,  when 
they  become  bulky,  are  called  tophi,  and  in  the  course  of  chronic  gout  tophi 


GOUT 


91 


of  great  size  may  form  in  and  about  the  joints,  causing  their  great  defor- 
mity and  disability  (Fig.  35) .  They  become  encapsulated,  cause  a  persistent 
mild  inflammation,  and  may  sometimes,  through  stretching  the  skin  to 
atrophy,  break  through  and  appear  as  chalky  concretions  exposed  to  the  air. 

Digestive  and  nervous  disturbances,  arteriosclerosis  with  myocardial 
disease,  and  circulatory  disabilities,  chronic  nephritis  with  scarring  of  the 
kidney  are  common  accompaniments  of  the  disease.  The  patients  finally 
die  from  some  intercurrent  affection. 

From  the  present  knowledge  no  clear  idea  of  the  underlying  fault  is  to 


Fig.  35. — Gout.     Uratic  tophi  about  the  finger-joints. 

be  gained,  but  it  seems  as  though  it  might  be  elucidated  by  further  study  of 
the  ferments  concerned  in  the  production  of  uric  acid  and  in  the  influences 
which  modify  the  solubilities  of  that  substance.  It  seems  a  mere  evasion 
to  say  that  it  may  perhaps  be  controlled  by  some  organ  of  internal  secretion. 


LITERATURE 

Ebstein:    Gicht,  Wiesbaden,  1906,  II.  Aufl. 
Jones:   Nucleic  Acids,  Longmans,  Green  &  Co.,  1914. 
Levene  and  Jacobs:   Jour.  Biol.  Chem.,  1912,  xii,  411. 
Magnus  Levy:    Harvey  lectures,  1909-10,  251. 
Minkowski:  "Gicht/'  Nothnagel's  Handb.,  vii,  2. 
McClure:  Arch.  Int.  Med.,  1917,  xx,  481,  641;  1918,  xxi,  84. 
Pratt:  New  York  State  Jour,  of  Med.,  November,  1916. 
Schade:'  Zeitsch.  f.  phys.  Chem.,  1913,  Ixxxiii,  347;  Ixxxvi,  238. 
Umber:  Ernahrung  u.  Stoffwechselkrankheiten,  1914,  335. 


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CLOUDY   SWELLING  OR  PARENCHYMATOUS   DEGENERATION 

When  the  liver  and  kidneys  and  some  other  organs  are  inspected  in  the 
body  of  a  person  who  has  died  of  typhoid  fever,  pneumonia,  diphtheria, 
or  any  one  of  many  other  acute  infections  or  intoxications,  they  are  com- 
monly found  swollen,  inelastic,  or  pasty,  and  on  section  very  dull  and 
opaque  in  appearance.  It  is  often  said  that  the  liver  looks  as  though  it 
had  been  boiled.  In  frozen  sections  the  epithelial  cells  are  seen  to  be  much 
enlarged  and  very  granular.  In  the  renal  epithelium  the  free  edge  of  the 


Fig.  36. — Cloudy  swelling  of  epithelium  of  renal  tubules. 

cell  is  ragged  and  irregular,  projecting  far  out  into  the  lining  of  the  tubule — 
even  far  enough,  sometimes,  to  meet  the  opposite  cells  and  greatly  narrow 
the  cavity  of  the  tubule  (Fig.  36).  The  same  appearance  is  found  in  the 
kidney  if  the  work  of  both  is  suddenly  put  upon  it  by  the  removal  of  the 
other.  This  cloudy  opacity  of  the  cells  with  swelling  has  long  been  known, 
but  even  yet  its  nature  is  not  clear.  Virchow  thought  it  the  expression  of  a 
nutritive  stimulus  and  increased  absorption  of  food  material.  Cohnheim, 
on  the  contrary,  thought  it  a  kind  of  localized  coagulation  process.  It  is 
known  that  the  altered  appearance  is  not  necessarily  indicative  of  an  irrev- 


CLOUDY   SWELLING   OR   PARENCHYMATOUS   DEGENERATION         93 

ocable  change  in  the  cell,  for  after  the  acute  infection  is  past,  the  cells 
recover  their  normal  appearance.  This  was,  therefore,  regarded  as  one  of 
the  mildest  forms  of  "  degeneration "  of  the  cell. 

The  protein  nature  of  the  abundant  granules  which  crowd  the  body  of 
the  swollen  cell  has  been  generally  accepted  and  proven  by  their  solubility 
in  alkalies  and  acetic  acid,  and  by  their  positive  xanthoprotein  reaction, 
as  well  as  by  other  tests,  and  the  problem  remains  as  to  their  origin  and 
their  relation  to  the  essential  structures  of  the  cell. 


Fig.  37. — Cloudy  swelling  of  epithelium  of  liver. 

The  confused  literature  is  reviewed  by  Ernst  in  his  recent  paper  without 
arriving  at  any  definite  conclusion  as  to  the  nature  of  the  granules,  although 
he  raises  the  question  as  to  their  relation  to  the  preexisting  granules,  and 
states  that  the  weight  of  evidence  is  in  favor  of  their  being  derived  from  the 
mitochondria  and  their  variations. 

In  the  renal  epithelial  cells  there  are  found,  especially  in  the  more  chronic 
forms  of  nephritis,  but  occasionally  in  the  acuter  form,  globules  of  much 
larger  size  than  any  of  the  granules  ordinarily  seen,  globules  of  a  density 
and  high  refractive  index  to  make  them  at  once  conspicuous  objects  (Fig. 


94  TEXT-BOOK   OF   PATHOLOGY 

38).  These,  it  is  true,  vary  greatly  in  size,  and  are  thought  by  some 
writers  (Pfister)  to  show  gradual  transitions  into  the  ordinary  granules. 
Fahr  objects  to  this  since,  as  is  well  known,  the  large  droplets  stain  sharply 
with  the  Weigert  fibrin  stain.  They  probably  play  a  prominent  part  in 
the  formation  of  hyaline  casts  in  the  tubules. 

Anitschkoff  has  tried  to  determine  the  relation  of  the  granules  in  cloudy 
swelling  to  the  mitochondria  by  experiment,  and  finds  that,  by  the  applica- 
tion of  hypotonic  solutions  to  the  cells,  the  mitochondria  swell  up  into 
droplets,  which,  after  a  time,  take  the  specific  stain  only  at  their  margins. 
The  production  of  cloudy  swelling  is,  he  thinks,  a  complex  process,  con- 
sisting of  a  series  of  changes  in  the  mitochondria  which  begins  by  their 
decomposition  into  smaller  granules,  which  then  swell  into  droplets  some- 
times large  enough  to  touch  one  another  and  give  the  whole  cell  a  web- 
like  appearance.  This  is  analogous  to  the  swelling  of  colloid,  which  is 
intensified  by  acids,  as  shown  by  M.  Fisher,  and  corresponds  with  the  ob- 
servation of  Orgler  upon  the  increase  in  the  water  contents  of  the  altered 
tissues.  Naturally,  this  process  is  reversible  under  experimental  condi- 
tions, but  it  is  not  so  easy  to  assume  that  this  is  true  in  the  body,  where  the 
granules  may  burst,  or,  as  in  the  kidney  cells,  be  discharged  into  the  tubule. 
Further,  a  distinction  must  be  maintained  between  the  increase  in  the 
mitochondria  in  cells  undergoing  hypertrophy,  and  the  swelling  and  dis- 
organization of  those  structures  in  injured  cells,  where  the  change  can  be 
regarded  as  the  effect  of  excessive  function  only  in  the  beginning,  if  at  all. 
Dibbelt,  in  studying  the  effect  of  diphtheria  toxin  in  the  kidney,  finds  in 
the  same  way  that  the  first  effect  consists  in  a  stimulation  of  the  mito- 
chondria to  activity,  followed  by  a  molecular  disintegration,  with  the  lib- 
eration of  lipoid  substances.  Fahr,  on  the  other  hand,  in  discussing  the 
hyaline  droplets  in  the  kidney  cells,  makes  a  sharp  distinction  between 
mitochondria  and  secretory  granules.  Normally,  droplets  distinguishable 
from  the  mitochondria  by  their  staining  reaction  exist  in  the  epithelium 
of  parts  of  the  tubule.  Pathological  droplets  staining  intensely  by  Wei- 
gert's  fibrin  stain  occur,  however,  in  different  situations  in  the  tubules, 
and  are  thought  to  be  not  merely  evidences  of  the  activity  of  secretory 
granules,  but  new  formed  globules,  indicating  the  disintegration  of  the  cell. 

All  this  is  very  contradictory  and  confused,  but  at  least  one  may  see  that 
it  is  scarcely  believed  any  longer  that  the  granular  opacity  of  the  organ 
cells  in  infections  and  intoxications  is  due  to  the  accumulation  of  protein 
food  materials,  but  that  it  is  intimately  related  to  changes  in  the  specific 
granules  of  the  cell.  More  study  is  necessary  to  make  the  matter  quite 
clear. 

LITERATURE 
Anitschkoff,  Dibbelt,  Ernst,  Fahr:  Verh.  Dtsch.  Path.  Gesellsch.,  1914,  xvii,  81,  103, 

114,  119. 
Landsteiner:  Ziegler's  Beitrage,  1903,  xxxiii,  237. 


HYALINE   DEGENERATION 


95 


HYALINE  DEGENERATION 

This  expression  is  loosely  employed  to  class  together,  in  the  present  state 
of  our  ignorance,  a  great  many  unrelated  substances,  usually  recognizable 
only  with  the  microscope,  which  have  in  common,  besides  their  protein 
nature,  only  their  translucent  clear  or  hyaline  appearance  and  their  ten- 
dency to  stain  brightly  with  such  acid  dyes  as  eosin. 

Naturally,  there  can  be  nothing  chemically  specific  about  such  a  hetero- 


Fig.  38. — Colloid  or  hyaline  droplets  in  the  epithelium  of  renal  tubules. 

geneous  group,  and  it  is  easy  to  withdraw  from  it  such  a  constant  and 
sharply  characterized  substance  as  amyloid,  which,  although  it  is  hyaline 
and  stains  with  eosin,  is  easily  recognized  by  special  microchemical  reac- 
tion as  well  as  by  its  peculiar  distribution. 

Ernst  has  pointed  out  the  possibility  of  dividing  these  substances  into 
two  groups,  according  to  whether  the  hyaline  material  is  derived  from  the 
metamorphosis  of  epithelial  and  other  cells  or  from  connective  tissue. 
This  rough  subdivision,  which  is  open  to  many  criticisms,  is  based  on  the 
reaction  to  the  van  Gieson  stain  with  which  epithelial  hyaline  stains  yellow- 
ish brown,  while  connective-tissue  hyaline  takes  the  red  fuchsin  stain. 


96 


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Since  we  know  so  little  of  the  chemical  nature  of  the  various  substances, 
nothing  remains  but  to  describe  their  appearance.  In  all  cases  the  death 
of  the  tissue  precedes  its  conversion  into  a  hyaline  material,  so  that  we 
are  dealing  with  necrotic  and  usually  coagulated  cells  which  have  under- 
gone even  further  change  in  assuming  the  hyaline  aspect. 

Epithelial  Hyaline. — In  areas  of  necrosis  in  such  organs  as  the  liver  or 
kidney  or  skeletal  or  cardiac  muscle,  the  protoplasm  of  the  dead  cell  coagu- 
lates, of  course,  with  the  aid  of  coagulable  fluid,  which  filters  in  from  ad- 


Fig.  39. — Hyaline  changes  in  muscle.     Typhoid  fever. 

jacent  capillaries  and  tissue  spaces.  But  it  does  not  at  once  become  glossy 
or  hyaline.  Instead,  it  seems  to  require  time  and  perhaps  compression  or 
the  infiltration  of  more  coagulable  fluid  before  the  details  of  the  structure 
of  the  cells  are  quite  lost  and  fused  into  a  homogeneous,  shining  mass.  A 
good  example  is  found  in  the  clumps  of  hyaline  material  sometimes  found 
shrunken  in  the  interior  of  the  sarcolemma  sheath  of  the  fibres  of  the  rectus 
abdominis  muscles  in  typhoid  fever  and  the  pneumonias  following  measles 
and  influenza  (Fig.  39).  Many  other  instances  will  be  referred  to  in  other 
places. 

This,  which  involves  the  whole  cell,  must  be  very  different  from  the 


HYALINE   DEGENERATION 


97 


process  which  gives  origin  to  the  globules  or  droplets  of  hyaline  appearance 
so  often  seen  in  the  renal  epithelium  (Fig.  38).  Other  hyaline  droplets 
which  seem  to  be  formed  in  some  analogous  way  are  the  so-called  RussePs 
fuchsinophile  bodies,  which  may  be  found  in  tumors  or  in  old  granulation 
tissue.  Perhaps  the  "  corpora  amylacea"  which  occur  in  the  alveoli  of 
the  lung  and  in  the  prostate  may  be  regarded  as  similarly  formed  by  the 
stratified  accretion  of  the  hyaline  debris  of  cells,  or  the  secretion  of  epi- 
thelial cells  around  some  nucleus  which  itself  may  be  a  dead  cell. 


^^O^>^"  "i*-*~  •**    "-*     ^-^ 


Fig.  40. — Hyaline  vessel-walls  in  a  tumor  of  the  uterus. 

The  globules  of  hyaline  material  seen  in  diseased  renal  epithelium  are  sometimes 
spoken  of  as  colloid  droplets,  and  the  condition  is  called  colloid  degeneration.  This  is 
confusing,  and  it  is  obviously  wrong  to  speak  of  the  accumulation  of  the  colloid  of  the 
thyroid  even  when  excessive,  as  a  colloid  degeneration,  since  it  is  only  the  normal  se- 
cretion of  the  gland. 

The  hyaline  casts  found  in  the  renal  tubules  which  have  in  themselves 
the  general  character  of  hyaline  material  must  be  derived  from  disin- 
tegrated and  amalgamated  epithelial  cells,  together  with  their  secretions, 
and  they  are  found  to  stain  in  a  corresponding  way. 

Connective-tissue  Hyaline. — In  the  framework  of  lymph-glands  draining 


98  TEXT-BOOK   OF   PATHOLOGY 

malignant  tumors  or  tuberculous  lesions,  hyaline  material  was  first  de- 
scribed. But  the  same  appearance  can  be  found  in  scar  tissue  or  in 
the  compact  fibrous  tissue  which  underlies  old  granulation  tissue  in  the 
walls  of  thickened  and  diseased  blood-vessels  (Fig.  40).  Especially  in  the 
walls  of  the  vessels  of  the  uterus  or  ovaries  when  they  shrink  and  become 
obliterated  in  old  age  does  one  see  the  vitreous  or  hyaline  change  take  place 
in  the  connective  tissue  that  narrows  the  lumen.  In  the  ovary  every  corpus 
luteum,  when  it  loses  its  specific  cells,  is  finally  reduced  to  a  cell-free,  hya- 
line, shining  mass,  the  corpus  albicans  or  candicans. 

We  must,  one  supposes,  regard  such  hyaline  fibrous  tissue  as  dead,  and 
frequently  there  are  evidences  of  coagulative  processes  which  have  oc- 
curred all  through  it,  after  which  it  has  become  more  compact  and  glisten- 
ing. Often  calcium  is  deposited  in  such  dead  tissue.  But  while  it  is  hya- 
line, it  takes,  with  greater  or  less  brilliancy,  the  fuchsin  red  of  van  Gieson's 
stain,  because  its  inherent  chemical  value  is  not  quite  lost  by  its  becoming 
melted  down  into  hyaline. 

Thrombi,  after  long  standing,  fuse  in  the  same  way  into  a  formless, 
homogeneous  mass  in  which  fibrin,  platelets,  nuclei  of  leucocytes,  and  red 
corpuscles  lose  their  identity  in  the  uniform  hyaline  mass.  This  is  espe- 
cially true  in  the  lower  strata  of  the  thrombi  that  occupy  old  aneurysmal 
sacs,  where  one  may  no  longer  be  able  to  distinguish  the  hyaline  thrombus 
from  the  hyaline  fibrous  wall  of  the  sac. 

More  rapidly  produced  are  the  hyaline  thrombi  which  appear  in  the 
capillaries,  especially  in  the  renal  glomeruli  in  some  infectious  diseases 
(diphtheria,  hog  cholera,  plague).  They  fill  the  capillaries  like  a  homo- 
geneous injection  mass,  and  can  usually  be  stained  by  the  Weigert  fibrin 
stain,  so  that  they  veritably  look  like  a  colored  injection.  It  was  thought 
that  they  too  were  composed  of  fibrin,  but  Flexner  has  shown  that  they 
consist  largely  of  agglutinated  red  blood-corpuscles. 

Unsatisfactory  as  it  is,  this  general  conception  of  nondescript  hyaline 
materials  derived  by  necrobiotic  processes  from  the  cells  and  tissues  is 
useful  so  long  as  we  are  quite  unable  to  define  their  nature  any  more  closely. 

LITERATURE 
Lubarsch:  "  Hyaline  and  Amyloid  Degeneration,"  Ergebn.  d.  allg.  Path.,  1897,  iv,  449. 

AMYLOID  INFILTRATION 

There  was  observed  long  ago,  by  Rokitansky  and  the  Viennese  school, 
a  curious  material  lodged  in  the  substance  of  various  organs,  and  this  was 
later  studied  in  greater  detail  by  Virchow.  This  amyloid  was  so  called 
because  of  its  fancied  resemblance  to  starch  and  its  fancied  resemblance  to 
cellulose.  It  is  a  translucent,  glistening  substance,  usually  so  firm  and 
often  so  abundant  as  to  enlarge  and  render  rigid  the  organs  in  which  it 
occurs. 

It  is  in  persons  who  have  passed  through  a  long  wasting  illness  that  it  is 


AMYLOID    INFILTRATION  99 

found.  In  the  organs  of  those  who  have  died  after  suffering  for  months  or 
years  from  some  exhausting  suppurative  process,  such  as  an  old  osteo- 
myelitis, some  chronic  destructive  infection,  such  as  tuberculosis  or  actino- 
mycosis,  or  from  such  protracted  intoxication  as  may  accompany  syphilis, 
chronic  nephritis,  or  cancer,  this  substance  is  riot  uncommonly  discovered 
at  autopsy.  With  the  improvement  in  surgical  technique,  which  elim- 
inates much  of  such  chronic  suppurative  and  tuberculous  disease,  it  is 
less  common  than  formerly,  but  it  is  still  frequent  enough  in  homes  for 
the  incurable  and  such  places. 

The  spleen,  liver,  and  kidneys  are  perhaps  the  commonest  sites  for  its 
deposit,  but  it  occurs  in  every  other  organ  at  times,  not  even  excepting  the 
brain. 

In  the  spleen  it  appears  in  two  forms,  in  one  of  which  it  is  confined  to  the 
Malpighian  bodies,  and  stands  out  as  clear,  rounded  globules  against  the 


Fig.  41. — Amyloid  infiltration;   sago  spleen. 

red  background  of  the  splenic  pulp  (Fig.  41).  Virchow,  recalling  a  favor- 
ite red-wine  soup  with  sago,  named  it  very  appropriately  sago  spleen.  In 
the  other  form  the  amyloid  is  diffusely  spread  through  the  splenic  pulp, 
and  being  everywhere  mixed  with  the  tissue,  it  is  less  translucent  and  glis- 
tening. 

In  the  liver  it  may  be  very  inconspicuous,  but  if  abundant,  the  liver  is 
greatly  enlarged  and  firm,  and  on  section  the  tabulation  is  rendered  in- 
visible by  the  diffuse  infiltration  of  translucent  amyloid.  Minute  streaks 
of  yellowish,  opaque  liver  tissue  stretch  through  it,  and  there  are  usually 
patches  of  liver  which  are  practically  free  from  any  admixture  of  it. 

The  kidneys  are  often  pale,  large,  smooth,  and  firm,  but  on  the  other 
hand  they  may  show  any  stage  of  the  distortion  which  follows  the  ex- 
treme scarring  of  the  organ  and  still  be  found  to  contain  amyloid.  This 
is  lodged  in  the  glomeruli  and  in  the  walls  of  the  arterioles  and  straight 


100  TEXT-BOOK    OF    PATHOLOGY 

conducting  tubules,  and  occasionally  one  may  discern  it  with  the  naked 
eye,  although  usually  it  is  too  finely  divided  for  that. 

The  adrenals  may  contain  much  or  little.  In  extreme  cases  the  organ 
is  greatly  enlarged  and  composed  almost  entirely  of  translucent  amyloid, 
almost  like  an  enlarged  mould  of  the  normal  structure.  In  the  intestinal 
wall  it  is  sometimes  possible  to  recognize  its  presence  by  the  pallor  and 
rigidity  of  the  mucous  membrane,  but  this  is  rare. 

In  lymph-glands  it  is  not  commonly  abundant,  but  in  a  recent  case  in 
which  it  was  widely  distributed  the  cervical  lymph-glands  were  greatly 
enlarged  and  were  found  to  be  composed  of  almost  solid  masses  of  amyloid. 

While  the  condition  of  the  spleen,  liver,  and  adrenals  is  easy  to  recognize, 
one  might  overlook  its  existence  in  the  kidneys  and  in  other  organs.  In 
its'  detection  great  help  is  afforded  by  the  peculiar  microchemical  reactions 
which  can  be  applied  to  the  fresh  organs.  They  are  as  follows: 

1.  A  solution  of  iodine  stains  the  tissues  in  general  yellow,  but  makes  the 
amyloid  stand  out  sharply  in  deep  brown.     This  is  especially  striking  if 
the  tissue  is  made  acid  in  reaction  with  acetic  acid.     If  strong  sulphuric 
acid  is  used  instead,  the  amyloid  turns  blue  or  black  with  iodine,  and  hence 
its  supposed  resemblance  to  cellulose. 

2.  Various  aniline  dyes,  such  as  methyl-violet,  methyl-green,  thionin, 
etc.,  cause  the  amyloid  to  show  a  metachromatic  stain;   that  is,  it  stains 
red  while  the  tissue  takes  the  obvious  blue  or  green  color  of  the  dye. 

These  stains  can  be  applied  to  frozen  sections  in  which  the  amyloid 
also  shows  its  acidophilic  character,  staining  intensely  pink  with  eosin, 
and  brownish  with  van  Gieson's  stain. 

When  thus  brought  into  distinct  relief  by  specific  stains,  it  becomes 
quite  clear  that  the  amyloid  substance  is  merely  poured  into  the  crevices 
of  the  tissue,  and  not  situated  in  any  of  the  cells.  It  is  a  true  infiltration, 
as  though  melted  paraffin  had  been  forced  into  the  tissue-spaces  and  al- 
lowed to  solidify.  In  the  spleen  it  crowds  the  cells  of  the  Malpighian  body, 
between  which  it  lies  until  most  or  all  of  them  atrophy  and  disappear 
(Fig.  42).  Everywhere  it  appears  in  the  substance  of  the  walls  of  the 
smallest  blood-vessels,  sometimes  between  the  muscle-cells  of  the  media, 
sometimes  in  the  intima.  The  vessels  of  capillary  calibre  are  most  com- 
monly chosen  for  such  a  coating  of  amyloid. 

In  the  liver  it  is  found  in  only  one  situation,  and  that  is  about  the  en- 
dothelium  of  the  capillaries,  and  hence  between  those  cells  and  the  liver- 
cells.  The  amyloid  becomes  so  bulky  in  that  situation  that  it  presses  on 
the  capillary  and  liver-cells,  and  causes  the  latter  to  melt  away  into  thin 
threads  of  protoplasm  and  finally  to  disappear  (Fig.  43) . 

The  same  crowding  is  apparent  to  an  extreme  degree  in  the  adrenal, 
where  the  tissue  is  practically  reduced  to  nothing  in  advanced  cases.  In 
the  intestinal  mucosa  amyloid  accompanies  the  minute  blood-vessels  in 
the  villi.  Application  of  iodine  makes  each  one  brown  separately,  so  that 
the  mucosa  assumes  the  appearance  of  brown  velvet. 


AMYLOID    INFILTRATION 


101 


In  the  kidney  it  lodges  in  the  glomerulus,  between  the  endothelium  of 
the  capillaries  and  their  epithelial  covering,  and  consequently  soon  nar- 
rows the  capillary  to  a  very  minute  calibre  or  obliterates  it.  Elsewhere  it 
is  found  as  a  mantle  for  the  tiny  arterioles  and  venules  in  the  cortex  and 
pyramids,  and  also  for  the  conducting  tubules.  It  is  easy  to  understand 
that  the  application  of  iodine  to  the  cut  surface  of  such  a  kidney  would 
reveal  the  glomeruli  as  brilliant,  chestnut-brown  points  in  a  tissue  every- 
where very  finely  streaked  with  brown  (Fig.  142). 


Fig.  42.  —  Amyloid  infiltration  of  Malpighian  bodies  of  spleen. 


It  is  unnecessary  to  describe  in  detail  the  distribution  in  other  organs, 
where  it  follows  the  same  principle  of  infiltrating  between  capillary  en- 
dothelium and  the  adjacent  cells.  Wherever  it  is  present  in  abundance  it 
causes  atrophy  of  the  pre-existing  tissues.  Its  distribution  is  usually  suf- 
ficient to  distinguish  it,  even  if  specific  stains  cannot  be  applied,  from  other 
hyaline  materials  which  stain  with  eosin  but  have  not  the  peculiar  chemical 
character  of  amyloid. 


102 


TEXT-BOOK   OF   PATHOLOGY 


Chemical  Nature. — Amyloid  is  a  very  resistant  substance,  which  ap- 
parently persists,  when  once  formed,  although  some  experiments  tend  to 
show  that  when  it  is  produced  in  animals  it  will  disappear  after  a  time  if 
the  animal  is  allowed  to  recover  from  the  injections  of  bacteria  or  toxin 
which  are  used  to  produce  it.  It  was  thought  not  to  be  attacked  even  by 
digestive  ferments,  but  now  it  has  been  shown  that  it  can  be  digested  slowly 
by  artificial  gastric  juice.  In  the  attempt  to  determine  its  chemical  nature 


Fig.  43. — Amyloid  infiltration  of  liver.     Compression  and  atrophy  of  liver-cells. 

it  was  first  extracted  in  a  fairly  pure  form  by  taking  advantage  of  its  solu- 
bility in  baryta  water.  Oddi  then  discovered  that  while  different  specimens 
vary  widely  in  composition,  all  sorts  of  amyloid  contain  chondroitin- 
sulphuric  acid,  a  substance  found  normally  in  cartilage,  but  whose  struc- 
ture is  still  unknown.  Amyloid,  however,  is  of  protein  nature,  and  is 
apparently  a  compound  of  chondroitin-sulphuric  acid  with  a  histone. 
Details  of  the  rather  fruitless  attempts  to  determine  its  composition  may 
be  read  in  Neuberg's  paper. 


CARBOHYDRATE   METABOLISM — GLYCOGEN  103 

Davidsohn  has  speculated  on  the  way  in  which  it  is  formed.  Since  it 
cannot  be  transported  in  the  blood-stream,  it  must  be  formed  in  situ,  and 
this  he  thinks  is  accomplished  by  a  ferment  formed  in  the  spleen,  since  amy- 
loid is  not  to  be  produced  in  an  animal  without  a  spleen. 

Much  has  been  said  of  its  experimental  production.  Krawkow  succeeded 
in  this  by  repeated  injections  of  bouillon  cultures  of  Staphylococcus  aureus, 
but  others  have  found  that  turpentine  or  other  pus-producing  poison  or 
cultures  of  various  other  bacteria  or  their  toxins  will  also  cause  its  ap- 
pearance. The  horses  used  for  the  manufacture  of  diphtheria  antitoxin 
often  show  amyloid  changes  in  their  organs,  and  so  do  mice  and  rats  inocu- 
lated with  transplantable  tumors. 

A  point  of  peculiar  interest  is  that  amyloid  seems  to  go  through  several 
stages  in  its  formation — at  first  it  will  not  stain  with  iodine,  although  giving 
a  metachromatic  stain  with  methyl-violet.  It  is  only  in  the  latest  stages 
that  it  will  give  the  blue  or  black  color  with  sulphuric  acid  and  iodine. 
The  early  stage  of  non-stainable  amyloid  recognized  by  Davidsohn  was 
called  achrooamyloid.  Quite  recently  we  observed  an  instance  in  a  young 
man  with  advanced  pulmonary  tuberculosis  in  whom  a  typical  sago  spleen, 
enormous,  bacon-like  liver,  and  advanced  renal  amyloid  were  found. 
Nevertheless,  although  the  diagnosis  was  unmistakable  to  the  naked  eye, 
none  of  the  amyloid  would  stain  with  iodine. 

Besides  the  general  amyloid  infiltration,  there  occur  localized  amyloid 
deposits,  sometimes  in  the  form  of  tumor-like  masses,  usually  in  connec- 
tion with  cartilage-containing  structures,  such  as  the  bronchi  (Herxheimer, 
Schilder). 

LITERATURE 
Davidsohn:   Ergebn.  d.  wiss.  Medizin,  1910,  i,  330;    Virch.  Arch.,  1907,  clxxxviii,  395; 

1908,  cxcii,  245. 

Leupold:  Ziegler's  Beitrage,  1918,  Ixiv,  347. 
Schmidt:  Verb.  Dtsch.  Path.  Gesellsch.,  1904,  vii,  2. 
Neuberg:  Ibid.,  1904,  vii,  19. 
Schilder:  Ziegler's  Beitrage,  1909,  xlvi,  602. 


CARBOHYDRATE  METABOLISM— GLYCOGEN 

Carbohydrates  as  they  appear  in  the  body  are,  for  the  most  part,  prac- 
tically inaccessible  to  our  staining  methods  and  do  not  appear  in  our  micro- 
scopical studies  of  the  tissues  except  in  the  form  of  glycogen,  which  we  can 
make  evident  by  certain  stains.  Nevertheless  we  can  study  accurately 
by  chemical  methods  the  various  phases  of  the  carbohydrate  metabolism, 
and  recognize  quantitatively  the  presence  of  sugars,  etc.,  in  different  fluids 
and  tissues. 

It  has  been  shown  that  carbohydrates  can  be  formed  in  the  liver  from 
many  of  the  amino-acids  which  form  the  constituents  of  proteins,  and  there- 
fore from  the  proteins  themselves.  The  evidence  is,  on  the  whole,  against 
their  formation  from  fats.  Most  of  the  carbohydrate  is,  however,  ab- 


104  TEXT-BOOK   OF   PATHOLOGY 

sorbed  in  a  soluble  form  in  the  intestine  and  conveyed  to  the  liver  and  to  the 
general  circulation  in  turn.  In  the  liver  it  is  probable  that,  through  the 
activities  of  the  cells,  the  soluble  sugar  which  has  already  passed  the  in- 
testinal wall,  chiefly  in  the  form  of  dextrose,  is  polymerized  and  becomes 
glycogen  (Fig.  20) .  Apparently  the  liver-cells  are  not  the  only  ones  which 
can  carry  out  this  function,  for  glycogen  is  found  lodged  in  many  other 
tissues.  In  the  epithelial  cells,  in  cartilage,  etc.,  there  is  constantly  gly- 
cogen present,  while  it  is  normally  lacking  in  the  nervous  system,  pancreas, 
salivary  glands,  breasts,  thyroid,  hypophysis,  adrenals,  bone-marrow,  etc. 
Its  amount  varies  in  the  muscles  and  liver  according  to  the  activity  of 
those  organs,  the  state  of  nutrition,  etc.  In  the  heart  muscle  it  is  usually 
more  abundant  than  in  the  skeletal  muscles.  In  the  embryo  it  is  in  general 
more  abundant  than  in  the  adult,  but  its  presence  is  by  no  means  charac- 
teristic of  embryonic  tissue,  and  we  are  not  justified  in  speaking  of  patho- 
logical new-growths  as  composed  of  embryonic  tissue  merely  because  they 
contain  much  glycogen.  It  is,  nevertheless,  true  that  many  rapidly  grow- 
ing tumors  are  especially  rich  in  this  substance. 

For  its  redistribution  glycogen  must  be  again  converted  into  diffusible 
sugar,  which  may  be  brought  to  the  muscles  to  act  as  a  store  of  energy. 
In  the  blood — especially  in  the  leucocytes — some  glycogen  may  be  demon- 
strated under  varying  circumstances,  but  this  cannot  be  regarded  as  the 
mode  of  transport,  and  the  dissolved  sugar  escapes  our  microchemical  tests. 
In  order  to  bring  this  about  certain  diastatic  ferments  must  be  brought 
into  play — the  process  of  mobilizing  the  carbohydrate.  This  is  easy  enough 
in  such  organs  as  the  liver  and  muscles,  which,  with  respect  to  glycogen, 
act  largely  as  storehouses,  but  in  others,  like  the  cartilages  and  epithelial 
layers,  the  glycogen  seems  to  form  an  integral  part  of  the  cell-body  and  is 
not  readily  mobilized. 

The  diastatic  ferment  converts  the  glycogen  into  the  more  readily  sol- 
uble dextrose,  which  then  enters  the  blood  and  is  carried  to  the  muscles  or 
other  places,  where  it  is  required  to  furnish  energy  or  heat,  and  there,  by 
the  aid  of  other  ferments,  undergoes  the  process  of  glycolysis,  with  final 
oxidation  to  carbon  dioxide  and  water.  This  diastatic  ferment  may  con- 
tinue to  act  after  death,  so  that  haste  is  necessary  and  proper  fixation  in 
substances  such  as  strong  alcohol,  if  we  wish  to  demonstrate  glycogen  in 
the  tissues.  Solution  of  the  glycogen  in  the  fluids  of  the  cell  may  also 
occur  postmortem,  so  that  estimates  of  the  glycogen  content  of  the  cells 
after  death  become  uncertain  unless  carried  out  with  care. 

Glycogen  may  be  stained  brown  with  iodine  or  bright  red  by  Best's 
carmine  method,  and  is  usually  in  rounded  masses  in  the  cell  protoplasm 
or  in  the  interstitial  tissue,  but  not  in  the  nucleus  (Fig.  20) ;  if  it  has  been 
dissolved  postmortem  in  the  cell  protoplasm,  it  does  not  quickly  pass  the 
cell  boundaries,  but  is  precipitated  in  granular  masses  by  the  alcohol  or 
other  fixing  fluid. 

In  pathological  conditions  produced  by  intoxications,  disturbances  of 


CARBOHYDRATE  METABOLISM — GLYCOGEN          105 

circulation,  inflammation,  etc.,  glycogen  may  appear  in  tissues  ordinarily 
devoid  of  it  or  containing  very  little.  The  cells  about  areas  of  necrosis  or 
inflammation  may  be  especially  rich  in  it.  This  is  due  to  the  impairment 
of  their  function,  which  does  not  readily  allow  them  to  get  rid  of  the  carbo- 
hydrate mass,  exactly  as  is  true  in  the  case  of  fat  accumulations.  In 
many  rapidly  growing  tumors,  especially  those  of  teratomatous  character 
and  the  more  malignant  growths,  it  is  likely  that  glycogen  may  be  found, 
although  there  are  many  exceptions  to  this  rule,  especially  in  those  derived 
from  cells  whose  functions  are  directed  rather  to  the  production  of  mucin, 
glycoproteids,  milk-sugar,  etc.,  where  glycogen  is  not  likely  to  appear. 

In  diabetes  mellitus  the  glycogen  content  of  most  of  the  tissues  is  found  to 
be  decreased,  although  for  some  reason  the  cells  of  part  of  the  convoluted 
tubules  of  the  kidney,  the  heart  muscle,  and  the  leucocytes  become  loaded 
with  it.  No  good  explanation  for  this  is  known.  It  is  thought  that  it 
may  be  due  to  their  inability  to  get  rid  of  the  glycogen,  which  is  brought 
to  them  by  the  sugar-rich  blood — or  that,  in  the  case  of  the  kidney  cells, 
they  reabsorb  carbohydrate  from  the  urine  in  the  tubule.  Diabetes  seems 
to  rest,  in  part  at  least,  on  such  a  disturbance  in  carbohydrate  metabolism 
that  the  dextrose  is  not  stored  up  as  polymerized  sugar  (glycogen)  in  the 
liver  and  elsewhere,  or  else  on  the  extraordinarily  active  mobilization  of  the 
sugar  in  the  organs — in  either  case  proper  glycolysis  and  consumption  of 
the  sugar  thus  thrown  into  the  blood  are  lacking,  and  the  sugar  is  lost  by 
being  excreted  through  the  kidney.  Probably  this  disturbance  of  glycoly- 
sis is  in  many  instances  due  to  the  loss,  through  disease,  of  the  ferment-like 
internal  secretion  of  the  pancreas,  which  ordinarily  takes  part  in  glycolysis. 
Much  difference  of  opinion  prevails  as  to  this  latter  point,  and  it  is  im- 
possible as  yet  to  make  any  definite  statement.  (See  further  discussion 
under  Diabetes.) 

Glycogen,  then,  must  be  regarded  as  a  normal  constituent  of  many 
organs — absent  in  others  and  present  in  a  third  group  in  both  a  stabile  and 
a  labile  form,  the  latter  of  which  is  most  easily  mobilized  to  furnish  soluble 
sugar  to  the  blood.  Under  pathological  conditions  where  nourishment 
and  functional  activity  of  cells  are  depressed,  there  may  appear  unaccus- 
tomed accumulations  of  glycogen  simply  because  the  cell  is  no  longer  able 
to  make  use  of  this  material,  and  by  depolymerization  set  it  free  into  the 
circulation.  Removal  of  the  disabling  agency  soon  leaves  such  cells  free 
to  resume  their  ordinary  metabolism,  and  the  glycogen  disappears. 


QHAPTER  VIII 
DISTURBANCES  OF  MINERAL  AND  PIGMENT  METABOLISM 

Calcium.  Its  source,  distribution,  deposition  in  necrotic  and  other  tissues.  Its  relation 
to  various  functions  of  the  body.  Iron:  its  distribution  and  functional  importance.  Dis- 
turbances in  its  quantitative  relations.  Chlorosis.  Hcemochromatosis.  Pigment:  func- 
tion and  distribution.  Endogenous  and  exogenous  pigmentation.  Jaundice.  Dust 
diseases. 

METABOLISM  OF  CALCIUM 

CALCIUM,  which  in  various  combinations  plays  many  important  roles  in 
the  animal  body,  is  absorbed  in  the  intestinal  tract,  and  in  very  consider- 
able quantity  reexcreted  into  the  intestine,  although  the  excretion  is  also 
carried  on  to  a  less  extent  in  the  urine.  Its  most  obvious  application  in  the 
body  is  in  the  formation  of  the  rigid  tissues  of  the  skeleton,  but  it  seems  to 
have  a  very  important  influence  upon  the  activity  of  the  heart,  the  excita- 
bility of  nerves,  the  clotting  of  blood,  etc.,  and  is  found  to  form  a  constant 
constituent  of  the  blood  and  tissues. 

The  pathological  disturbances  in  calcium  metabolism  might  readily 
fall  into  two  groups:  those  in  which  there  is  an  inadequate  supply  or  ex- 
cessive withdrawal  of  calcium,  and  those  in  which  the  reverse  occurs  and 
the  tissues  become  the  seat  of  abnormal  accumulations  of  lime  salts. 
In  both  instances  the  disturbance  may  be  local  or  general,  and  indeed  it 
seems  possible  that  calcium  may  be  removed  from  one  place,  only  to  be 
deposited  again  at  another  place  in  the  body. 

Calcium  Deficiency. — Experimentally  one  may,  by  feeding  a  diet  poor 
in  calcium,  reduce  the  consistence  of  the  bones  so  that  they  are  easily  cut 
or  broken.  The  ordinary  process  of  ossification  (Fig.  44)  is  distorted,  and 
new-formed  bone  is  calcified  only  at  the  expense  of  the  old.  Similarly  in 
certain  diseased  conditions  whose  causation  is  obscure  (rickets  and  osteo- 
malacia)  we  find  changes  which  are  very  similar  to  the  osteoporosis  pro- 
duced by  withdrawal  of  lime  salts  from  the  food;  but  different  also,  in 
many  respects,  especially  in  the  production  of  much  osteoid  tissue — which 
is  bone  tissue  morphologically  but  uncalcified.  In  both  rickets  and  osteo- 
malacia  there  appears  to  be  an  active  withdrawal  of  lime  from  the  already 
formed  bone  (halisteresis),  but  this  is  perhaps  more  obvious  in  osteoma- 
lacia.  In  these  diseases  we  find  extraordinary,  complicated  histological 
changes  which  appear,  however,  to  depend  upon  chemical  alterations, 
and  to  arise  in  response  to  changes  in  the  available  amount  of  calcium 
or  to  disturbances  in  the  power  of  the  tissue  thus  freshly  produced  to 
seize  upon  the  dissolved  calcium  and  fix  it  in  solid  form. 

The  processes  of  building  up  and  breaking  down  of  bone  go  on  constantly 

106 


METABOLISM    OF    CALCIUM 


107 


through  life,  and  it  is  apparently  the  result  of  a  disproportion  between  these 
that  the  constructive  processes  are  in  old  age  overshadowed  by  the  other- 
wise normal  destructive  processes.  The  osteoclasts  or  giant-cells,  whose 
function  is  to  erode  away  and  dissolve  the  old  bone,  continue  their  work, 
while  the  osteoblasts,  whose  function  it  is  to  rebuild,  slacken  in  their  new 
bone  production.  The  result  is  the  senile  osteoporosis  which  attenuates 
the  bony  structures  until  the  bone  becomes  very  much  rarefied  and  easily 
broken.  Whether  this  depends  upon  changes  in  the  available  quantity  of 


Fig.  44. — Process  of  calcification  in  normal  line  of  ossification  in  fetal  bone, 
vessels  with  osteoblasts  depositing  bone  on  remaining  matrix. 


Blood- 


calcium  it  is  difficult  to  say.  So,  too,  in  the  so-called  arthritis  deformans, 
which  is  accompanied  by  great  irregularity  in  ossification  and  rarefaction 
in  the  bones,  the  excessive  excretion  of  phosphorus  seems  to  point  to  a 
general  chemical  disturbance  which  is  associated  with  the  destruction  of 
the  bone. 

The  effects  of  withdrawal  of  calcium  upon  the  other  tissues  are  far  less 
evident,  but  it  has  been  shown  experimentally  that  this  substance,  when 
injected,  diminishes  the  excitability  of  the  nervous  system.  Conversely, 


108  TEXT-BOOK   OF    PATHOLOGY 

it  might  be  supposed  that  in  such  conditions  of  nervous  hyperexcitability 
as  tetany,  a  symptom-complex  which  follows  upon  the  destruction  of  the 
parathyroid  glands,  there  might  be  an  active  withdrawal  of  calcium  from 
the  tissues;  and,  indeed,  a  great  many  observations  have  been  made  which 
support  this.  Erdheim  has  shown  that  the  destruction  of  the  parathyroids 
results  in  an  extreme  decrease  in  the  process  of  ossification  and  in  the 
normal  calcification  of  the  dentine,  so  that  fractured  bones  heal  very 
poorly  and  the  teeth  become  so  softened  as  to  break.  After  actual  re- 
moval of  calcium  from  the  blood  by  dialysis  the  nerves  of  extremities  per- 
fused with  such  blood  become  electrically  hyperexcitable. 

Calcium  Excess. — In  the  other  group  of  conditions,  in  which  the  de- 
position of  calcium  in  unusual  situations  takes  place,  we  meet  with  many 
difficulties  in  finding  an  explanation  for  each  step.  Aside  from  the  modi- 
fication in  the  density  and  in  the  quantity  of  the  calcified  tissues  of  the 
bones,  we  may  find  gritty  or  mortar-like,  or  even  compact,  hard,  stone- 
like  concretions  of  lime  salts  in  various  parts  of  the  body  in  positions  where 
they  can  have  no  direct  relation  to  the  skeleton.  Thus  nothing  is  com- 
moner than  the  finding  of  necrotic  or  caseous  tubercles  in  the  lung  or  else- 
where which  have  become  encapsulated  with  a  dense  connective  tissue, 
and  in  the  central  parts  of  which  rough  granules  of  lime  have  appeared  in 
the  cheesy  substance.  These  may  become  so  abundant  and  so  com- 
pactly placed  that  it  is  impossible  to  cut  through  the  stony  mass.  The 
lymph-glands  of  the  mesentery  undergo  the  same  changes  after  tubercu- 
lous infection,  and  may  be  finally  converted  into  rough  white  masses  like 
pebbles.  The  walls  of  the  aorta  and  other  large  arteries  are  found  to  con- 
tain plaques  of  calcified  material  which  conform  with  the  curve  of  the  wall, 
and  are  usually  smoothly  covered  internally  with  endot helium.  Such 
plaques  are  formed  in  the  necrotic  patches  of  thickened  intima  in  the 
course  of  the  disease  arteriosclerosis,  and  when  fully  formed  resemble  bits 
of  eggshell  embedded  in  the  vessel- walls  (Figs.  171).  In  the  smaller  vessels 
such  areas  of  calcification  are  found  in  the  muscular  coat  (Figs.  177,  178). 

With  advancing  age,  and  probably  in  association  with  such  conditions 
as  bring  about  calcification  of  the  blood-vessels,  we  find  the  calcification 
of  such  cartilages  as  the  costal  and  tracheal,  which  ordinarily  remain  free 
from  this  substance. 

Sublimate  poisoning  and  anaemic  necrosis  in  the  kidneys  are  frequently 
followed  by  an  abundant  precipitation  of  calcium  in  the  form  of  casts  in 
the  tubules  or  in  the  necrotic  cells  themselves  (Fig.  45),  and  similarly  it 
is  extremely  common  to  find  calcified  plates  or  spicules  or  even  great,  stone- 
like  masses  developed  in  tumors  whose  circulation  has  become  deficient, 
so  that  necrosis  of  the  tissues  has  resulted.  This  is  analogous  to  the  de- 
position of  such  granules  in  any  necrotic  tissue  or  about  the  bodies  of  dead 
parasites,  such  as  trichinae,  which  have  been  long  embedded  in  the  muscles. 
We  find  no  difficulty  in  understanding  that  tumors  which  spring  from  the 
bone  themselves  produce  actual  bone  in  sheets  and  spicules,  because  we 


METABOLISM    OF    CALCIUM 


109 


are  accustomed  to  ascribe  to  the  osteoblasts  the  power  of  forming  bone. 
In  some  other  tumors,  such  as  the  so-called  psammomata,  tumors  which 
often  arise  from  the  coats  of  the  brain  or  the  pineal  gland,  etc.,  there  appear 
small  calcified  grains  which  are  often  closely  surrounded  by  the  tumor- 
cells  and  may  even  replace  groups  of  them. 

Except  in  the  case  of  the  growing  bone,  the  osteosarcomata,  and  other 
tumors  springing  from  the  bone,  those  tissues  which  become  incrusted  or 


Fig.  45. — Calcification  of  necrotic  renal  epithelium.     Sublimate  poisoning. 

impregnated  with  gritty  particles  of  lime  are  usually  dead.  They  have 
generally  assumed  the  vitreous,  glistening  appearance  which  we  are  accus- 
tomed to  associate  with  the  descriptive  term  "hyaline."  Even  in  the  case 
of  elastic  fibres  and  other  substances  which  are  homogeneous  in  the  normal 
state,  it  seems  probable  that  we  shall  find  that  those  which  become  cal- 
cified are,  after  all,  dead.  We  may  confidently  look  for  dead  tissues  as  the 
basis  for  such  precipitation  when  we  find,  for  example,  a  cuirass-like  shell 


110  TEXT-BOOK   OF    PATHOLOGY 

of  lime  about  the  heart  in  an  old  case  of  pericarditis,  or  a  stony  plug  in  the 
veins  of  the  spleen  or  of  the  pelvic  plexuses  where  thrombi  have  lain  for 
weeks  or  months  (phleboliths) . 

The  reason  for  this  process  has  been  sought  with  eagerness  in  recent 
years,  because  simple  explanations  which  once  seemed  satisfactory  are 
found  to  be  baseless.  There  seems  to  be  something  peculiar  about  these 
tissues,  living  or  dead,  which  gives  them  the  power  to  catch  up  the  calcium 
from  the  circulating  fluids  and  hold  it  finally  in  solid  form;  and  the  Ger- 
mans have  called  such  tissues  " Kalkf anger."  But  so  far  no  precise  and 
satisfactory  chemical  explanation  has  been  found.  It  is  shown  that  the 
lime  salts  deposited  in  dead  tissues  are  generally  the  same  and  in  the  same 
proportion  as  those  in  bone — about  87  per  cent,  of  calcium  phosphate  and 
10-15  per  cent,  of  calcium  carbonate.  Some  authors,  however,  have  found 
only  one  of  these  salts  in  pathological  calcification.  Magnesium  salts 
seem  to  play  a  subordinate  part  in  both  situations,  and  although  some  ob- 
servers have  found  them  present  in  the  proportions  found  in  the  bones, 
we  are  still  imperfectly  informed  with  regard  to  the  precipitation  of  these 
salts.  When  calcium  is  present  in  great  quantities  in  the  blood,  as  in  the 
rabbit,  calcification  of  dead  tissue  takes  place  very  rapidly,  so  that  the 
rabbit  is  an  especially  favorable  animal  for  the  study  of  this  process.  If 
we  ligate  the  blood-vessels  of  the  rabbit's  kidney,  the  tissue  becomes  quite 
densely  calcified  within  a  few  days. 

Necrotic  fat  tissue  seems  very  prone  to  calcification,  and  this  has  given 
origin  to  the  theory,  expressed  by  Klotz,  that,  in  general,  calcification  is 
preceded  by  an  accumulation  of  fat  with  decomposition  of  the  fat  into  fatty 
acids  and  another  component.  This  is  followed  by  the  formation,  by  a 
process  of  double  decomposition,  of  insoluble  calcium  soaps,  and  later 
completed  by  the  conversion  of  these  soaps  into  calcium  phosphate  and 
carbonate,  with  the  liberation  once  more  of  the  fatty  acid.  Unfortunately, 
although  the  theory  is  tempting,  it  has  been  shown  that  Klotz 's  methods 
were  inadequate  to  prove  his  point,  and  it  has  not  been  possible  to  show, 
except  perhaps  in  the  necrosis  and  calcification  of  fat  itself,  that  there  is 
more  than  a  trace  of  calcium  soap  in  any  such  area — not  sufficient  to  justify 
us  in  assuming  that  it  plays  an  important  part.  Nevertheless,  the  in- 
vestigations have  been  concerned  chiefly  with  finished  calcium  deposits, 
and  it  may  well  prove  that  the  calcium  soaps  have  a  transitory  existence  in 
leading  to  this  result.  Later  Klotz  found  that  by  injecting  cholesterin  in 
oil  so  that  it  became  lodged  in  many  phagocytic  cells  he  could  produce 
focal  deposits  of  calcium  corresponding  exactly  with  the  localization  of  the 
fatty  material.  Wells,  who  has  offered  these  criticisms,  has  no  equally 
simple  explanation  in  its  place,  but  finds  that  certain  substances,  when 
introduced  in  the  tissue  fluids  of  an  animal  like  the  rabbit,  have  far  greater 
powers  of  absorbing  calcium  salts  and  retaining  them  than  have  others. 
Thus,  while  pieces  of  fat,  spleen,  thymus,  etc.,  are  found  to  contain,  after 
a  stay  of  fourteen  weeks  in  the  peritoneum  of  a  rabbit,  only  about  12  mgm. 


DISTURBANCES   IN    THE    METABOLISM    OF    IRON  111 

of  calcium,  a  similar  piece  of  cartilage  has  absorbed  154  mgm.  And  this  is 
true  even  if  the  cartilage  be  boiled,  so  that  there  can  be  no  question  of  vital 
activity.  Different  forms  of  cartilage  differ  in  this  respect,  and  while  the 
above  is  true  of  epiphyseal  cartilage,  that  which  ordinarily  does  not  become 
ossified,  such  as  the  rings  of  the  trachea,  will  take  up  hardly  more  than  the 
spleen.  Wells  thinks,  therefore,  that  the  beginning  of  calcification  is  based 
upon  a  simple  physical  absorption  of  these  hyaline  substances;  that  the 
process  in  the  calcification  of  pathological  or  dead  tissues  is  identical  with 
that  in  ossification.  Calcium  is  carried  in  the  blood  in  amounts  not  far  from 
saturation  point,  held  in  solution  by  the  colloids  and  the  carbon  dioxide. 
This  unstable  double  salt  of  calcium  bicarbonate  and  dicalcium  phosphate 
is  adsorbed  in  the  hyaline  matrix  and  precipitated  by  a  reduction  in  the 
quantity  of  carbon  dioxide.  Calcium  deposition,  according  to  him,  seems  to 
depend,  alike  in  normal  and  most  pathological  conditions,  rather  on  physico- 
chemical  processes  than  on  chemical  reactions. 

Another  type  of  calcification  has  been  described  in  the  so-called  metas- 
tasis of  lime  salts,  which  is  said  to  depend  usually  upon  the  saturation  of  the 
circulating  fluids  with  those  salts  as  the  result  of  extensive  breaking  down 
and  solution  of  the  bony  tissues  in  some  part  of  the  body.  Then  the  cal- 
cium is  deposited  elsewhere  where  the  carbon  dioxide  content  of  the  fluid 
is  least,  as  in  the  mucosa  of  the  stomach  and  sometimes  in  the  vessel- 
walls.  The  existence  of  this  process  has  been  called  into  question  by  some 
writers,  and  at  least  it  must  be  quite  rare. 

Occasionally,  as  in  the  tuberculous  lung  or  in  the  walls  of  the  sclerotic 
aorta,  the  stony,  calcified  material  may  in  time  be  replaced  by  a  for- 
mation of  true  bone  with  Haversian  systems,  and  a  marrow  cavity  in 
which  all  the  characteristic  cells  of  the  bone-marrow  appear.  This  seems 
to  occur  only  upon  the  immediate  foundation  of  a  mass  of  formless  calcium 
which  has  itself  occupied  the  place  of  the  dead  tissue,  and  is  perhaps  to  be 
regarded  as  a  kind  of  reparative  process. 

LITERATURE 

Aschoff:    Lubarsch-Ostertag  Ergeb.,  1902,  viii,  561. 

Klotz:  Jour.  Exp.  Med.,  1906,  viii  322.     Proc.  Soc.  Exp.  Biol.  Med.,  1915,  xii,  159. 
MacCallum,  Lambert,  and  Vogel:  Jour.  Exp.  Med.,  1914,  xx,  149. 
Ricker:  Lubarsch-Ostertag  Ergeb.,  1896,  iiii,  643. 
Schultze:  Ibid.,  1910,  xivi,  706. 

Wells:  "Calcification  and  Ossification,"  Archives  Internal  Med.,  1911,  vii,  721.    Har- 
vey Lectures,  New  York,  1910-11,  102. 

DISTURBANCES  IN  THE  METABOLISM  OF  IRON 

Distribution  of  Iron  in  the  Body. — The  whole  nature  of  the  interchange  of 
iron  in  the  body  is  very  imperfectly  understood,  although  it  is  known  to 
be  of  profound  vital  significance. 

Iron  exists  in  the  body  of  an  adult  in  the  haemoglobin  of  the  red  cor- 
puscles and  in  all  the  cells  of  other  tissues.  The  amount  contained  in  the 


112  TEXT-BOOK   OF   PATHOLOGY 

blood  is  about  3  gm.  That  contained  in  invisible  form  in  other  cells  has 
been  estimated  roughly  at  1  to  3  gm. 

It  is  similarly  a  constituent  of  the  blood  and  tissues  of  other  animals 
and  of  vegetable  cells,  being  present  in  chlorophyll  in  combinations  some- 
what allied  to  that  found  in  haemoglobin.  Hence  it  enters  into  the  human 
body  in  animal  and  vegetable  food.  The  complex  organic  compounds  are 
decomposed  in  the  intestine  in  such  a  way  that  the  iron  is  absorbed  in  the 
ionic  form.  Bunge's  statement  that  it  could  be  absorbed  only  when  pre- 
sented in  the  form  of  the  higher  organic  combination  is  rendered  improb- 
able by  this  fact,  and  further  disproved  by  the  familiar  clinical  experience 
of  the  effect  of  administering  inorganic  compounds  in  anaemias,  and  by  the 
results  of  direct  experiments  which  show  the  absorption  of  these  com- 
pounds. 

The  ingested  iron  is  absorbed  in  the  duodenum  and  the  upper  part  of 
the  small  intestine.  As  has  been  shown  in  cases  of  intestinal  fistula,  the 
chyme  of  the  lower  part  of  the  ileum  contains  none.  On  the  other  hand, 
the  excess  is  excreted  into  the  colon  and  leaves  the  body  with  the  faeces. 
By  microchemical  methods  it  may  be  demonstrated  in  the  walls  of  the 
duodenum,  and  again  in  those  of  the  colon,  but  not  in  the  walls  of  the 
lower  ileum. 

The  exact  mechanism  of  absorption  is  not  clearly  known.  Some  is 
directly  received  by  the  epithelial  cells  and  transferred  later.  Some 
appears  to  be  carried  into  the  tissues  by  leucocytes,  or  may  possibly  enter 
in  association  with  lipoid  droplets  (A.  B.  Macallum).  Part  of  it  is  thought 
to  pass  by  way  of  the  thoracic  duct,  but  it  may  be  assumed  that  the  greater 
part  enters  by  way  of  the  portal  vein  and  reaches  the  liver.  We  are  equally 
ignorant  of  the  exact  mechanism  of  excretion,  but  in  this  respect  iron  seems 
to  show  analogies  with  calcium. 

In  the  blood,  iron  is  found  in  the  haemoglobin,  a  combination  of  a  very 
complex  protein,  globin,  with  haemochromogen  or  its  oxidation  product, 
hsematin.  Haematin  (C34H34N405Fe,  Abderhalden)  may  be  decomposed 
into  haematoporphyrin  through  the  loss  of  its  iron,  and  this  in  itself  is  a 
complex  carbon  compound  containing  pyrrol  derivatives,  and  related  to 
an  analogous  decomposition  product  of  chlorophyll.  Abderhalden  points 
out  that  the  formation  of  haemoglobin  involves,  therefore,  the  process  of 
formation  of  haematin  and  its  subsequent  union  with  the  highly  specific 
globin,  which,  since  all  must  start  with  the  simplest  building-stones  which 
can  pass  the  intestinal  wall,  leaves  several  points  at  which  the  production 
of  the  haemoglobin  may  be  deranged. 

The  intermediary  exchange  of  iron  is  beset  with  difficulties  of  interpreta- 
tion. Red  blood-corpuscles  are  destroyed  in  the  body,  probably  very 
largely  by  the  spleen.  The  haemoglobin  thus  set  free  passes  intact  or 
partly  decomposed  from  the  spleen  to  the  liver.  Doubtless  most  of  the 
iron  absorbed  from  the  intestine  passes  in  the  same  way  directly  to  the 
liver. 


DISTURBANCES    IN   THE   METABOLISM    OF   IRON  113 

From  the  hsematin  separated  from  the  globin  iron  is  liberated  in  the  liver, 
and  the  iron-free  residue  constitutes  the  bile-pigment,  bilirubin,  which  is 
an  isomer  of  haematoidin. 

W.  H.  Brown  criticizes  this  statement  because  powdered  haematin  in- 
jected into  the  peritoneum  does  not  produce  hsematoidin  or  haemosiderin. 
It  seems,  however,  that  the  appropriate  conditions  are  imperfectly  repro- 
duced in  this  experiment. 

The  fate  of  the  iron  thus  set  free  in  the  liver,  and  of  that  brought  there 
from  the  intestines,  has  not  been  traced,  but  it  is  clear  enough  that  it  is 
somehow  worked  up  into  haemoglobin. 

The  iron  of  the  tissues  which  is  largely  a  constituent  of  the  chromatin  is 
tenaciously  held  by  the  cells  and  shared  with  the  blood  only  in  conditions 
of  grave  anaemia. 

At  birth  the  foetus  is  rich  in  iron  which  was  stored  in  its  body  from  the 
mother,  but  during  suckling  very  little  iron  is  absorbed  with  the  milk, 
which  is  extremely  poor  in  that  substance.  Therefore,  the  iron  content  is 
low  at  the  end  of  the  period  of  suckling,  but  rises  rapidly  when  the  infant 
begins  to  take  other  food  than  milk.  M.  B.  Schmidt  found  that  if  the  iron- 
free  diet  were  continued  in  growing  mice  after  the  termination  of  suckling, 
they  gradually  became  anaemic  and  were  stunted  in  their  growth.  The 
offspring  of  such  mice  were  studied  through  several  generations,  through- 
out which  the  feeding  was  continuously  "iron  free."  If,  now,  iron  were 
given  to  one  of  a  litter  of  such  meagre,  anaemic  mice,  it  quickly  outgrew 
the  control  brother,  and  as  quickly  acquired  a  high  percentage  of  haemo- 
globin and  a  nearly  normal  blood  count,  showing  that  the  manufacture  of 
haemoglobin  had  been  halted  by  the  failure  of  the  tissues  to  acquire  and 
then  set  free  sufficient  iron,  and  that  this  matter  was  quickly  set  aright 
by  the  supply  of  inorganic  iron.  The  rapid  growth  that  ensues  indicates 
the  fundamental  importance  of  iron.  The  spleen  appears  to  be  the  organ 
in  which  blood-corpuscles,  destroyed  there  or  elsewhere,  give  up  their  iron 
to  be  carried  to  the  liver.  But  this  idea  of  the  function  of  the  spleen, 
which  is  regarded  by  Chevallier  also  as  an  organ  of  assimilation  of  iron, 
preserving  and  transferring  it  for  the  manufacture  of  haemoglobin,  must  be 
made  to  accord  with  the  fact  that  the  spleen  is  a  great  site  of  blood  destruc- 
tion, and  the  further  fact  that  its  extirpation  has  a  beneficial  effect  in  such 
severe  anaemias  as  pernicious  anaemia. 

The  function  of  iron  in  the  body  is  at  least  to  be  definitely  associated 
with  the  transfer  of  oxygen,  and  probably  more  generally  with  the  processes 
of  oxidation  of  the  tissues.  Its  role  in  connection  with  its  presence  in  the 
chromatin  of  the  cells  is  not  so  clear,  but  it  seems  to  affect  directly  or  in- 
directly the  process  of  growth.  As  in  the  case  of  fats  and  lipoids,  it  is 
evident  that  the  forms  in  which  iron  is  active  in  carrying  out  its  important 
functions  are  those  in  which  it  is  invisible  even  with  the  aid  of  most  micro- 
chemical  reactions.  When  it  becomes  visible,  it  is  because  it  is  cast  out  of 
functional  activity  and  lies  scattered  in  the  tissues  in  pigmented  granules. 


114  TEXT-BOOK   OF   PATHOLOGY 

Much  has  been  written  recently  concerning  its  relation  to  the  process  of 
calcification.  It  appeared  from  the  work  of  Gierke  and  others  that  sub- 
stances about  to  become  the  seat  of  a  deposit  of  lime  salts  first  absorbed  a 
quantity  of  iron.  Hueck  opposed  this  on  the  ground  that  the  microchem- 
ical  reactions  showing  the  presence  of  iron  in  calcified  areas  were  due  to 
impurities  of  fixing  fluids,  etc.  He  even  suggested  the  test  for  iron  in 
tissues  soaked  in  a  weak  iron  solution  as  a  means  of  demonstrating  the 
distribution  of  calcium.  Noesske  found  that,  while  perfectly  fresh  bones 
and  calcified  tissues  showed  no  iron,  it  was  to  be  demonstrated  in  those 
situations  if  the  body  had  lain  for  some  time.  He,  therefore,  thought  that 
in  this  interval  iron  had  been  absorbed  from  the  adjacent  tissues. 

Sumita,  Eliascheff,  and  others  return  to  the  original  idea  that  iron  is 
actually  to  be  found  as  a  forerunner  of  the  deposition  of  calcium  in  tissues 
examined  when  perfectly  fresh  after  every  precaution  has  been  observed 
to  avoid  the  objection  that  calcified  material  eagerly  absorbs  iron  from  the 
most  dilute  solution.  Sprunt  found  an  incrustation  of  elastic  tissue  fibres 
with  calcium  and  with  iron,  while  Gigon,  in  studying  a  lung  supposed  to 
contain  a  similar  combination  of  lime  and  iron,  as  shown  by  microchemical 
methods,  found  by  analysis  no  calcium,  but  much  iron  in  association  with 
sodium  salts.  The  results  are  very  contradictory,  but  there  is,  at  least, 
much  evidence  that  iron  and  calcium  are  deposited  together,  although  it 
is  not  so  clear  as  to  which  is  the  pioneer. 

Two  definite  affections  may  be  mentioned  here  as  examples  of  disturb- 
ances in  the  metabolism  of  iron,  the  others,  which  appear  to  be  rather 
more  incidental  processes,  leading  to  local  accumulations  of  iron-containing 
pigment,  being  discussed  elsewhere. 

Chlorosis. — Young  girls  frequently  develop  a  peculiar  greenish  pallor 
with  great  weakness,  perversion  of  appetite,  digestive  disturbances,  and 
constipation.  The  blood  shows  a  nearly  normal  number  of  red  corpuscles, 
which,  however,  are  very  pale,  so  that  the  haemoglobin  index  may  be  ex- 
tremely low.  The  disease  is  readily  cured  or  even  passes  away  itself  with 
improvement  in  the  state  of  the  digestive  organs,  so  that  little  is  known 
with  regard  to  its  pathological  anatomy.  It  is  influenced  by  purgatives, 
and  in  a  most  remarkable  way  by  the  administration  of  iron  in  any  form. 
Whether  the  inorganic  iron  thus  given  actually  forms  the  material  for  the 
new  production  of  haemoglobin,  or  stimulates  its  production  by  liberating 
the  supply  of  combined  iron  from  the  tissues,  remains  uncertain.  Nor  do 
we  know  whether  the  defect  in  the  formation  of  haemoglobin  is  due  to  the 
inadequate  absorption  of  iron  or  to  some  difficulty  in  its  combination  with 
haematoporphyrin  to  form  haematin,  or  finally  to  lack  of  the  necessary 
globin.  One  might  imagine  that  if  these  combinations  are  formed  under 
the  influence  of  ferments,  the  digestive  disturbances  could  explain  their 
absence. 

Hsemochromatosis. — A  disease  described  by  Hanot  and  Chauffard,  and 
named  by  v.  Recklinghausen,  in  which  an  extraordinary  deposition  of  iron- 


DISTURBANCES   IN   THE   METABOLISM   OF   IRON 


115 


Fig.  46. — Haemochromatosis.     Pigmentation  of  liver. 


Fig.  47  — Hsemochromatosis.     Pigment  deposit  in  tissues  of  the  liver. 


116  TEXT-BOOK  OF  PATHOLOGY 

containing  pigment  (haemosiderin),  together  with  other  pigment  (hsemo- 
fuscin)  which  contains  no  iron,  is  found  in  practically  all  the  organs,  in- 
cluding the  skin.  It  is  often  associated  with  cirrhosis  of  the  liver  and  pan- 
creas and  with  diabetes,  hence  the  name,  "bronzed  diabetes,"  which  is 
appropriate  in  many  cases. 

The  skin  is  of  a  dusky  bronze  hue,  and  in  sections  the  pigment  may  be 
demonstrated  by  its  giving  the  Prussian-blue  reaction.  The  liver,  pan- 
creas, kidneys,  lymph-glands,  heart  muscle,  etc.,  are  found  to  be  of  a 
bright,  chestnut-brown  color,  and  show  microscopically  astounding  col- 
lections of  pigment  in  clumps  and  granules  (Fig.  46).  The  pigment  lies 
chiefly  in  phagocytic  cells,  such  as  Kupffer's  cells  of  the  endothelium  of  the 
liver,  but  it  is  also  lodged  in  the  connective  tissue  and  in  the  liver-cells 
themselves  (Fig.  47).  In  the  other  organs  it  has  a  corresponding  posi- 
tion— apparently  its  presence  as  a  foreign  body  leads  to  much  new- 
growth  of  encapsulating  fibrous  tissue.  Most  of  it  can  be  stained  blue 
with  ferrocyanide  and  hydrochloric  acid,  but  part  of  it  remains  brown  and 
responds  to  no  tests  for  iron  (hsemof uscin) . 

There  is  no  obvious  anaemia,  no  especial  evidence  of  wide-spread  blood 
destruction,  and  no  especial  activity  of  the  blood-forming  organs  to  repair 
a  destruction  of  blood  which  would,  of  course,  occur  to  any  one  as  the 
probable  source  of  so  much  iron-containing  pigment. 

Here  the  disturbance  of  iron  metabolism  must  occur  at  some  other  point. 
In  sharp  contrast  with  chlorosis,  in  which  it  appears  that  absorption  of 
iron  or  its  combination  into  haemoglobin  is  deranged,  there  is  found  an  ade- 
quate haemoglobin  production,  little  or  no  blood  destruction,  but  at  the 
same  time  an  overwhelming  accumulation  of  haemosiderin.  In  lack  of 
definite  information  one  may  make  the  surmise  that  it  may  prove  that  the 
normal  excretion  of  the  excess  of  iron  through  the  mucosa  of  the  colon  is 
defective,  and  that  the  pigment  represents  a  retention.  But  this  is  far 
from  standing  as  a  satisfactory  explanation,  and  haemochromatosis  remains 
a  problem.  Indeed,  the  studies  of  Howard  and  Stevens  and  of  McClure 
show  perhaps  a  slight  negative  balance  in  the  case  of  iron,  but  no  marked 
general  disturbance  of  metabolism. 

LITERATURE 

Abderhalden:  Lehrb.  d.  physiol.  Chemie,  1909,  491. 

Gierke:  Virch.  Arch.,  1902,  clxvii,  318. 

Howard,  C.  P.,  Stevens,  F.  A.:  Archives  of  Inter.  Med.,  1917,  xx,  897. 

McClure,  C.  W.:  Ibid.,  1918,  xxii,  610. 

Macallum,  A.  B.:  Jour,  of  Physiol.,  1894,  xvi,  268.    Proc.  Roy.  Soc.,  1891,  1,  277. 

Opie:  Jour.  Exp.  Med.,  1899,  iv,  279. 

Schmidt,  M.  B.:  Verh.  Dtsch.  Path.  Gesellsch.,  1912,  xv,  91. 

Sprunt,  T.  P.:  "Haemochromatosis,"  Archives  of  Inter.  Med.,  1911,  viii,  75. 


DISTURBANCES    OF    PIGMENT   METABOLISM  117 

DISTURBANCES  OF  PIGMENT  METABOLISM 

Pathological  disturbances  of  metabolism  are  by  no  means  limited  to  pro- 
teins, carbohydrates,  and  fats,  but  involve  irregularities  in  the  formation 
and  distribution  of  many  other  substances  which  ordinarily  serve  a  normal 
function.  Were  we  better  informed,  it  would  be  most  logical  to  discuss 
each  of  these  according  to  its  chemical  nature  and  relations,  but  we  know 
so  little  that  we  can  hardly  escape  from  the  temptation  to  group  them 
according  to  some  striking  peculiar  feature.  It  is  for  this  reason  alone 
that  we  discuss  in  one  chapter  pigments  which  are  often  hardly  related, 
except  through  the  fact  that  they  are  colored. 

Most  of  these  pigments  serve  important  purposes,  and  very  little  of  their 
history  concerns  pathology  except  when,  like  the  slag  heap  that  indicates 
the  activity  of  a  smelter,  they  show  by  their  accumulation  the  presence 
of  some  unusual  activity  in  the  body.  Ordinarily,  enough  of  the  coloring- 
matter  of  the  skin  or  hair  is  produced  to  confer  on  the  animal  those  colors 
which  are  the  beauty  of  the  animate  world,  and  which  serve  so  well  in  the 
protection  and  even  in  the  propagation  of  each  individual's  life.  Or  they 
are  concerned  in  the  interior  of  the  body  with  the  mechanisms  for  carrying 
oxygen  to  the  tissues  and  in  the  production  of  bile,  and  an  exquisite  econ- 
omy is  observed  in  their  use  and  the  maintenance  of  their  proper  propor- 
tions. Only  when  something  disturbs  these  mechanisms  do  we  find  the 
pigments  or  disjointed  by-products  in  their  formation  accumulated  some- 
where in  excess,  or,  on  the  other  hand,  lost  to  the  body  to  such  a  degree 
that  it  lacks  its  normal  colors. 

Certain  colored  substances  are  formed  in  the  body  and  elaborated  to 
typical  forms,  although  we  may  meet,  too,  with  less  complex  materials  which 
are  destined  to  be  built  up  into  these  type  forms  or  are  the  results  of  their 
decomposition.  These  are  endogenous  pigments.  Beside  these  there 
are  foreign  materials — colored  particles  breathed  into  the  lungs  or  taken 
into  the  stomach  or  through  the  skin,  or  fluids  which  impregnate  the  body 
with  colored  deposits,  and  these  are  called  exogenous  pigments. 

ENDOGENOUS  PIGMENTS 

Of  these,  several  kinds  are  met  with,  the  principal  ones  being  those  which 
are  specially  produced  to  color  the  skin,  and  hair  and  eyes,  usually  grouped 
as  the  melanins,  those  which  are  directly  or  indirectly  derived  from  the 
haemoglobin  of  the  blood,  and  those  which  are  somehow  associated  with 
fat-like  substances  and  come  from  the  wear  and  tear  and  breaking  down  of 
the  tissue-cells. 

Melanins. — The  melanins  may  assume  various  colors,  but  are  usually 
dark  brownish  or  black.  Their  enormous  variety  and  the  ways  in  which 
they  normally  occur  more  abundantly  in  those  races  exposed  to  sun  and 
wind,  their  abundance  largely  dependent  upon  hereditary  powers  of  the 
cells,  their  rapid  appearance  in  the  form  of  tan  and  freckles  in  response  to 


118 


TEXT-BOOK  OF  PATHOLOGY 


exposure— all  these  things  are  hardly  our  concern,  but  belong  to  the  field  of 
physiology.  Still  the  study  of  their  abnormal  production  and  distribution 
may  throw  some  light  upon  their  normal  origin.  Melanins  are  complex 
substances  containing  no  iron,  but  rich  in  sulphur.  Much  discussion  has 
arisen  as  to  their  origin  and  as  to  their  chemical  nature,  but  since  no  two  of 
them  seem  to  have  the  same  composition,  the  latter  point  still  remains 
obscure.  In  general,  it  is  found  that  such  substances  may  be  produced 
by  the  action  of  oxidizing  ferments,  such  as  tyrosinase,  upon  materials  like 

tyrosin,  ornithin,  etc.,  which 
contain  the  groups  pyrrol, 
pyridine,  skatol,  or  indol, 
but  that  it  is  hardly  possi- 
ble that  melanin  should 
be  produced  from  hsematin 
unless  some  other,  sulphur- 
containing  substance  be 
brought  into  the  reaction. 
The  evidence  seems  to  be 
entirely  against  the  origin 
of  melanins  from  the  con- 
stituents of  the  blood.  On 
the  contrary,  it  was  shown 
by  Wieting  and  Hamdi  and 
others  that  these  granules 
are  formed  in  the  epithelial 
cells  apparently  especially 
as  products  of  the  nucleus, 
and  although  they  may  be 
held  for  a  little  in  these 
"melanoblasts, "  they  may 
also  be  given  over  to  other 
wandering  cells  of  connec- 
tive-tissue origin,  the  chro- 
matophores.  Thus  the  pig- 
ment of  the  eye  is  thought 
to  be  formed  in  the  retina 
and  secondarily  transferred 
to  the  cells  of  the  choroid. 

Except  in  a  few  cases,  we  are  not  at  all  well  informed  with  regard  to  the 
abnormal  development  of  melanins  in  the  skin.  There  are  pigmentations 
which  are  doubtless  only  accentuations  of  the  normal,  and  occur  chiefly 
in  the  most  pigmented  areas  of  the  body,  such  as  the  chloasma  of  tuber- 
culosis and  of  pregnancy,  in  which  brownish  flecks  appear  on  the  face  and 
body,  and  the  areolae  of  the  nipples,  axillae,  etc.,  become  more  deeply  colored. 
Probably,  too,  in  the  healing  of  many  destructive  skin  diseases,  and  in  the 


Fig.  48. — Melanotic 


sarcoma, 
in  liver. 


Secondary  nodules 


DISTURBANCES    OF   PIGMENT   METABOLISM 


119 


area  about  an  old  healing  ulcer,  increase  of  melanin  produces  part  of  the 
brown  coloration,  although,  especially  in  the  latter  instance,  blood-pig- 
ment plays  a  part.  In  Addison's  disease,  which  results  from  the  destruc- 
tion of  the  adrenal  glands,  the  skin  gradually  assumes  a  darker  hue  until 
finally  it  is  like  that  of  old  bronze.  Whence  this  pigment  comes  we  do 
not  know,  nor  are  we  well  informed  as  to  its  nature. 


Fig.  49. — Pigmented  cells  of  melanotic  sarcoma  in  contrast  with  others  not  pigmented. 

Pressure  atrophy  of  the  liver. 

The  most  striking  example  of  the  massive  production  of  melanin  is  seen 
in  the  so-called  melanotic  tumors,  which  usually  spring  from  the  skin 
or  from  the  pigmented  tissues  of  the  eye.  Such  tumors,  which  in  their 
early  and  apparently  innocent  stages  are  known  as  moles  or  pigmented 
na3vi  (Fig.  504),  seem  to  be  derived  from  the  melanoblasts,  inasmuch  as 
their  metastatic  nodules  continue  to  form  melanin,  which  could  not  be 
expected  of  mere  pigment-carrying  cells,  the  chromatophores.  The  weight 
of  evidence  in  the  prolonged  strife  as  to  their  sarcomatous  or  carcinomatous 


120  TEXT-BOOK  OF  PATHOLOGY 

nature  is  apparently  with  those  who  hold  that  they  are  really  of  epithelial 
origin.  Growing  with  extreme  rapidity  and  invading  the  most  distant 
parts  of  the  body  arid  of  pigment,  these  tumor-cells  continue  to  manu- 
facture such  quantities  of  coloring-matter  that  not  only  is  the  mass  itself 
coal  black  (Figs.  48,  507),  but  the  pigment  is  carried  away  and  appears 
in  the  urine  either  as  such  or  in  a  modified,  colorless  form,  which  turns 
again  on  exposure,  or  when  an  oxidizing  substance  is  added,  to  pigment 
which  stains  the  urine  black.  No  one  seems  to  have  followed  very  precisely 
the  wandering  of  this  pigment,  although  it  is  known  that  melanins  injected 
into  the  circulation  of  an  animal  become  decolorized  by  the  reducing  action 
of  the  tissues,  only  to  blacken  again  when  they  are  oxidized. 

Ochronosis  is  a  rather  rare  condition  in  which  a  brown  or  blackish 
pigment,  probably  allied  to  the  melanins,  is  deposited  especially  in  the 
cartilages  and  ligaments,  but  also  in  the  aorta  and  sometimes  in  the  kid- 
neys. The  patient  becomes  conspicuous  on  account  of  the  bluish  color 
that  shimmers  through  the  skin,  where,  as  on  the  nose  and  ears,  the  pig- 
mented  cartilages  are  near  the  surface.  It  is  due  to  metabolic  disturbances 
often  accompanied  by  alkaptonuria,  or  to  the  introduction  of  small  quan- 
tities of  such  a  substance  as  carbolic  acid,  as  in  the  prolonged  treatment  of 
an  ulcer  with  that  antiseptic.  Poulsen  thinks  that  the  pigment  is  pro- 
duced by  the  action  of  such  a  ferment  as  tyrosinase  upon  tyrosin  or  homo- 
gentisinic  acid,  or  upon  derivatives  of  the  phenol  introduced  by  the  surgical 
dressings. 

The  malarial  parasite,  while  still  within  the  red  blood-corpuscle,  pro- 
duces particles  of  a  shining,  brownish-black  pigment  at  the  expense  of  the 
haemoglobin-containing  cell.  This  is  probably  derived  directly  from  the 
haemoglobin,  although  it  is  iron  free  and  by  most  authors  regarded  as  a 
form  of  melanin.  The  remainder  of  the  haemoglobin  dissipated  in  the 
plasma  after  the  parasite  breaks  out  of  the  cell  forms  an  iron-containing 
pigment.  Spleen,  liver,  and  other  organs  become  so  laden  with  a  combina- 
tion of  these  pigments  as  to  be  quite  blackened  (Figs.  383  and  384). 

Of  the  second  group  of  endogenous  pigments,  those  derived  from  the 
blood,  we  may  distinguish  several  forms.  The  source  of  all  is  haematin, 
which,  in  combination  with  a  globin,  forms  haemoglobin,  and  it  is  after  the 
haemoglobin  has  been  set  free  from  its  suspension  in  the  corpuscle  that  the 
decomposition  may  take  place.  Many  things,  ranging  from  distilled 
water  through  a  series  of  organic  or  inorganic  poisons  to  the  most  subtly 
modified  blood-sera,  may  act  as  haemolytic  substances  capable  of  dis- 
integrating the  red  corpuscles  and  setting  free  the  haemoglobin.  If  it  be 
thus  set  free  in  large  amounts  in  the  general  circulation,  it  may  be  excreted 
through  the  kidneys,  producing  the  so-called  haemoglobinuria.  This  is 
not  an  uncommon  accompaniment  of  malaria  in  some  countries  (black- 
water  fever),  and  there  has  been  much  discussion  as  to  whether  it  is  caused 
by  the  malaria  or  the  quinine  given  to  cure  it. 

Another  form  occurs  in  paroxysmal  attacks  in  certain  predisposed  per- 


DISTURBANCES    OF    PIGMENT  METABOLISM  121 

sons  whose  red  corpuscles  seem  very  fragile  and  liberate  the  haemoglobin 
on  the  slightest  injury.  Even  the  mere  exposure  to  cold  produces  an  excre- 
tion of  haemoglobin,  and  it  has  been  found  that  this  is  because  the  haemolytic 
substances  present  can  combine  and  act  only  at  a  low  temperature.  The 
kidneys  become  loaded  with  clumps  of  a  yellowish  material  which  seems 
to  have  come  through  the  glomeruli  and  lodged  in  the  tubules.  In  a 
similar  way  poisoning  with  chlorates  produces  the  excretion  of  a  modified 
hemoglobin,  methsemoglobin,  and  that  with  sulphonal  and  allied  poisons 
causes  the  appearance  of  iron-free  haematoporphyrin. 

Some  bacteria  have  the  power  of  causing  haemolysis,  and  in  general  in- 
fections, where  the  blood  becomes  filled  with  these  bacteria,  there  is  much 
destruction  of  red  corpuscles.  After  death  the  laked  blood  stains  the  tissues 
so  that  at  autopsy  the  walls  of  the  heart  and  the  linings  of  the  blood- 
vessels are  of  a  dull  red  color.  Through  the  walls  of  the  superficial  veins 
this  color  may  diffuse  to  such  an  extent  that  one  sees  a  network  of  purplish 
bands  shimmering  through  the  skin.  Nor  is  this  cadaveric  staining 
exclusively  the  effect  of  such  general  infections,  for  in  any  body  which  has 
lain  some  time  after  death  the  tissues  which  are  in  contact  with  large  accum- 
ulations of  blood  are  stained  deep  red.  It  is  not  particularly  a  patho- 
logical phenomenon,  but  one  which  might  confuse  the  unwary. 

Pigments  Arising  From  the  Decomposition  of  Haemoglobin. — Ordinarily, 
although,  as  we  know,  the  red  corpuscles  circulate  intact  only  a  relatively 
short  time,  so  that  in  every  hour  millions  of  them  fall  to  pieces,  there  is  no 
noticeable  coloring  of  the  blood-plasma  with  haemoglobin.  Nor  is  the 
haemoglobin  excreted  from  the  body  in  the  urine — instead,  it  is  taken  up 
by  various  cells  and  converted  into  different  sorts  of  yellowish-brown  pig- 
ment. Just  here  our  knowledge  of  the  process  proves  somewhat  incomplete, 
but  it  is  generally  accepted  that  the  liver-cells  form  bilirubin  from  such  raw 
material,  while  if  the  blood  is  laked  in  a  mass,  as,  for  example,  in  some 
cavity  of  the  body,  so  that  it  is  not,  except  at  its  edges,  in  contact  with 
living  cells,  a  red-brown  pigment,  called  hcematoidin,  is  formed,  which 
most  authors  think  is  identical,  or  at  least  isomeric,  with  bilirubin.  When, 
however,  the  haematin  or  the  whole  haemoglobin  is  taken  up  by  living 
cells,  even  including  the  liver-cells  at  times,  there  may  be  formed  another 
yellowish-brown,  granular  pigment — hcemosiderin.  These  are  the  main 
types,  although  there  are  others  of  less  importance.  Of  bilirubin  we  shall 
speak  in  connection  with  jaundice.  Like  it,  haematoidin  is  an  iron-free 
substance  (CieHig^Os)  which  occurs  in  amorphous  or  crystalline  form, 
or  sometimes  as  a  diffuse  staining  of  tissue.  It  is  often  recognizable  in  the 
central  portions  of  large  haemorrhagic  infarcts,  in  thrombi  or  old  haemor- 
rhages, sometimes  in  cysts  in  which  haemorrhages  have  occurred,  as  in  the 
thyroid,  or  in  the  brain  in  healing  apoplectic  haemorrhages. 

It  is  probably  of  relatively  uncommon  occurrence  as  contrasted  with  the 
third  of  these  colored  materials,  the  hcemosiderin.  To  this  we  can  give 
no  formula,  for  it  is  merely  a  mixture  of  pigments  in  which  iron  exists  in 


122  TEXT-BOOK  OF  PATHOLOGY 

a  most  accessible  form,  so  that  its  presence  may  be  readily  shown  by  the 
application  of  the  Prussian-blue  reaction.  Haemosiderin  is  the  common 
blood-pigment  which  results  upon  any  small  extravasation  of  blood  into 
the  tissues,  in  so  far  as  that  blood  is  not  immediately  reabsorbed  as  such. 
Thus  in  every  sort  of  wound  and  bruise,  in  every  sort  of  inflammation  in 
which  red  corpuscles  escape  from  the  vessels,  in  purpura,  in  scurvy,  and 
in  every  other  disease  where  there  are  ecchymoses  or  more  extensive  haem- 
orrhages into  the  tissues,  or  about  the  stings  of  insects  or  reptiles,  it  may 
be  found  after  some  days.  When  the  poison  is  of  a  hsemolytic  character, 
and  in  fact  in  any  condition  in  which  blood  or  the  coloring-matter  of  blood 
escapes  into  direct  contact  with  the  tissues,  there  may  be  formed  in  the 


Fig.  50.— Hsemosiderin  in  phagocytic  cells  near  an  organizing  thrombus. 

phagocytic  cells  yellow  or  yellowish-brown,  shapeless  granules  of  hsemo- 
siderin  (Fig.  50). 

A  few  common  examples  may  illustrate  the  mode  of  occurrence  of  this 
pigment.  In  old  insane  persons,  especially,  perhaps,  those  forms  of  insan- 
ity arising  from  syphilis  and  chronic  alcoholism  with  arteriosclerosis,  one 
may  find  lining  the  dura  mater  a  thick,  blood-stained  membrane  which 
will  peel  off  in  thin  layers  and  which,  on  being  washed  free  of  blood,  proves 
to  have  an  ochre  or  orange-yellow  color.  This  so-called  chronic  hcemorrhagic 
pachymeningitis  may  be  the  result  of  a  single  haemorrhage,  but  is  usually 
produced  by  something,  perhaps  itself  a  small  haemorrhage,  which  causes 
the  formation  of  a  thin  layer  of  vascular  granulation  tissue  from  the  cap- 
illaries of  which  new  haemorrhages  occur  and  cause  the  growth  of  a  new 
layer  of  tissue.  In  the  wandering  phagocytic  cells  which  pervade  this 


DISTURBANCES    OF    PIGMENT   METABOLISM 


123 


tissue  hsemosiderin  appears  in  granules  which  give  the  yellow  color  to  the 
whole.  A  quite  similar  rusty-brown  membrane  may  be  found  in  haemor- 
rhagic  hydrocele  sacs  where  the  tunica  vaginalis  testis  has  long  been 
inflamed.  Sometimes  a  haemorrhagic  infarction  of  the  lung  may  heal,  and 
the  area,  once  turgid  with  crumbling  red  corpuscles,  is  found  shrunken  and 
firm  with  scar  tissue  and  of  the  color  of  a  mass  of  iron  rust.  In  the  interior 
much  of  the  pigment  may  be  the  iron-free  hsematoidin,  but  that  in  the 
more  marginal  portions  is  found  to  stain  blue  with  ferrocyanide  and  hydro- 
chloric acid,  and  to  be  made  up  of  amorphous  granules  inclosed  in  cells 
which  are  often  fairly  bursting  with  their  load  of  pigment.  Again,  when 
the  mitral  valve  is  contracted  so  that  blood  does  not  readily  escape  from 
the  lungs,  we  may  find  them  distinctly  brown  on  section.  A  piece  of  such 
a  lung  washed  free  of  blood  and  dipped  in  ferrocyanide  of  potassium  and 
then  in  weak  hydrochloric  acid  becomes  bright  blue,  and  we  find  that 


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Fig.  51. — Heart-failure  cells  in  the  lung.     Chronic  passive  congestion. 

this  is  because  blood-corpuscles  have  for  months  oozed  into  the  alveolar 
cavities,  and  have  there  given  up  their  hsemoblobin,  to  have  it  converted 
into  phagocytes,  probably  the  alveolar  epithelial  cells,  into  hsemosiderin. 
Microscopically,  these  cells  are  seen,  swollen  with  yellow  granules,  lying  in 
the  alveoli  or  in  the  sputum  which  has  been  coughed  up  from  the  lung. 
Their  dependence  upon  this  chain  of  events  has  given  them  the  name 
"heart-failure  cells"  (Fig.  51). 

Arnold  finds  that  many  of  the  iron-staining  granules  are  due  to  the 
assimilation  of  fluid  iron-holding  material  by  the  specific  granules  of  the 
cell  protoplasm,  and  not  to  mere  engulfing  of  hsemosiderin  granules  by 
phagocytic  cells,  and  Neumann  states,  too,  that  in  the  heart-failure  cells  the 
pigment  masses  often  have  a  coal-black  central  point  and  are  really  formed 
by  the  incrustation  of  particles  of  soot  by  the  iron-containing  hsemosiderin. 


124 


TEXT-BOOK    OF    PATHOLOGY 


Not  in  all  cases  is  the  formation  of  haemosiderin  such  a  local  process, 
however,  for  there,  are  many  forms  of  general  anaemia  in  which  the  destruc- 
tion of  the  red  corpuscles,  usually  by  some  unrecognized  agency,  sets  free 
continuously  a  great  excess  of  haemoglobin  into  the  circulating  blood. 
This  may  cause  the  production  of  an  excess  of  bile-pigment  or  it  may  result 
in  a  wide-spread  deposition  of  haemosiderin  in  the  cells  of  many  organs. 
In  the  so-called  pernicious  anaemia,  of  whose  true  nature  we  are  ignorant, 


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Fig.  52. — Hsemosiderin  granules  in  the  liver-cells  and  endothelium.    Pernicious  anaemia. 

the  cells  of  the  liver  and  often  of  the  cortex  of  the  kidney,  spleen,  etc., 
become  laden  with  haemosiderin  in  fine  granules  (Fig.  52). 

In  haemochromatosis,  a  disease  of  which  mention  has  already  been  made, 
there  is  an  even  greater  deposition  of  haemosiderin  and  of  another  iron-free 
pigment,  haemofuscin,  without  any  extensive  destruction  of  red  corpuscles. 

We  know  that  such  pigment  is  transported  from  one  part  of  the  body 
to  the  other,  and  transferred  from  cell  to  cell,  and  that  much  of  it  reaches 
the  bone-marrow,  where  it  must  be  thought  of  as  furnishing,  according  to 
the  economical  scheme,  the  iron-rich  material  for  the  formation  of  new 


DISTURBANCES   OF   PIGMENT   METABOLISM  125 

haemoglobin  by  the  erythroblasts,  but  that  step  in  the  process  is  far  from 
clear.  When  there  has  arisen  in  any  way  a  deposit  of  hsemosiderin  in  the 
tissue  of  the  intestinal  wall  or  in  the  liver  and  spleen,  decomposition  of  the 
body  after  death  or  even  the  excessive  formation  of  hydrogen  sulphide 
in  the  intestine  or  in  the  infected  peritoneum  may  give  rise  to  the  forma- 
tion of  black  iron  sulphide  throughout  the  superficial  layers  of  the  tissue. 
This  is  pseudomelanosis. 

The  third  group  of  endogenous  pigments  may  be  more  briefly  dismissed, 
since  we  know  little  to  tell  of  them.  Nevertheless,  we  may  probably  look 
forward  to  learning  some  day  that  their  significance  is  greater  than  we  have 
thought.  These  are  the  yellowish  granules  which  are  found  in  many 
organs,  such  as  the  seminal  vesicles,  heart  muscle,  ganglion-cells,  and  prob- 
ably also  the  interstitial  cells  of  the  testes  and  the  cells  of  the  corpus  luteum 
and  adrenal.  They  give  something  of  the  characteristic  color  to  the  organ, 
and  in  some  cases  this  color  is  intensified  when  the  cells  of  the  organ  waste 
away.  It  seems  that  the  pigments  are  in  some  instances  produced  from  the 
cell  protoplasm  in  the  process  of  wasting,  wherefore  Lubarsch  and  Sehrt 
call  them  "wear  and  tear  pigments."  Others  have  loosely  called  them 
lipochromes,  but  they  do  not  give  the  reactions  which  have  been  set  forth 
for  the  "true"  lipochromes,  such  as  have  been  found  in  plants  and  are 
found  in  fats,  and  perhaps  in  the  lutein  cells  of  animals.  Their  distinctive 
feature  is  that  they  are  in  a  sense  colored  lipoids  and  stain  brightly  with 
Sudan  and  other  fat  stains.  Perhaps  the  best  example  of  their  accumula- 
tion in  gross  is  seen  in  the  wasted,  shrunken  heart  of  old  or  cachectic  people 
(brown  atrophy  of  the  heart).  There  the  muscle  has  a  chestnut-brown 
color,  and  microscopically  the  spaces  at  the  ends  of  the  nucleus  in  the 
narrow,  thread-like  muscle-fibre  are  filled  with  brown  granules  which  are 
shining  and  red  after  staining  with  sudan.  Of  course,  they  are  normally 
there,  but  they  are  vastly  more  abundant  in  the  brown,  atrophic  heart 
(Fig.  26). 

Jaundice. — Jaundice  or  icterus  results  from  the  diffusion  of  bile-pigment 
throughout  the  body,  with  imbibition  of  the  tissues.  There  has  been  and 
still  exists  an  active  dispute  as  to  whether  this  pigment  is  necessarily  the 
bilirubin  formed  by  the  liver-cells,  or  whether  from  the  laked  blood  the 
same  pigment  can  be  formed  by  other  tissues.  This  question  appeared  to 
be  settled  by  the  experiments  of  Minkowski  and  Mering,  Moleschott,  and 
others  who  rather  crudely  destroyed  the  liver  in  geese  and  were  then 
unable  to  produce  jaundice.  But  recently  evidence  has  appeared  in  favor 
of  the  opposite  view,  and  Dr.  Whipple  even  tells  me  that,  after  completely 
extirpating  the  liver  in  a  dog  or  after  ligating  off  all  connection  between  the 
thorax  and  the  abdomen,  so  that  the  heart  of  the  dog  pumped  blood  only 
through  the  head  and  thorax,  the  introduction  of  laked  blood  was  quickly 
followed  by  the  staining  of  the  tissues  with  unquestionable  bile-pigment. 

Still,  even  if  this  is  true,  it  is  without  doubt  the  liver  which  usually  pro- 
duces bilirubin,  and  in  nearly  all  cases  it  is  from  some  disturbance  in  the 


126  TEXT-BOOK    OF    PATHOLOGY 

liver  and  its  ducts  that  we  have  jaundice.  Since  the  yellow  color  appears 
over  the  whole  body,  and  is  easily  shown  to  be  due  to  the  presence  of  bile 
in  the  circulating  blood,  the  bile,  on  being  formed  by  the  liver-cell,  must 
pass  into  the  circulation  instead  of  the  intestine  by  way  of  the  ducts. 
According  to  most  observers  this  takes  place  by  way  of  the  lymphatic 
channels,  but  there  are  those  who  believe  that  it  passes  directly  into  the 
veins.  With  the  appearance  of  jaundice  the  patient  is  usually  depressed, 
his  pulse  is  slowed,  and  his  skin  itches.  The  bile-pigments  and  acids  appear 
in  the  urine,  which,  when  the  jaundice  is  intense  enough,  becomes  brownish 
green  and  gives  a  green  froth.  The  cogulation  of  the  blood  becomes 
slowed,  and  surgeons  hesitate  to  operate  upon  jaundiced  persons  lest  they 
bleed  to  death. 

Minkowski  held  that  jaundice  might  result  from  the  secretion  by  the 
liver-cell  of  its  product  through  the  outer  side  directly  into  the  lymph- 
sheath  of  the  liver-cell  cord.  Evidence  seems  to  be  rapidly  accumulating, 
however,  to  show  that  probably  all  forms  of  jaundice  are  due  to  mechanical 
obstruction  at  some  point  or  other  to  the  outflow  of  bile.  Eppinger,  in  his 
recent  monograph,  ascribes  many  forms  to  the  plugging  of  the  bile  capil- 
laries by  solid,  thrombus-like  masses,  which  seem  to  result  from  the  passage 
into  the  capillary  of  an  albuminous,  coagulable  substance.  Just  as  in  the 
kidney  injury  of  the  renal  epithelium  allows  the  passage  of  albumin-con- 
taining urine,  so  injury  to  the  liver-cells  has  a  similar  result.  Such  plug- 
ging is  quickly  followed  by  the  bursting  of  the  capillary  and  the  liberation 
of  the  dammed-up  bile  into  the  neighboring  lymphatic  canal.  On  a  grosser 
scale,  he  thinks  the  same  ruptures  occur  when  the  obstruction  is  far  down 
in  the  common  duct. 

Certainly  it  seems  clear  enough  that  when  a  gall-stone  lodges  in  the  com- 
mon duct,  or  even  when  several  gall-stones  lodge  in  branches  of  the  hepatic 
ducts,  we  have  cause  for  jaundice  (not  so,  of  course,  when  the  cystic  duct 
is  obstructed  nor  when  the  gall-bladder  is  full  of  gall-stones,  for  that 
whole  apparatus  serves  only  as  a  reservoir).  So,  too,  when  a  tumor  fills 
up  the  common  duct  or,  growing  outside,  compresses  it.  A  tumor  of  the 
pancreas  or  of  the  stomach  may  do  this,  and  secondary  nodules  or  metas- 
tases  from  such  tumors  growing  in  the  liver  may  compress  the  branches 
of  the  hepatic  ducts  (cf.  Fig.  548),  and,  by  producing  local  areas  of  obstruc- 
tion, cause  nearly  as  intense  jaundice. 

One  sometimes  sees  the  most  profound  jaundice  as  the  result  of  an  ascend- 
ing growth  of  bacteria  along  the  mucosa  of  the  gall-ducts,  with  the  pro- 
duction of  abscesses  about  their  terminations  (cholangitic  abscesses). 
This  seems  rather  due  to  the  occlusion  of  the  ducts  themselves  than  to 
any  pressure  on  the  ducts  leading  from  other  parts  of  the  liver,  for  one 
may  have  numerous  large  abscesses  pro'duced  by  amoeba  or  by  bacteria 
brought  in  through  the  portal  vein  without  any  appreciable  jaundice. 

In  the  cases  in  which  obstruction  is  produced  far  down  in  the  common 
duct  by  the  pressure  of  a  tumor,  the  gall-ducts  are  found  dilated  and  thinned 


DISTURBANCES   OF   PIGMENT  METABOLISM  127 

out,  and  the  gall-bladder  is  dilated  to  its  extreme  capacity  with  bile.  In 
those  cases,  however,  in  which  the  obstruction  arises  from  the  impaction 
of  gall-stones  which  have  lain  in  the  gall-bladder  or  in  the  branches  of  the 
hepatic  ducts,  one  usually  finds  the  ducts  roughened  and  thickened  and  the 
gall-bladder  likewise  contracted  and  thick  walled  (Courvoisier's  law). 

Such  is  the  jaundice  from  obvious  mechanical  obstruction.  Slightly 
different  only  is  the  common  form,  in  which  an  inflammation  of  the  mucosa 
of  the  gall-duct,  with  abundant  mucus  formation,  may  be  sufficient  to  cause 
transient  jaundice.  This  may  reach  the  deepest  bronze  if  the  inflammation 
is  intense  enough  and  involves  the  minuter  ducts  in  the  liver,  as  it  is  sup- 
posed to  do  in  the  so-called  biliary  cirrhosis. 

Other  forms  of  jaundice  are  harder  to  explain.  Thus  in  acute  yellow 
atrophy  of  the  liver,  which  is  undoubtedly  only  a  name  applied  to  the  wide- 
spread necrosis  of  the  liver  which  might  result  from  the  action  of  many 
different  poisons,  there  may  be  the  deepest  jaundice,  although  there  is  no 
obvious  obstruction  to  the  gall-ducts,  and  most  of  the  liver-cells  are 
incapacitated  for  producing  bile.  Still,  those  which  remain  are  probably 
disconnected  from  their  ordinary  outlet  by  the  destruction  of  the  liver-cells 
which  formed  the  walls  of  the  intervening  portion  of  the  bile  capillary, 
and  hence  their  secretion  escapes  finally  into  the  blood.  So  it  must  be  in 
cirrhosis  of  the  liver,  which  we  may  look  upon  as  the  healing  of  repeated 
slight  injuries  of  a  similar  type,  with  eventual  reestablishment  of  inter- 
rupted connections  betweeen  the  liver-cell  cords  and  the  bile-ducts,  or  in 
the  cell  cords  themselves.  In  those  cases  in  which  a  massive  destruction 
of  whole  lobules  occurs,  we  are  perhaps  less  likely  to  find  jaundice  than  in 
those  in  which  minuter  lesions  destroy  merely  a  few  cells  here  and  there 
but  none  the  less  interrupt  the  continuity  of  the  bile  capillary.  Still  the 
reestablishment  of  these,  connections  is  very  rapid  and  effective,  and,  after 
all,  jaundice  occurs  in  cirrhosis  chiefly  in  those  cases  in  which  there  are  infec- 
tion and  swelling  of  the  mucosa  of  the  gall-ducts. 

The  jaundice  which  is  produced  by  toxins  and  hsemolytic  substances 
has  much  in  common  with  that  seen  in  such  infectious  diseases  as  pneumonia 
and  general  septicaemias.  Stadelmann  produced  icterus  experimentally 
with  injections  of  toluylene-diamine,  arseniuretted  hydrogen,  etc.,  and 
found  not  only  haemolysis,  but  the  production  of  quantities  of  bile  so  thick 
that  it  practically  blocked  the  gall-ducts.  In  this  sense  he  regards  it  as 
an  obstructive  jaundice,  and  Eppinger  supports  him  by  finding  his  bile 
thrombi  plugging  in  these  cases  the  bile-capillaries.  In  the  infectious 
forms  no  such  obstruction  could  be  found  by  Eppinger  or  Abramow,  who 
have  studied  the  subject.  The  pathogenesis  in  these  cases  is  still  in 
question,  and  they,  with  the  toxic  hsemolytic  forms,  constitute  the  chief 
material  for  the  support  of  the  idea  of  a  true  hsematogenous  jaundice  with- 
out the  intervention  of  the  liver. 

Jaundice  of  the  newborn  is  also  obscure,  although,  of  course,  the  types 
caused  by  syphilis  or  by  congenital  atresia  of  the  duct,  etc.,  are  clear 


128 


TEXT-BOOK   OF   PATHOLOGY 


enough.  The  common  form,  which  lasts  about  two  weeks  and  is  peculiar 
in  showing  no  tinting  of  the  sclerse  nor  any  bile  in  the  urine,  seems  to  be 
definitively  not  an  obstructive  process.  Another  type  of  jaundice  has  been 
studied  recently  which  shows  many  peculiarities.  This  is  a  congenital 
hereditary  affection,  thus  often  occurring  in  several  members  of  a  family, 
and  is  associated  with  a  marked  anaemia  and  enlargement  of  the  spleen. 


Fig.  53. — Bile-canaliculi  in  jaundice  plugged  with  bile-pigment  (a,  a).     Phagocytic  cells 
in  capillaries  containing  similar  plugs  of  bile-pigment  (6,  6). 

Iron  therapy,  which  improves  the  anaemia,  seems  to  cure  some  of  them, 
and  in  one  case  which  I  saw  splenectomy  produced  a  complete  cure. 

Microscopically,  in  advanced  jaundice,  one  finds  a  diffuse  staining  of  the 
tissues,  but  in  the  liver  especially  there  are  masses  of  green  bile-pigment 
forming  casts  of  the  bile-canals,  and  especially  branching  moulds  in  the 
intercellular  bile  canaliculi,  which  are  dilated  and  distorted  and  often 
ruptured  by  these  accumulations.  It  is  the  denser  portions  of  these  moulds 
that  Eppinger  regards  as  bile  thrombi,  formed  with  the  addition  of  some 
coagulable  material,  and  causing  evident  obstruction  of  the  canal  (Fig. 
53). 


DISTURBANCES    OF    PIGMENT   METABOLISM 


129 


The  liver  tissue  is  seen  to  be  rather  disorganized  and  broken  where  this 
occurs,  and  there  is  a  diffuse  staining  of  the  liver-cells  about  the  plugs  of 
green  material.  Beside  this  one  may  see  that  the  endothelial  cells  of 
the  blood-capillaries  are  stained  green,  and  that  there  are  many  large 
phagocytic  cells  with  clear  cytoplasm,  but  loaded  with  fragments  of  the 
green  plugs,  lying  in  the  capillaries.  These  have  a  single  nucleus,  although 
they  are  often  accompanied  by  many  leucocytes  and  are  probably  to  be 
regarded  as  the  phagocytic  cells  of  the  endothelium,  which  in  the  liver  are 
known  to  be  so  active. 

EXOGENOUS  PIGMENTS 

These  are  nearly  always  relatively  simple  substances,  which  get  into  the 
body  in  some  way  and  color  the  tissues.     Most  common  are  those  found  in 


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Fig.  54. — Anthracosis  of  bronchial  lymph-gland.     Hyaline  alteration  of  gland  tissue. 

the  various  dust  diseases,  or  konioses,  in  which  the  lungs  become  loaded 
with  the  particles  which  are  breathed  in  by  those  who  ply  a  dusty  trade. 
The  miller  fills  his  lungs  with  flour,  the  smoker  with  soot,  the  coal-miner 
with  coal-dust  (anthracosis) ,  the  grinder  with  metallic  dust  (siderosis)  or  with 
the  dust  from  cut  stone  (chalicosis),  and  so  on.  These  should  be  called 
pneumonokonioses,  and  their  variety  is  as  the  variety  of  dusts.  The  most 
10 


130  TEXT-BOOK   OF   PATHOLOGY 

common  is  the  ordinary,  practically  universal  anthracosis,  which  is  found 
in  every  one  and  every  animal  of  sufficiently  advanced  age,  especially  if 
they  live  in  a  city.  The  pigment  is  sometimes  in  discrete  patches,  collected 
along  the  interlobular  septa,  but  when  it  is  very  abundant,  as  in  the  coal- 
miner,  it  fills  almost  all  the  tissues  of  the  lung.  Such  lungs  are  often  very 
hard  on  account  of  the  constant  attempt  at  encapsulation  of  the  pigment 
in  scar  tissue,  and  some  pigments  are  so  irritating  and  require  so  dense  a 
capsule  that  the  lung  tissue  becomes  almost  stony  (Fig.  54). 

The  nature  of  the  coal-pigment  has  been  disputed,  and  it  probably  is  a 
mixture  of  soot  and  a  great  variety  of  insoluble  particles,  but  Traube  was 
able  to  show  in  some  lungs,  doubtless  those  of  actual  coal-miners,  that  the 
granules  were  really  fragments  of  carbonized  coniferous  plants,  as  could 
be  seen  from  the  characteristic  bordered  pits  of  the  cells  which  had  per- 
sisted throughout.  Engulfed  by  phagocytic  cells  in  the  alveoli,  or  even  in 
the  free  state,  these  particles  gain  entrance  to  the  lymphatics  of  the  lungs, 
and  are  carried,  probably  with  frequent  interruptions  and  transfers,  to 
other  phagocytic  cells,  to  the  bronchial  lymph-glands,  which  are  blackened 
and  indurated  by  their  presence.  These  glands  are  often  found  adherent 
to  the  pulmonary  veins  in  such  an  intimate  way  that  there  may  arise  an 
actual  transfer  of  pigment  to  the  vein-wall,  or  even  a  hole  in  the  wall 
through  which  pigment  is  swept  into  the  blood-stream.  This  may  explain 
the  occasional  presence  of  coal-pigment  in  the  abdominal  lymph-glands  or 
in  the  spleen  and  liver,  for  it  has  been  found  that  little  if  any  of  the  dirt 
and  colored  matter  taken  into  the  intestine  passes  through  the  walls  into 
the  lymph-glands. 

Metallic  dust  may  be  inhaled,  and  colored  substances  derived  from  it 
distributed  in  the  tissues.  Most  striking  is  the  rusty  pigmentation  of 
phagocytic  cells  about  a  needle  or  any  other  iron  particle  which  has  long 
been  embedded  in  the  tissue.  These  cells  look  almost  as  if  they  had  actually 
gnawed  off  particles  of  the  metal  and  carried  it  away.  The  same  thing  is 
true  of  the  silver  sutures  used  by  some  surgeons  and  left  in  the  tissues. 
Years  afterward  they  may  be  recognized  by  a  gray  cloud  about  them,  which 
is  found  to  be  due  to  the  presence  of  swarms  of  branching  cells  loaded  with 
fine  particles  of  blackish  silver.  The  long-continued  administration  of  any 
silver  salt  by  mouth,  as  was  once  the  habit  in  the  treatment  of  epilepsy, 
gastric  disturbances,  etc.,  often  led  insidiously  to  the  production  of  argyria, 
in  which  the  skin,  connective  tissues,  and  the  framework  of  various  organs 
assumed  a  leaden  color  from  the  fine  deposit  of  what  is  probably  a  silver 
albuminate.  Any  one  who  has  ever  seen  one  of  these  victims  can  never 
forget  the  ghastly  gray-blue  color  of  his  face  and  hands. 

The  lack  of  normal  pigments  is,  of  course,  quite  as  important  a  divergence 
from  the  normal  as  their  unusual  accumulation.  Hereditarily  some  persons 
possess  very  little  pigment  anywhere  in  the  skin,  hair,  or  eyes.  These  are 
albinos,  who,  although  their  melanins  are  scant,  have  a  normal  store  of 


DISTURBANCES    OF    PIGMENT   METABOLISM  131 

haemoglobin.  They  suffer  from  the  dazzling  effect  of  the  light  in  their 
unpigmented  eyes,  in  which  the  ordinary  effect  of  the  camera  obscura  is 
much  impaired.  Localized  absence  of  pigment  in  patches  which  are  often 
surrounded  by  skin  of  denser  pigmentation  is  not  uncommon  (leucoderma, 
vitiligo),  and  is  a  characteristic  of  some  deep  scars,  in  the  formation  of 
which  the  melanoblasts  seem  not  to  have  wandered  in. 

LITERATURE 

Eppinger:  Ergeb.  d.  inn.  Med.  u.  Kinderh.,  1908,  i,  107 
Hueck:   Ziegler's  Beitr.,  1912,  liv,  68. 
Lubarsch  and  Sehrt:  Virch.  Arch.,  1904,  clxxvii,  248. 
Poulsen:   Ziegler's  Beitr.,  1910,  xlviii,  348. 
Stadelmann:    Ikterus,  Stuttgart,  1891. 
Wieting  and  Hamdi:   Ziegler's  Beitr.,  1907,  xlii,  23. 
Whipple:   Jour.  Exp.  Med.,  1913,  xvii,  612. 


CHAPTER  IX 
DEFENCES  OF  THE  BODY  AGAINST  INJURY 

Immediate  and  late  reactions  to  injury.  Inflammation,  fever,  immunity  production,  and 
repair.  Inflammation  an  elaborate  mechanism  to  combat  injury.  Details  of  vascular 
and  phagocytic  phenomena.  The  wandering  cells. 

Reactions  to  Injury. — We  may  say  without  hesitation,  except  perhaps 
in  the  case  of  tumors  of  whose  origin  we  are  ignorant,  that  the  underlying 
cause  of  every  abnormal  change  in  the  body  is  some  sort  of  injury.  Often 
we  may  see  the  direct  effects  of  such  injuries,  but  in  many  cases  they  are 
confused  with  the  efforts  of  the  body  to  annul  or  repair  the  hurt. 

In  the  course  of  ages,  through  the  action  of  external  agencies,  the  human 
body  has  been  elaborated  to  its  present  form,  which  is  marvelous  in  its 
perfect  adaptation  in  every  detail  to  its  uses.  Variations  from  this  stan- 
dard in  some  respects  are  compatible  with  life  so  long  as  they  are  not  too 
extreme,  although  they  may  handicap  the  individual  in  his  struggle  for 
existence.  Why  such  a  form  should  have  been  developed  involves  broader 
questions  than  we  can  consider  here.  The  same  questions  arise  in  connec- 
tion with  every  other  species,  and  it  is  a  matter  of  interest  to  the  palaeontol- 
ogist and  the  general  biologist  that,  once  established,  such  creatures  should 
go  on  transmitting  through  ages  all  the  details  of  their  structure  to  their 
offspring,  and  that  individuals  should  possess  the  inherent  tendency  to 
maintain  that  form  and  to  return  to  it  as  they  recover  from  maiming  and 
distorting  injuries.  So  great  is  this  tendency  in  the  lower  orders  of  animals 
and  in  plants  that  if  only  a  fragment  of  the  body  is  left  it  can  reconstruct 
the  whole.  Even  in  man,  such  is  the  tenacity  with  which  the  standard  is 
adhered  to  that  within  the  life  of  the  individual  great  strides  are  made  to 
return  to  the  normal  when  tissues  and  organs  have  been  disarranged. 

It  seems,  however,  that  there  are  two  distinct  chains  of  events,  the  first 
being  the  perfection  of  a  structure  and  form  adapted  to  the  environment, 
but  subject  to  extremely  slow  variations,  which  maintain  this  adapta- 
tion and  are  hereditary  and  stamp  the  species.  The  second  group  of 
phenomena  is  subservient  or  auxiliary  to  this,  and  consists  in  the  develop- 
ment of  protective  mechanisms  which  guard  the  life  of  the  individual. 
But  one  cannot  so  sharply  classify  and  divide  these  things,  for  they  over- 
lap. Mechanisms  which  protect  the  individual,  form  some  of  the  char- 
acters of  the  species,  and  the  repairing  of  a  wound  in  the  individual  is  in 
great  degree  guided  by  the  hereditary  tendency  toward  the  form  charac- 
teristic of  the  species  and  independent  of  the  momentary  action  of  the 
environment. 

132 


REACTIONS   TO    INJURY  133 

It  is  this  group  of  hereditary  and  gradually  perfected  mechanisms  for 
defence  that  we  must  discuss.  Of  these,  some  are  quite  simple  and  obvious 
in  their  character.  The  body  is  covered  with  a  relatively  impervious  skin, 
further  protected  in  places  by  hair  and  nails.  It  is  true  that,  compared 
with  a  turtle  or  a  rhinoceros,  we  are  defenceless  in  that  regard,  but  ordi- 
narily our  need  is  perhaps  not  so  great.  Our  respiratory  tract  is  lined  with 
cilia,  which  keep  dust  out  of  the  lungs,  aided  by  sneezing  or  coughing  when 
necessary.  Irritating  substances  are  ejected  from  the  stomach  by  vomit- 
ing. Wounds  are  warded  off  by  all  sorts  of  reflex  muscular  movements, 
and  so  on.  All  these,  in  so  far  as  they  are  functional,  have  become  or  were 
always  involuntary  processes  tending  toward  the  protection  of  the  body 
from  injury. 

But  still  injuries  occur  from  mechanical,  physical,  or  chemical  causes, 
and  from  the  invasion  of  living  plant  or  animal  parasites,  and  these  in- 
juries, which  generally  imply  the  destruction  of  some  of  the  tissue,  call  into 
activity  several  kinds  of  reactions  or  responses  which  have  been  elaborated 
through  ages  of  natural  selection  and  bequeathed  to  their  offspring  by 
those  whom  they  have  helped  to  survive.  They  are  of  several  types,  and 
appear  to  be  rather  independent  of  one  another,. for.  some  injuries  call  out 
one,  some  another,  but  most  often  they  all  come  in  combination  or  in  suc- 
cession. They  are:  Inflammation,  fever,  immunity  production,  repair. 

Inflammation  is  a  complicated  vascular  and  cellular  response,  which 
follows  almost  immediately  upon  the  injury,  and  is  adapted,  by  bringing 
much  blood  to  the  spot  and  pouring  out  its  elements  upon  the  injured 
tissues,  to  prevent  the  extension  of  the  injury,  hold  in  check  the  injurious 
agent,  or  even  destroy  it.  Through  the  agency  of  some  of  the  cells  which 
are  brought  in,  and  in  other  more  purely  mechanical  ways,  it  is  also  im- 
portant in  clearing  away  the  debris  of  injured  or  dead  tissue  and  preparing 
the  way  for  the  process  of  repair. 

Fever  is  another  complex  response  through  which,  by  certain  changes  in 
the  heat-regulating  mechanisms,  the  temperature  of  the  body  is  raised 
chiefly  through  the  saving  of  heat.  It  is  thought  that  this  is  bound  up 
with — 

Immunity  production,  a  response  to  certain  types  of  injury  which  quietly 
and  slowly  forms  substances  specifically  adapted  to  annul  and  prevent  the 
inroads  of  that  particular  injurious  agent.  Sometimes  this  power  remains 
inherent  in  the  tissues  for  life. 

Repair  is  the  new  formation  of  tissue  to  replace  that  which  was  de- 
stroyed. It  may  be  local,  in  which  case  the  repair  is  often  a  kind  of  patch- 
ing with  tissue  of  a  different  sort.  Or  it  may  occur  in  addition  at  a  dis- 
tance from  the  point  of  injury,  and  consist  in  the  new  formation  of  the  sort 
of  tissue  which  was  destroyed  in  such  a  way  as  to  make  up  for  the  defi- 
ciency which  its  loss  occasioned.  Then  it  is  often  called  compensatory 
hyperplasia. 

Repair  must,  therefore,  not  be  confused  with  inflammation  nor  regarded 


134  TEXT-BOOK   OF   PATHOLOGY 

as  a  part  of  it.  It  is  true  that  the  result  of  the  local  tissue  growth  is  not 
always  what  we  should  regard  as  the  ideal  outcome  of  an  attempt  at  heal- 
ing. Awkward  scars  or  an  altogether  excessive  mass  of  fibrous  tissue  may 
be  produced  which  may  even  interfere  seriously  with  the  function  of  the 
organ  and  be  entirely  out  of  proportion  with  what  would  seem  necessary 
for  the  repair  of  the  actual  gap  first  produced  by  the  injury.  Usually  this 
is  because  the  injurious  agent  persists  and  repeatedly  frustrates  healing 
by  injuring  the  repairing  tissue  itself,  so  that  layer  after  layer  of  this  new 
tissue  is  laid  down  and  consolidated  into  a  firm  scar.  Possibly  this  might 
not  be  so  to  such  an  extent  were  it  not  for  the  inflammatory  outpouring  of 
fibrin  which  it  has  become  the  habit  of  this  mechanism  to  replace  by 
fibrous  tissue,  rather  than  to  remove  in  any  other  way. 

It  is  a  mechanism  like  the  others  which  seems  to  have  been  perfected 
through  long  generations  toward  a  rather  complex  end,  for  not  only  does 
it  repair  gaps  in  the  tissue,  but  it  is  protective  in  the  sense  that  it  brings 
about  the  encapsulation  of  any  noxious  material  and  prevents  its  further 
influence  upon  the  neighboring  tissues.  While  we  are  familiar  with  its 
ordinary  course,  and  can  even  prophesy  what  will  happen  in  a  given  case, 
we  are  not  so  well  informed  as  to  the  exact  mechanism  which  impels  these 
cells  to  grow.  If,  therefore,  we  speak  of  the  impulse  to  repair,  or  dis- 
turbance in  the  equilibrium  of  tissues,  or,  on  the  other  hand,  of  chemical 
or  mechanical  stimuli  acting  directly  upon  the  cell  and  causing  its  pro- 
liferation, we  are  using  vague  terms,  all  of  which  may  possibly  have  the 
same  meaning. 

This  reaction,  like  the  others,  is  imperfect,  and  may  produce  unsatis- 
factory or  even  harmful  results;  but  if  the  person  survives,  there  is  set  at 
work  a  remodeling  process  through  which,  in  time,  much  is  done  toward 
restoring  the  tissues  to  the  normal  standard.  This  involves  other  mechan- 
isms which  obliterate  blood-vessels  in  one  place  and  form  them  in  another, 
rarefy  and  fret  away  tissue  at  one  point  or  strengthen  it  at  another.  Sel- 
dom does  any  one  live  long  enough  to  have  this  completed,  but  we  find 
evidence  at  autopsy  that  it  has  been  at  work. 

INFLAMMATION 

According  to  the  definition  of  inflammation  given  above,  it  seems  pref- 
erable to  use  this  name  for  the  immediate  protective  and  defensive  reaction 
to  an  injury.  It  is  a  complex  phenomenon,  elaborated  to  a  certain  degree 
of  perfection  in  which  the  blood-vessels  with  their  contents  and  the  wander- 
ing cells  from  adjoining  regions  play  the  greatest  parts.  Its  aim  seems  to 
be  the  prevention  of  further  injury  by  antagonizing  the  injurious  agent, 
and  this  must  be  thought  to  include  the  solution  and  removal  of  foreign 
materials  (which  may  be  the  dead  cells  themselves)  because  such  material 
is  in  itself  a  cause  of  injury. 

The  removal  of  foreign  material  or  of  cellular  debris  may  take  place,  as 
in  the  desquamation  of  the  epidermis  or  the  bursting  of  an  abscess  by  me- 


INFLAMMATION  135 

chanical  means,  which  hardly  form  part  of  the  inflammatory  reaction,  so 
that  perhaps  this  process  of  cleaning  up  the  field  so  that  repair  may  occur 
may  be  regarded  as  incidental  to  the  main  aim  of  combating  the  injury. 
At  any  rate,  the  reaction  seems  to  be  quite  distinct  from  the  process  of 
repair.  It  is  confusing,  however,  that  inflammation,  cleansing  of  the  site 
of  injury,  and  repair  commonly  overlap  and  proceed  together  inextricably 
mingled  in  the  same  area.  One  might  construct  a  simile  in  which  the  fire 
department,  hurrying  to  a  burning  house,  represents  the  inflammation, 
although  often  long  before  the  fire  is  extinguished  workmen  are  found  carry- 
ing away  the  charred  timbers  and  enthusiastic  carpenters  are  rebuilding 
wherever  they  can  approach  near  enough.  If  this  combination  of  activi- 
ties be  carried  on  for  a  long  time,  it  is  easy  to  foretell  a  curious  distorted 
building  as  the  result  of  the  carpenters'  efforts.  But  would  any  one  say 
that  it  was  the  fire  that  had  directly  stirred  the  carpenters  to  work? 

We  must  discriminate  between  the  direct  effect  of  the  injurious  agent 
upon  the  tissues  and  the  inflammatory  reaction.  This  direct  effect  may 
be  the  killing  of  some  of  the  cells,  with  further  injury  not  sufficient  to  cause 
death,  diminishing  as  one  passes  away  from  the  point  at  which  the  destruc- 
tive agent  impinged  upon  the  tissue.  Sometimes  the  injury  is  hardly 
visible,  although  it  stirs  up  an  intense  inflammation,  but  generally  it  is 
necessary  that  at  least  a  few  cells  be  killed,  that  this  may  result.  Exten- 
sive injuries  which  cause  metabolic  disturbances  in  the  cells  may  arouse  no 
inflammatory  reaction  at  all;  cells  may  gradually  waste  away  from  disease 
or  malnutrition  or  from  pressure,  as  in  a  hydronephrotic  kidney,  and  there 
is  little  or  no  inflammation;  but  let  a  few  cells  die  and  coagulate  into  what 
is  virtually  a  foreign  body,  or  introduce  any  foreign  body,  and  an  inflam- 
matory reaction  appears  at  once.  This  reaction  is  not  attuned  to  all  sorts  of 
injuries,  nor  even  necessarily  to  the  most  severe,  for  a  man  may  have  his 
leg  cut  off  by  the  surgeon  and  the  wound  will  heal  with  evidences  of  an 
inflammation  which  is  directed  toward  the  annihilation  of  the  few  dying 
cells  which  happen  to  have  been  cut  in  two  in  the  line  of  incision,  quite 
regardless  of  the  more  serious  catastrophe  that  the  man  had  lost  his  leg. 
Or  a  vein  may  be  opened  aseptically  and  an  animal  bled  nearly  to  death; 
wonderful  reparatory  processes  will  occur  in  the  distant  bone-marrow  to 
restore  the  blood,  and  fluid  will  pour  from  the  tissues  into  the  blood- 
vessels, but  there  will  be  no  inflammation.  Cauterize  the  wound,  however, 
with  a  hot  iron  or  with  boiling  oil,  as  they  did  in  the  time  of  Pare,  and  the 
inflammatory  reaction  will  appear  in  its  full  force.  We  are  tempted  to 
ask  whether,  after  all,  inflammation  as  a  reaction  responds  only  to  the 
presence  of  dead  cells,  and  their  diffusible  decomposition  products,  and 
whether,  in  the  course  of  the  development  and  elaboration  of  the  reaction, 
this  has  evolved  itself  as  the  general  signal  for  inflammation,  but  we  know 
that  we  may  greatly  intensify  the  reaction  by  the  use  of  some  other  more 
irritating  substance  to  kill  the  cells. 

Given  the  adequate  injury,  the  inflammatory  reaction  begins  with  a 


136 


TEXT-BOOK   OF   PATHOLOGY 


red  flush.  It  can  be  followed  in  any  place  near  the  skin,  perhaps  especially 
well,  as  Samuel  pointed  out,  in  such  an  object  as  the  rabbit's  ear,  where  the 
blood-vessels  can  be  seen,  but  for  the  minute  details  it  is  best  to  study  with 
the  microscope  such  transparent  tissue  as  the  mesentery  or  tongue  of  the 
frog  or  the  wing  of  the  bat.  If  the  tip  of  the  rabbit's  ear  be  painted  with 
croton  oil  or  dipped  in  hot  water,  the  whole  process  comes  on  with  a  rush. 
First,  after  a  momentary  contraction,  there  is  the  widening  of  the  arteries 


Fig.  55A. — Portion  of  inflamed  diaphragm  cleared  by  Spalteholtz's  method  to  show  the 
abundant  dilated  blood-channels. 


and  veins,  so  that  the  blood  courses  through  them  very  rapidly,  and  simul- 
taneously the  widening  of  all  the  minute  arterioles  and  venules  in  the 
affected  area,  so  that  channels  come  into  view  which  were  evidently  com- 
pletely collapsed  before  (Figs.  55A  and  B) .  This  much  is  commonly  attained 
if,  by  compressing  the  veins  or  by  cutting  the  sympathetic  nerves,  we  cause 
the  dilation  of  the  vessels.  But,  in  addition,  in  the  inflamed  ear,  all  the 
spaces  between  these  visible  widened  channels  become  uniformly  red. 
A  needle  passed  through  one  of  these  spaces  in  the  mechanically  congested 


INFLAMMATION  137 

ear  will  draw  no  blood;  but  in  the  inflamed  ear  there  is  free  bleeding  from 
the  puncture.  Evidently,  then,  the  capillaries  are  uniformly  distended 
with  blood.  While  this  change  takes  place  at  first  in  the  actually  injured 
area,  it  soon  spreads  to  the  adjacent  part  of  the  ear,  and  finally  even  to  its 
root  or  over  the  side  of  the  head.  The  ear  is  much  warmer  than  the  other, 
because  blood  rushes  through  it  so  fast  that  it  has  the  temperature  of  the 
interior  of  the  body,  and  it  is  gone  again  before  there  is  time  to  cool  off. 


Fig.  55B. — Portion  of  a  normal  diaphragm,  showing  in  contrast  relatively  few  visible 

blood-channels. 

This  lasts  only  a  short  time  before  the  ear  becomes  swollen  and  the  skin 
tense.  If  it  be  pinched,  the  impression  of  the  finger  remains  for  a  time. 
It  becomes  so  thick  and  heavy  that  it  hangs  down,  and  its  function  must 
thereby  be  interfered  with.  Besides  it  is  very  tender  and  even  spontane- 
ously painful.  At  the  least  touch  the  animal  jerks  back  as  if  burnt.  Two 
or  three  days  later  the  artery  may  be  found  contracted  again  to  something 
near  its  normal  size.  In  the  injured  area  the  redness  persists,  though  it 
may  be  a  darker,  more  violet  color— the  ear  is  cooler— blood  seems  to  be 


138 


TEXT-BOOK   OF   PATHOLOGY 


passing  through  the  vessels  very  slowly,  and  the  swelling  is  gradually  pass- 
ing away.  It  may  require  ten  or  twelve  days  for  all  to  become  normal 
again — the  part  which  has  actually  been  injured  is  the  last  to  recover,  and 
then  usually  with  the  loss  of  its  surface  epithelium,  but  even  there  the 
circulation  finally  returns  to  the  normal,  the  epithelium  is  repaired,  and  the 
inflammation  is  over. 

If  a  transparent  tissue  is  selected,  the  whole  process  can  be  watched  in 
its  development.     In  the  region  where  the  tissue  has  been  injured,  and  for 


Pig.  56. — Inflamed  omentum  showing  outwandered  leucocytes  about  a  small  vessel. 

some  distance  around  it,  the  small  blood-vessels  are  seen  to  widen.  All 
the  capillaries  are  stretched  by  the  increased  stream  of  blood,  and  con- 
tracted channels,  which  could  not  be  seen  before,  reopen,  and  the  blood 
courses  through  areas  which  were  quite  pale  before.  The  stream,  pulsat- 
ing in  the  arterioles  and  steady  in  the  venules,  now  rushes  through  with 
vertiginous  rapidity.  Though  we  cannot  see  it,  there  is  probably  even  at 
this  stage  some  filtering-out  of  clear  fluid  from  the  vessels  into  the  crevices 
of  the  surrounding  tissue.  After  a  time,  although  the  stream-bed  remains 
wide,  the  current  slows  down  until  one  loses  the  impression  of  a  homo- 


INFLAMMATION  139 

geneous,  yellowish-red  fluid  hurrying  along,  and  it  becomes  possible  to 
catch  glimpses  of  the  corpuscles  as  they  pass.  Throughout  all  this  one  can 
see  that  in  the  venules,  where  there  is  no  pulsation  to  disturb  it,  the  ar- 
rangement of  the  corpuscles  is  peculiar  in  that  they  float  in  the  centre  of 
the  stream,  separated  everywhere  from  the  vein-wall  by  the  clear  plasma. 
With  the  slowing  of  the  stream  leucocytes  begin  to  appear  in  this  mar- 
ginal stream  and  are  rolled  along  the  wall.  They  even  seem  to  find  the 
wall  sticky,  so  that  they  adhere  now  and  then,  only  to  be  turned  over  and 
dragged  along  by  the  rest.  Still  later  some  of  them  refuse  to  be  dislodged, 
and  one  can  see  that  they  have  fastened  themselves  to  the  wall  by  piercing 


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Fig.  57. — Acute  diffuse  inflammation.  Tissue  is  cedematous  and  shows  exudate  of 
leucocytes  and  red  corpuscles  in  a  network  of  fibrin.  Some  mononuclear  wandering 
cells  are  present. 

it  with  a  protoplasmic  process  which  may  even  project  a  little  way  on  the 
outside.  Such  a  leucocyte  soon  becomes  dumb-bell  shaped,  with  half  its 
body  outside  the  endothelial  wall,  the  nucleus  squeezing  its  way  through 
the  small  hole  forced  by  the  protoplasm.  It  is  not  long  before  the  whole 
cell  escapes  through  this  gap  and  wanders  away  among  the  fibres  of  the 
surrounding  tissue.  These  are  chiefly  polymorphonuclear  neutrophile 
leucocytes,  which  are  the  most  numerous  in  the  blood,  and  this  is  the  process 
of  active  emigration  which  formed  the  crucial  feature  in  Cohnheim's  clas- 
sical observation,  and  which  is  one  of  the  most  significant  occurrences  in 
the  whole  process  of  inflammation  (Fig.  56). 


140 


TEXT-BOOK   OF   PATHOLOGY 


Along  with  the  leucocytes,  or  behind  them,  red  corpuscles  escape  pas- 
sively to  the  outside,  and  during  the  whole  time  fluid  has  filtered  through 
unobserved  until  now  the  cells  and  fibres  of  the  tissue  around  the  blood- 
vessel are  spread  apart  widely  by  its  great  accumulation — the  inflammatory 
oedema.  Since  this  fluid  is  coagulable  like  the  plasma  of  the  blood,  and 
since  there  are  injured  cells  in  the  neighborhood  to  set  free  thrombokinase, 
there  soon  appears  a  delicate  coagulum  of  fibrin  stretching  in  fine  filaments 
through  the  spaces  forced  open  by  the  fluid  (Figs.  57,  58,  59). 

If  the  injury  is  extreme,  the  current  of  blood  may  come  to  a  complete 


a.-'V^"*   "    " 

^L     xv^.,A>ArfMf  I  .  '  ~  .       *       * 


Fig.  58. — Inflamed  rabbit's  ear  showing  blisters  in  the  skin  and  inflammatory  infiltra- 
tion of  the  subcutaneous  tissue. 


stop  in  some  of  the  vessels,  and  there  emigration  of  leucocytes  ceases. 
But  in  the  others,  although  the  corpuscles  pass  along  very  slowly,  enough 
fresh  blood  seems  to  be  brought  to  nourish  the  tissues. 

The  leucocytes  and  the  fluid  press  toward  the  point  where  the  tissues 
are  most  injured  and  surround  those  cells.  If  bacteria  are  present,  the 
leucocytes  may  swallow  them  unless  they  have  diffused  around  themselves 
too  strong  a  poison.  Then  it  seems  impossible  for  the  leucocytes  to  ap- 
proach without  being  killed,  perhaps  because  in  order  to  do  this  they  have 
to  pass  through  dead  tissue  around  the  bacteria  where  they  receive  no 


INFLAMMATION 


141 


oxygen.    It  is  almost  like  firemen  who  are  checked  by  the  smoke,  but  keep 
on  rushing  in  past  the  dead  bodies  of  those  which  preceded  them. 

Finally,  as  a  rule,  if  the  injury  is  not  enough  to  cause  the  death  of  the 
animal,  the  bacteria  are  overcome.  This  is  effected  by  the  continued 
action  of  the  fluid  and  the  leucocytes  in  ways  which  we  shall  discuss.  Or 
if  there  have  been  no  bacteria,  the  dead  tissue  is  permeated  by  the  exuded 
fluid  and  invaded  by  the  leucocytes. 


5 


Fig.  59. — Acute  myositis.     Diffuse  acute  inflammation  with  mononuclear  wandering 
cells  as  well  as  leucocytes,  red  corpuscles,  and  fibrin. 

After  this  the  process  becomes  an  effort  to  clean  up  the  debris.  Partly 
by  self-digestion,  partly  through  digestion  by  the  leucocytes,  the  dead  cells 
and  fibres  are  liquefied  or  reduced  to  a  fine  granular  fluid  and  absorbed 
through  the  walls  of  the  lymphatics.  The  dead  bodies  of  leucocytes  suffer 
the  same  fate,  and  those  which  remain  alive  aid  by  carrying  particles 
through  the  walls  of  the  lymphatics,  where  they  are  swept  along  into  the 
next  lymph-gland.  There  any  such  particles  or  dead  cells  are  exposed  to 
the  digestive  action  of  the  cells  of  the  lymph-gland. 


142  TEXT-BOOK   OF   PATHOLOGY 

Thus  the  area  is  cleared  of  debris;  the  blood-vessels  gradually  return  to 
their  normal  calibre,  their  walls  again  become  normal  and  contract,  and 
the  circulation  resumes  its  normal  rate.  Naturally  gaps  are  left  in  the 
tissue  where  cells  have  died  and  been  removed,  but  the  repair  of  these  gaps 
will  form  another  chapter. 

It  is  seen  from  this  that  inflammation  is  really  a  complex  but  well- 
rounded  mechanism,  designed  chiefly  to  pour  over  injurious  substances 
and  dead  tissue  a  fluid  and  cells  rich  in  neutralizing  materials  and  diges- 
tive ferments,  which  tend  to  quench  the  action  of  the  injuring  agent  and 
to  liquefy  the  debris  for  removal.  From  this  point  of  view  it  seems  a 
purposeful  and  beneficial  reaction. 

Probably  every  inflammation  is  accompanied  by  some  general  disturb- 
ance, such  as  fever,  of  which  we  shall  have  more  to  say  later.  When 
the  injury  is  intense  enough,  poison  may  be  absorbed  from  the  injurious 
agent  or  even  from  the  dead  tissue  to  affect  the  nervous  system  and  other 
organs  and  to  cause  disturbance  of  their  functions,  and  what  we  know  as 
illness.  "Even  the  fever  itself  may  bring  along  with  it  disturbances  in 
function.  In  all  cases,  too,  there  is  likely  to  be  a  change  in  the  blood  in 
general,  consisting  in  a  great  increase  in  the  number  of  leucocytes.  This 
leucocytosis  is  a  convenient  index  of  the  existence  of  an  obscure  inflamma- 
tion, and  results  from  the  great  over-production  of  the  cells  of  the  bone- 
marrow  and  their  liberation  into  the  blood. 

While  the  inflammatory  reaction  may  thus  happily  succeed  in  over- 
coming the  injury  and  restoring  the  cleansed  area  to  a  condition  in  which 
it  is  ready  for  repair,  it  is  not  always  so.  The  injurious  agent  may  persist, 
as  in  the  case  of  bacterial  infections,  or  it  may  be  frequently  repeated,  in 
the  case  of  physical  or  chemical  injuries,  so  that  a  smouldering  fire  is  kept 
up  for  a  long  time.  The  persistent  reaction,  which  is  then  often  spoken  of 
as  chronic  inflammation,  comes  to  differ  from  that  which  is  quickly  finished, 
chiefly  in  that,  among  the  wandering  cells  which  appear  in  the  tissue,  there 
arrive  swarms  of  mononuclear  forms  which  are  slow  to  move,  being  at- 
tracted chiefly  by  dead  tissue  or  other  substances  unlike  those  which  draw 
the  neutrophile  leucocytes.  The  congestion  of  the  vessels  and  the  oedema 
may  subside,  being  kept  up  chiefly  along  the  frontier.  Most  confusing, 
however,  is  the  fact  that,  if  so  much  time  is  occupied,  reparatory  processes 
appear  and  are  closely  interwoven  with  those  of  defensive  character. 
The  mononuclear  cells  emigrate  in  small  numbers  with  the  polymorphonu- 
clears  in  the  acuter  forms,  but  now  they  come  in  such  numbers  that  one 
cannot  escape  the  idea  that  many  of  them  wander  in  from  the  crevices  of 
the  adjacent  tissue  or  are  even  formed  in  situ  by  multiplication  of  those 
which  first  appear.  They  assume  many  forms,  and  many  of  them  grow  to 
a  great  size  as  they  move  about,  swallowing  up  particles  of  dead  tissue  or 
even  whole  cells  which  have  been  injured.  When  the  area  is  finally  and 
permanently  rid  of  the  injurious  substance,  and  when  all  the  debris  of  dead 
tissue  is  cleared  up,  these  cells  in  their  turn  slip  away  into  the  spaces  of 


INFLAMMATION  143 

the  tissue  or  into  the  lymphatics  and  disappear  into  distant  parts  of  the 
body. 

With  this  bare  outline  of  the  inflammatory  process  we  may  pass  to  the 
discussion  of  some  of  the  underlying  principles. 

The  Widening  of  the  Vessels.— The  widening  of  the  blood-vessels  is 
probably  due  to  complete  paralysis  of  their  walls,  at  any  rate  in  the  actu- 
ally inflamed  areas.  Klemensiewicz,  who  holds  this  idea,  showed  that  the 
vessels  of  the  web  of  the  frog's  foot  could  be  made  to  contract  by  electrical 
stimulation  of  the  medulla  or  of  the  vessels  themselves,  but  if  the  foot  were 
inflamed,  no  such  stimulation  affected  them  in  the  least.  Section  of  the 
sympathetic  fibres  to  a  part  allows  of  a  temporary  great  dilatation  of  the 
vessels.  In  the  rabbit's  ear  section  of  the  auricular  nerves,  on  the  contrary, 
causes  their  contraction.  Sensory  stimulation  will  reflexly  cause  vascular 
engorgement,  but  while  all  these  conditions  may  be  produced  first,  and 
will  thereupon  modify  the  course  of  an  inflammation  set  up  in  that  region, 
they  are  quite  different  from  the  changes  in  the  vessels  which  inflamma- 
tion entails,  and  which  cannot  be  greatly  altered  by  section  or  stimulation 
of  nerves  when  it  is  once  well  developed.  Inflammation  in  a  rabbit's  ear 
flushed  by  section  of  the  sympathetic  proceeds  more  rapidly  and  intensely 
than  in  a  normal  ear,  and  inflammation  in  a  rabbit's  ear  rendered  anaemic 
by  section  of  the  auricular  nerves  goes  on  imperfectly,  so  that  in  the  end 
the  injured  ear  becomes  necrotic  and  drops  off.  But,  after  all,  these  are 
only  superimposed  influences,  and,  as  we  have  shown,  inflammation  runs 
its  course,  complete  in  each  detail,  in  a  limb  which  has  been  amputated 
and  then  reunited  by  vascular  suture,  so  that  there  can  be  no  possibility 
of  the  existence  of  any  nervous  connection  with  the  central  nervous  system. 
Schaefer,  however,  states  that  if  the  nerves  are  allowed  to  degenerate  in 
this  experiment,  inflammation  does  not  pursue  its  normal  course.  All  this 
is  in  accord  with  Klemenseiwicz's  statement  that  the  walls  of  the  vessels, 
including  the  capillaries,  are  completely  paralyzed  and  deprived  of  their 
contractility. 

The  experiments  of  Dale  and  others  on  shock  have  shown  that  it  is  prob- 
able that  the  paralysis  of  the  capillaries,  which  is  responsible  for  that  con- 
dition, is  due  to  poisoning  by  some  substance  resembling  or  identical  with 
histamine  derived  from  injured  tissue.  If  the  mangling  of  muscle  or  the 
bruising  of  intestines  can  allow  the  diffusion  of  enough  of  this  poison  to 
paralyze  capillaries  over  the  whole  body,  it  seems  probable  that  the  local 
injury  of  tissue  may  liberate  enough  of  the  same  material  to  poison  and 
paralyze  the  capillaries  in  the  area  which  becomes  inflamed.  Dr.  Abel 
shows  that  practically  every  tissue  is  capable  of  producing  histamine  in 
consequence  of  injury;  indeed,  that  it  can  be  extracted  from  normal  tissue. 
If  we  admit  that  the  paralysis  and  widening  of  the  capillaries  is  due  to  a 
capillary  poison  produced  by  the  primary  injury  to  the  tissue,  it  must  be 
regarded  as  a  purely  passive  result  of  the  injury,  and  it  gives  us  pause  in  a 
too  ready  explanation  of  the  widening  of  the  vessels  in  inflammation  as  a 


144  TEXT-BOOK   OF   PATHOLOGY 

purposeful  process  evolved  to  bring  an  excessive  amount  of  fluid  to  the 
area. 

The  Changes  in  the  Rate  of  Flow. — The  stream  in  any  given  stream-bed 
ordinarily  runs  more  slowly  when  it  reaches  a  widened  stretch,  but  here, 
where  there  is  a  choice  of  channels,  it  is  more  influenced  by  the  friction 
against  the  wall,  and  consequently  runs  through  these  widened  vessels  at 
a  rate  more  nearly  approaching  that  in  the  larger  vessels  than  before.  It 
is  for  this  reason  that  the  part  feels  hot — not  that  there  is  any  appreciable 
amount  of  heat  produced  by  increased  metabolism  in  the  inflamed  area, 
but  merely  because,  in  a  superficial  tissue,  the  blood,  when  coursing  nor- 
mally, has  time  to  cool,  while  now  there  is  no  such  opportunity  and  the 
temperature  of  the  part  approaches  that  of  the  interior  of  the  body. 
Probably  we  could  determine  no  difference  in  temperature  between  an 
inflamed  loop  of  intestine  and  a  normal  one  in  the  same  person. 

The  slowing  of  the  stream  and  the  passing  out  of  the  leucocytes  into  the 
marginal  or  plasma  zone  are  much  harder  to  explain.  One  is  practically 
compelled  to  think  that  there  is  a  change  in  the  endothelial  lining  of  the 
vessel  of  such  a  character  that  it  becomes  rough  or  sticky,  and  thus  offers 
more  friction  to  the  passage  of  the  blood-stream.  Some  have  thought  that 
the  blood  itself  becomes  thickened  by  the  loss  of  fluid  through  the  vessel 
walls,  and  that  this  increased  viscosity  might  explain  the  sluggish  stream, 
but  there  is  no  convincing  evidence  that  the  venous  blood  from  an  in- 
flamed area  has  any  perceptibly  greater  viscosity  than  the  arterial  blood. 

Indeed,  the  observations  upon  the  slowing  of  the  stream  have  usually 
been  made  upon  such  an  object  as  the  exposed  mesentery  of  the  frog,  where 
the  minute  vessels  could  be  examined  microscopically,  and  end,  as  a  rule,  in 
complete  stagnation  of  the  blood  from  the  intensity  of  the  injury,  so  that 
I  have  been  disposed  to  question  the  occurrence  of  such  slowing  in  a  more 
protected  tissue.  Schlarewsky  and  others  have  shown  that  any  suspended 
particles  passing  in  a  stream  of  fluid  through  a  tube  are  governed  by  a 
centripetal  force  which  keeps  them  in  the  axis  of  the  stream,  but  that, 
with  slowing  of  the  stream,  this  force  is  relaxed,  and  first  the  lighter,  then 
the  heavier,  particles  are  allowed  to  approach  the  periphery.  Apparently 
this  would  explain  the  marginal  position  of  the  leucocytes  as  the  stream 
slows,  but  it  does  not  touch  upon  their  adhering  to  the  wall  and  finally 
penetrating  it.  Nor  does  it  throw  any  light  upon  their  increasing  abundance 
in  the  whole  circulating  blood,  for  which  two  things  quite  different  causes 
must  be  sought. 

Chemiotaxis  and  Phagocytosis. — It  has  been  observed,  in  watching  free 
swimming  amrebse  and  other  unicellular  or  even  multinucleated  organisms 
which  are  mobile  and  jelly-like  (myxomycetes),  that  their  movements  are 
largely  influenced  by  changes  in  their  surroundings,  or  even  more  definitely 
by  physical  or  chemical  stimuli.  Of  special  interest  is  their  behavior 
toward  soluble  substances,  some  of  which  attract,  while  others  repel,  them. 
One  of  the  myxomycetes,  for  example,  which  grows  on  tanbark,  will  move 


INFLAMMATION  145 

actively  along  a  moist  surface  toward  a  drop  of  an  extract  of  that  bark, 
while  it  will  move  just  as  actively  away  from  a  solution  of  glucose  or  of 
some  salt.  Nevertheless,  it  can  be  accustomed  to  these  latter  things  so  as 
to  be  attracted  rather  than  repelled  by  them.  This  is  an  example  of 
chemiotaxis,  or  the  stimulation  to  motion  by  a  chemical  substance,  in  the 
one  case  positive,  in  the  other  negative.  Attempts  have  been  made  (A.  B. 
Macallum  and  others)  to  explain  this  activity  as  due  to  alterations  in  the 
surface  tension  of  the  protoplasmic  mass,  and  apparently  this  is  the  true 
basis,  although  it  becomes  complicated  when  we  come  to  explain  how  the 
response  changes  as  the  amoeboid  organism  accustoms  itself  to  a  repellent 
substance  and  is  finally  attracted  by  it.  Probably  a  similar  explanation 
will  hold  good  for  the  tactile  irritability  which  is  evident  in  those  amoebae 
or  other  cells  which  come  into  contact  with  some  insoluble  particle.  In 
such  a  case  the  protoplasm  flows  around  the  particle  and  encloses  it  com- 
pletely unless  it  is  too  large,  when  it  spreads  itself  over  the  mass  as  far  as 
possible. 

This  is  the  process  of  phagocytosis  in  its  beginning,  and  both  it  and  chemi- 
otaxis are  things  which  can  be  closely  simulated  by  non-living  substances. 
Thus  a  drop  of  chloroform  in  water  will  stretch  itself  along  a  thread  of 
shellac  brought  against  it,  and,  dissolving  it  as  it  goes,  keep  moving  along 
the  thread  until  it  is  saturated. 

All  of  this  applies  equally  well  to  the  mobile  cells  of  the  body,  par- 
ticularly to  the  leucocytes,  and  Metchnikoff  especially  has  laid  great 
stress  upon  the  fundamental  role  which  it  plays  in  inflammation,  for  while 
in  lower  forms  these  mobile  mesenchymal  cells  form  the  means  of  defence, 
arriving  at  the  point  of  injury  by  their  own  motility,  in  vertebrates  there  is 
added  a  convenient  blood-vascular  system,  with  its  rapid  current,  which 
brings  the  leucocytes  to  the  injured  area  and  then  slows  up  so  that  they 
may  emigrate  through  its  walls  and  reach  the  spot.  Were  it  not  for  this 
slowing  and  the  roughening  and  stickiness  of  the  endothelium  in  that 
region,  the  leucocytes  would  all  be  swept  by  without  any  chance  of  reach- 
ing the  place  where  the  injury  occurred. 

Many  ideas  have  been  expressed  as  to  the  reason  for  the  passage  of  the 
leucocytes  through  the  wall,  but  it  seems  that  the  weight  of  evidence  is  in 
favor  of  their  active  penetration  between  the  cells  in  response  to  the  at- 
traction of  some  diffusible  soluble  substance  which  is  either  the  injurious 
agent  itself  or  produced  by  its  destructive  action  on  the  cells  of  the  tissue. 
It  is  so  evident  that  dead  tissue  killed  by  any  mechanical  means  or  by  being 
deprived  of  its  blood  supply,  as  in  the  case  an  an  infarction,  can  act  in  this 
way  to  attract  the  leucocytes,  that  in  every  case  it  must  play  a  part. 
Experimentally  it  has  been  shown  that  extracts  of  dead  cells  are  positively 
chemiotactic.  Nevertheless,  the  leucocytes  appear  in  so  much  greater 
number  when  bacteria  or  some  chemical  irritant  cause  the  inflammation 
that  unquestionably  these  poisonous  substances  themselves  have  a  power- 
ful influence, 
ii 


146  TEXT-BOOK   OF   PATHOLOGY 

All  forms  of  leucocytes  are  not  equally  attracted  by  each  substance, 
and  indeed  some  things  actually  repel  one  form  while  attracting  another. 
Thus  while  in  most  inflammations  the  polymorphonuclear  neutrophile 
cells  are  prompt  to  respond  in  great  numbers,  cells  of  the  type  of  the  lym- 
phocyte are  most  abundant  in  the  inflamed  areas  in  typhoid  fever  and 
even  in  tuberculosis.  So,  too,  in  the  lesions  produced  by  many  animal 
parasites,  such  as  the  trichina,  the  polymorphonuclear  eosinophile  cells 
appear  in  great  numbers.  It  is  not  clear  that  any  bacteria  exercise  a 
definitely  repellent  action  on  the  neutrophile  leucocyte,  although  it  seems 
that  this  may  be  so  in  typhoid  fever. 

Leucocytosis. — How  the  impulse  is  sent  to  the  bone-marrow,  when  there 
is  a  localized  infection,  to  call  forth  the  storm-like  discharge  of  new  leu- 
cocytes into  the  blood,  is  not  very  clear.  Certainly  far  more  are  formed 
and  liberated  than  could  possibly  be  accounted  for  by  any  dearth  in  the 
circulating  blood  caused  by  their  departure  from  the  blood-vessels,  and  it 
seems  necessary  to  believe  that  some  chemical  substance  circulating  in  the 
blood  causes  this  great  hyperplasia.  If  one  reflects  that  a  leucocytosis  of 
30,000  to  40,000  per  cubic  millimetre  is  not  unusual,  the  colossal  number 
of  new  leucocytes  quickly  formed  and  thrown  into  circulation  becomes 
a  matter  of  wonder. 

The  Wandering  Cells. — It  is  clear  that  in  the  adult  animal  the  greater 
number  of  the  cells  are  intimately  and  permanently  attached  to  their 
neighbors,  and  in  virtue  of  this  coherence  tissues  are  formed  which  are 
stable.  The  rest  of  the  cells  are  not  so  fixed,  but  wander  about  loosely  or 
are  driven  about  with  great  speed,  as  in  the  case  of  the  red  corpuscles  and 
leucocytes  of  the  circulating  blood.  Even  in  the  circulating  blood  the 
leucocytes  have  the  power  of  moving  at  their  own  volition,  but  this  power 
comes  to  its  proper  expression  only  in  the  crevices  of  the  tissues,  where 
they  are  at  leisure  and  are  not  hurried  along  by  the  force  of  the  heart. 
There  it  is  easy  to  recognize  such  free  cells  by  their  clear-cut  outline,  their 
independence  of  attachment  to  other  cells,  and  by  their  bulging  or  lobose 
pseudopods.  If  the  tissue  is  allowed  to  grow  cold  before  fixation,  most 
of  these  cells  will  be  found  to  have  retracted  into  a  round  form,  but  if  it  is 
dropped  in  small  pieces,  perfectly  fresh  and  warm  from  the  living  animal, 
into  some  solution  which  will  fix  it  instantaneously,  the  wandering  cells  are 
seen  caught  in  all  sorts  of  attitudes,  and  often  stretching  out  long  arms  or 
twisting  their  way  among  the  fixed  cells. 

It  is  very  generally  agreed  now  that  these  wandering  cells  take  no  part 
in  the  formation  of  any  fixed  or  stable  tissue,  but  are  probably  always 
nomadic  until  they  perish.  It  is  not  so  certain  that  the  fixed  tissues  do  not 
give  origin  to  wandering  cells.  This  forms  the  subject  of  a  discussion 
which,  has  lasted  for  years,  and  is  even  now  far  from  a  conclusion.  It 
seems  proved  that  if  we  go  far  enough  back  in  the  development  of  the 
embryo,  it  may  be  shown  that  the  wandering  cells,  all  of  which  are  of  meso- 
blastic  origin,  arise  from  exactly  the  same  cells  as  give  rise  to  the  various 


INFLAMMATION 


147 


types  of  connective  tissue.  In  other  words,  in  this  early  stage  the  forma- 
tion of  blood,  including  red  corpuscles  as  well  as  leucocytes,  takes  place 
nearly  everywhere  in  the  mesenchyme  or  original  connective  tissue. 
Maximow  and  also  Danchakoff  have  described  this  very  clearly  in  a 
number  of  recent  papers,  and  have  shown  that  among  the  branched 
connective-tissue  cells  which  make  up  this  soft  tissue  there  appear  spaces 
(Fig.  60).  The  connective-tissue  cells  or  fibroblasts  bounding  these  con- 
stitute a  lining,  and  soon  become  modified  and  divide  to  form  round  cells, 
some  of  which  fall  into  the  space,  while  others  maintain  themselves  as  lining 


— Mz 


Fig.  60. — Early  development  of  wandering  cells  in  embryonic  tissue  (Maximow). 
Cross-section  of  a  vessel  of  the  area  vasculosa  with  primitive  blood-cells  (p.  biz)  in  the 
lumen.  Rounding  off  of  endothelial  cells  (ra)  and  their  conversion  into  blood-cells; 
mz,  mesenchyme  cells;  ed,  endothelium. 

cells.  These  are  the  first  endothelial  cells  and  the  forerunners  of  the  blood- 
cells.  From  such  round  cells  which  fall  into  the  new  blood-channel  there 
arise  red  corpuscles,  lymphocytes,  and  even  the  granulated  leucocytes, 
and  these  may  wander  out  among  the  other  cells  and  back  again.  Many 
of  those  which  remain  nucleated  and  devoid  of  haemoglobin  leave  the  blood- 
channels  and  pursue  a  wandering  existence  in  the  tissues. 

This  idea  of  the  single  or  monophyletic  origin  of  all  the  cells  from  the 
original  mesenchyma  cells  is  elaborated  by  Danchakoff  in  her  recent  papers 
in  which  she  shows  that  the  formation  of  red  cells  taking  place  within  the 


148  TEXT-BOOK   OF   PATHOLOGY 

vascular  bed  is  controlled  by  conditions  which  exist  there,  while  the  forma- 
tion of  the  granular  cells  occurring  largely  outside  the  vessels  is  affected 
by  extrinsic  differential  factors.  Her  papers  describe  in  much  detail  the  de- 
velopment and  interrelation  of  these  early  stages  and  should  be  consulted. 

Later  in  the  development  of  the  animal  such  processes  of  blood  forma- 
tion become  localized  in  certain  specialized  blood-forming  organs,  such  as 
the  bone-marrow,  the  lymphoid  tissues,  and  possibly  some  other  places. 
For  a  time  the  liver  is  active  as  a  blood-forming  tissue,  but  it  loses  this 
power  later.  The  spleen  appears  to  retain  the  haematopoietic  power 
through  life,  although  it  acts  also  as  a  scavenger  of  debris  of  blood-cells. 

Under  pathological  conditions  it  seems  that  very  many  other  situations 
in  the  body  may  become  endowed  with  the  capacity  for  blood  formation — 
a  change  sometimes  called  a  myeloid  transformation;  thus  actual  bone- 
marrow  may  be  formed  in  the  lung  or  the  kidney  or  in  the  artery  wall,  or 
the  spleen  may  come  to  contain  the  elements  which  are  recognized  in  the 
bone-marrow  as  the  producers  of  leucocytes  and  red  corpuscles.  But 
these  things  are  abnormal  and  transitory,  and  ordinarily  blood  formation 
is  rather  restricted  to  the  definite  blood-forming  organs.  In  this  way  the 
relation  of  the  wandering  cells  to  the  fixed  tissues  becomes  fairly  clear. 
That  they  are  of  common  original  stock  with  the  connective  tissues  is 
shown  by  the  early  development,  but  that  these  connective  tissues  draw 
away  and  become  specific  producers  of  similar  connective  tissues  only,  in 
later  life,  leaving  the  wandering  cells  to  be  formed  by  specialized  cells 
grouped  in  organs  for  that  purpose,  is  equally  clear. 

Description  of  the  cells  concerned  may  be  found  in  every  text-book  of 
histology,  although  it  is  true  that  some  of  the  types  become  conspicuous 
or  are  produced  only  under  pathological  conditions. 

In  the  circulating  blood  there  are  found  normally,  beside  the  red  cor- 
puscles and  platelets  (which  are  derivatives  of  the  megalokaryocytes  of 
the  bone-marrow),  several  types,  of  mobile  leucocytes.  Of  these,  the  poly- 
morphonudear  leucocytes  with  neutrophile  granules  are  most  prominent, 
and  form  about  70  per  cent,  of  all  the  white  cells.  Similar  to  them  in 
many  respects  are  the  eosinophile  cells,  which  differ  in  possessing  shining 
granules  staining  brightly  with  eosin,  but  these  form  only  1  or  2  per  cent. 
The  remainder  consist  of  cells  with  rounded  nucleus  and  protoplasm  con- 
taining few  granules  or  none  at  all.  The  smaller  of  these,  with  relatively 
little  protoplasm,  are  the  lymphocytes.  Larger  paler  cells  with  palely 
stained  round  or  indented  nucleus  are  variously  known  as  large  mononu- 
clear  cells,  large  lymphocytes,  etc.  Occasionally  there  are  found  single 
examples  of  the  forerunners  of  the  polymorphonuclear  leucocytes  in  the 
form  of  large  mononuclear  rounded  cells  with  neutrophile  or  even  eosino- 
phile granules  (myelocytes) ,  and  about  as  rarely  leucocyte-like  cells  which 
contain  distinctly  basophilic  granules  in  their  protoplasm  (mast  leucocytes) . 

In  the  bone-marrow,  where  the  manufacture  of  the  cell  contents  of  the 
blood  is  very  active,  there  are  found  all  the  precursors  of  these  cells. 


INFLAMMATION  149 

There  there  are  many  indifferent  non-granulated  cells,  much  like  the  primi- 
tive cells  in  the  embryonic  tissue,  from  which  so  many  varieties  arose. 
These  can  be  supposed  to  give  rise,  along  different  lines  of  specialization, 
to  the  cells  as  they  are  found  in  the  blood.  One  process  of  differentiation 
doubtless  leads  to  the  formation  of  larger  and  smaller  lymphocytes.  This 
certainly  occurs  in  the  bone-marrow,  although  these  cells  are  known  to  be 
produced  in  especially  great  numbers  by  the  lymphoid  tissue  distributed 
throughout  the  body.  Another  line  of  development  from  an  early  un- 
differentiated  type  of  cell  which  is  originally  the  same  as  that  just  described 
leads,  through  the  appearance  of  haemoglobin  in  the  protoplasm  to  the 
formation  of  normoblasts  (nucleated  red  corpuscles),  and  later  through  the 
loss  of  nucleus  to  the  non-nucleated  ordinary  red  corpuscles  or  erythrocytes. 
Sometimes  in  the  stress  of  rapid  delivery  of  these  red  corpuscles  to  the 
blood  in  cases  of  anaemia  some  of  the  nucleated  normoblasts  are  swept 
out  into  the  circulation.  The  third  line  of  development,  beginning  with 
an  indifferent  nucleated  cell,  leads  to  the  production  of  large  round  cells 
with  large,  pale  nucleus  and  non-granular  protoplasm  (myeloblast) ,  which 
may  acquire  either  neutrophile  or  eosinophile  granulations  (myelocyte). 
These  in  time  give  rise  respectively  to  the  neutrophile  and  eosinophile 
polymorphonuclear  leucocytes  (Fig.  61). 

Osteoblasts  and  osteoclasts  in  the  bone-marrow  take  no  part  in  blood 
formation,  but  the  large  giant-cells  with  budding  nucleus  and  granular 
protoplasm  (megalokaryocytes)  constantly  give  off  fragments  of  their 
protoplasm  to  the  blood-stream  and  thus  produce  the  platelets  (Wright). 

In  the  lymph-glands,  as  well  as  in  the  Malpighian  bodies  of  the  spleen, 
the  tonsils,  and  all  the  lymphoid  nodules  scattered  along  the  alimentary 
tract,  there  are  found  many  lymphocytes  lodged  in  a  reticulum  and  associ- 
ated closely  with  networks  of  lymph-sinuses  and  lymphatic  channels. 
In  the  reticulum  there  are  many  large  pale  cells  which  may  be  concentrated 
in  the  middle  of  each  lymph-cord  or  island  in  the  gland  to  form  the  so-called 
germinal  centre  (Fig.  62).  Although  it  was  stated  by  Flemming  that 
these  large  cells  gave  rise  by  mitosis  to  the  lymphocytes,  there  is  still  much 
dispute  about  the  actual  origin  of  the  smaller  cells.  Marchand,  in  re- 
viewing the  work  with  its  divergent  results,  concludes  that  large  macro- 
phages  are  certainly  formed  from  the  reticulum  cells  and  endothelium  of 
the  sinuses,  but  that  it  is  difficult  to  prove  the  origin  of  the  lymphocytes 
from  the  large  cells  of  the  germinal  centre. 

These  cells  have  different  morphological  characters  and  phagocytic 
powers,  and  although  we  know  that  lymphocytes  are  produced  in  this  tissue 
and  although  the  general  tendency  is  to  derive  them  from  the  reticulum 
cells,  this  origin  has  not  actually  been  proved. 

In  the  course  of  many  infections  the  sinuses  of  the  gland,  and  even  the 
neighboring  tissues,  become  packed  with  large  mobile  mononuclear  cells 
which  are  most  voraciously  phagocytic  and  engorge  themselves  with  every 
sort  of  cellular  debr.is  (Fig.  63).  Marchand  and  others  regard  these  as  the 


150 


TEXT-BOOK  OF  PATHOLOGY 


Original  cell 


Large  lymphocytes 


\ 


Small  •  V;^    m 

ymphocytes      *flj*»^i 


Neutrophilic  5C 

myelocyte  7^7  myelocyte 

*?'       I      i 


a    o 

^  lAononucleor 

j  wandering 

u  cells 

0  i 


©      © 

Plasma  cells 

B*        „'. 

^     Hononuclear 


Losmophile 
leucocytes 

Neutropliile 
leucocytes 


Mast  cells  ftasophilic  cells 
of  tissue         °/  blood 


> 

.A .- ;  * 


Lar^e  pho^rocytic 
Wandering   cells 


Fig.  61. — Genealogical  tree  of  the  wandering  cells  of  human  tissues  as  they  appear 
in  ordinary  sections.  The  cells  are  drawn  to  scale,  and  the  arrows  indicate  their  rela- 
tionship. 


INFLAMMATION 


151 


Fig.  62. — Germinal  centre  in  Malpighian  body  of  the  spleen. 


Fig.  63. — Lymph-gland  showing  phagocytic  wandering  cells  in  the  lymph-sinuses. 


152  TEXT-BOOK    OF    PATHOLOGY 

macrophages  derived  from  the  reticulum  cells  and  from  the  endothelium 
of  the  lymph-sinuses.  Mallory,  in  his  study  of  typhoid  fever,  has  laid 
special  stress  on  their  endothelial  origin,  and  even  speaks  of  them  as 
endothelial  leucocytes.  It  seems  to  me  difficult,  however,  to  distinguish 
between  these  and  the  large  mononuclear  wandering  cells  in  general,  and 
difficult  to  assign  to  them  with  certainty  an  origin  different  from  that 
accepted  for  those  which  infiltrate  tissues  at  a  distance  from  lymph-glands. 

Conditions  in  the  lymphoid  nodules  of  the  intestinal  wall  and  other 
organs,  in  the  Malpighian  bodies  of  the  spleen  and  the  tonsils,  correspond 
exactly  with  those  in  the  follicles  of  the  lymph-glands.  In  the  splenic 
pulp  there  are  also  cells  of  the  type  of  lymphoid  cells,  and  larger  ones  which 
act  as  macrophages.  That  they  may  be  contributed  in  great  numbers  to 
the  circulating  blood  is  shown  clearly  by  Morris'  recent  studies  of  the  blood 
of  the  splenic  vein.  Other  tissues,  including  the  connective  tissues  in 
general,  especially  where  they  lie  in  relation  to  the  walls  of  the  blood- 
vessels, the  omentum,  the  stroma  of  the  mucosse  of  the  intestine,  etc., 
harbor  wandering  cells  in  considerable  numbers  and  many  forms.  It  is 
true  that,  except  in  the  mucosa  of  the  intestine,  these  cells  are  normally 
very  inconspicuous,  but  they  appear  in  great  numbers  when  there  is  any 
stimulus  to  attract  them. 

Ranvier  described  the  so-called  clasmatocytes,  or  cells  which  could  break 
off  and  discharge  parts  of  their  protoplasm,  as  occurring  in  the  tissues, 
but  it  is  to  Marchand  especially  that  we  owe  the  recognition  of  the  normal 
existence  in  the  crevices  of  the  tissues  of  mononuclear  cells  which  have 
wandered  out  of  the  vessels  and  become  sessile  in  their  outer  walls  or  in 
the  neighborhood.  To  these  he  has  given  the  name  adventitial  cells. 
They  are  quite  amoeboid,  and  respond  to  chemiotactic  influences,  showing 
great  phagocytic  activity.  They  hurry  through  the  tissues  in  great  num- 
bers to  the  seat  of  injury  when  certain  sorts  of  inflammatory  processes 
are  set  up,  and  it  is  through  their  multiplication  that  a  part  at  least  of 
the  accumulation  of  cells  often  spoken  of  loosely  as  round-cell  infiltration 
arises.  Such  gatherings  of  cells  have  for  years  occasioned  discussion, 
and  this  is  one  of  the  sources  of  origin  which  Marchand  emphasizes  and 
defends.  The  others  will  be  referred  to. 

Besides  the  adventitial  cells,  there  are  others  in  the  tissues  which  are 
similar  in  their  general  form,  but  distinguished  by  their  staining  properties 
and  by  their  behavior.  These  are  the  mast  cells,  which  are  found  most 
abundantly  in  the  walls  of  the  bronchi  and  intestine  and  about  the  blood- 
vessels. Whereas  the  adventitial  cells  show  a  few  metachromatic  granules 
staining  red  with  azur  dyes,  the  mast  cells  are  full  of  large  basophilic 
granules,  which  stain  purple  with  dahlia  and  also  red  with  azur  or  poly- 
chrome methylene-blue. 

The  recent  papers  of  Maximo w  dealing  with  inflammation,  abscess 
formation,  the  participation  of  mononuclear  cells,  and  the  formation  of 
scar  tissue  throw  much  light  upon  the  subject.  JBy  the  use  of  porous 


INFLAMMATION 


153 


foreign  bodies  embedded  in  the  tissues  he  showed  that  lymphocytes  which 
had  wandered  out  from 'the  blood-vessels  appeared,  as  it  were,  in  pure 
culture  in  the  spaces  of  the  foreign  body,  and  subsequently  grew  and 
developed  until,  in  their  various  stages,  they  became  identical  with  all  the 


•*»  • 


•v— 


Fig.  64. — Group  of  polyblastic  or  wandering  cells  of  various  types:  ly.,  Lymphocytes; 
pi.,  plasma  cells;  ph.,  phagocytic  cells  of  large  size,  some  containing  blood-pigment,  others, 
I. ph.,  containing  much  fat;  g.,  foreign-body  giant-cell  formed  about  granules  and  crystals 
of  bismuth  ',fibr.,  connective-tissue  cell. 

forms  of  large  mononuclear  wandering  cells  with  abundant  protoplasm  and 
phagocytic  activity  (Fig.  64).  Fusion  of  several  such  cells  produces  giant, 
syncytium-like  cells  with  many  nuclei  which  are  particularly  able  to  en- 
gulf foreign  bodies  and  are  known  as  foreign-body  giant-cellsij  (This  was 


154 


TEXT-BOOK    OF    PATHOLOGY 


confirmed  by  Lambert,  who  cultivated  lymphoid  cells  in  vitro  with  lyco- 
podium  grains  as  foreign  bodies  (Fig.  65).  This  whole  group  of  wandering 
cells,  derived  by  gradual  metamorphosis  in  the  new  environment  from 
lymphocytes  which  had  emigarated  from  the  blood-vessels,  he  designates 
as  polyblasts,  suggesting  thereby  the  variety  of  forms  which  they  may 
assume.  He  thinks  it  conceivable,  though  not  probable  and  not  proven, 
that  they  may  become  fixed  tissue-cells.  At  most  he  will  say  that  they 
become  imprisoned  between  the  fibres  of  connective  tissue,  and  are  then 
hardly  distinguishable  from  those  cells.  Although  he  tends  to  regard 
them  as  the  product  of  emigrated  cells,  he  derives  them  equally  readily 

from  the  wandering  cells  of  the  tissue  which 
may  have  emigrated  a  long  time  before  and 
lain  latent  in  the  tissues  for  that  time.  Nor 
is  it  doubtfu  that  they  re-enter  the  blood- 
vessels at  times.  There  is  thus  no  real  in- 
consistency between  this  view  and  that  of 
Marchand. 

We  find  thus  three  sources  mentioned  for 
the  variegated  crowd  of  mononuclear  wan- 
dering cells  that  swarm  about  areas  where 
inflammation  has  existed  for  a  time:  (1)  The 
reticulum  cells  and  the  endothelial  cells  of 
the  sinuses  in  lymph-glands,  the  lymph- 
nodes  of  the  intestine,  and  in  the  spleen. 

(2)  Cells  which  are  normally  found  in  the 
adventitial  tissues  of  vessels  and  scattered 
elsewhere  in  the  crevices  of  the  tissue,  and 

(3)  lymphocytes  which  emigrate  from  the 
blood-vessels  and  in  the  tissues  develop  into 
amoeboid  forms,   quite  like  those  already 
there.    Other  possibilities  doubtless  exist,  as, 
for  example,  in  the  case  of  the  very  similar 
fat-granule  cells  found  in  softened  areas  of 
the  brain  which  Fr.  Marchand  describes  as 
originating  from  the  neuroglia  ceifc.    In  all 

cases,  however,  they  have  finally  the  same  general  characters,  and  although 
these  different  origins  are  quite  possible,  it  seems  unfortunate  that  so  much 
stress  should  be  laid  upon  this  point — for  Mallory  almost  every  phagocytic 
cell  is  an  endothelial  cell — for  Maximow  they  are  all  overgrown  lympho- 
cytes. To  me  it  seems  that  while  the  endothelial  cells  in  spleen,  liver,  and 
lymph-glands  have  undoubtedly  phagocytic  activity,  the  origin  of  wander- 
ing cells  from  them  is  least  well  proved.  Further,  it  is  perfectly  obvious 
that  myriads  of  mobile  wandering  cells  do  exist  normally  in  the  tissue,  and 
that  the  lymphocytes  do  actually  emigrate  from  the  vessels,  and,  accord- 
ing to  Maximow's  careful  observations,  change  their  form  in  the  new  en- 


Fig.  65. — Foreign-body  giant- 
cell  in  tissue  culture,  enclos- 
ing two  lycopodium  spores. 


INFLAMMATION  155 

vironment.  These  two  sources,  which  are  in  the  end  identical,  seem,  there- 
fore, perfectly  sufficient  to  explain  every  accumulation  of  the  mononuclear 
wandering  cells,  and  on  this  basis  we  shall  speak  of  them  by  that  name  only. 

Among  them  there  occurs  one  peculiar  form  which  is  obviously  derived 
from  the  lymphocyte  through  a  modification  of  its  nucleus  and  protoplasm. 
This  is  the  so-called  plasma  cell  described  by  Unna,  which  occurs  normally 
in  the  intestinal  mucosa  and  elsewhere  and  appears  in  great  numbers  in 
many  forms  of  long-standing  subacute  inflammatory  reactions  (Fig.  64). 
Tuberculous  granulation  tissue  and  gonorrheal  salpingitis  afford  examples 
of  such  conditions.  The  cells  are  rather  larger  than  lymphocytes — some- 
what amoeboid,  but  in  fixed  preparations  they  usually  assume  a  rounded  or 
oval  form,  with  the  nucleus  excentrically  placed,  generally  at  one  end  of  the 
cell.  The  nucleus,  whose  chromatin  is  in  coarse  masses,  is  surrounded  by  a 
pale  halo,  while  the  remaining  protoplasm  takes  a  bluish  stain  with  ordi- 
nary nuclear  dyes.  Such  cells,  which  may  be  regarded  as  a  type  slightly 
differentiated  from  the  rest  of  the  tribe  of  mononuclear  wandering  cells, 
are  conspicuous  because  they  are  so  constant  in  their  form.  They  are  not 
commonly  phagocytic,  but  probably  active  in  producing  a  digestive  ferment. 

Goldmann  has  studied  all  the  wandering  cells  of  the  tissue  with  reference 
to  their  behavior  toward  certain  dyes,  such  as  pyrrhol-blue,  isamin-blue, 
etc.,  which  can  be  injected  into  the  living  animal  and  are  taken  up  with 
sharp  selectiveness  by  certain  cells  only.  Kupffer's  stellate  cells  of  the 
endothelium  of  the  liver  capillaries  stain  brilliantly  in  this  way,  and  so  do 
the  interstitial  cells  of  the  testes.  Some  of  the  epithelial  cells  of  the  renal 
tubule  store  up  the  stain  in  granular  form  in  just  the  same  way,  while 
allowing  the  passage  into  the  urine  of  other  portions  of  it.  In  the  connec- 
tive tissues  by  no  means  all  the  wandering  cells  are  stained,  but  only  certain 
mononuclear  cells,  which  are  thus  distinguished  by  him  as  pyrrhol-cells 
from  lymphocytes,  mast  cells,  etc.  What  special  functional  activity  of 
these  cells  confers  this  peculiar  power  upon  them  is  not  clear. 

The  mere  fact  that  these  cells  take  up  in  their  nuclei  or  protoplasm  or 
in  their  granules  certain  stains  in  a  specific  way  does  not,  after  all,  afford 
us  much  information  as  to  their  true  character.  It  would  be  more  impor- 
tant to  determine  something  as  to  their  function.  Metchnikoff,  in  his 
studies  of  inflammation  and  immunity,  has  been  at  great  pains  to  show 
the  analogy  between  the  activities  of  the  wandering  cells  of  the  body  and 
those  of  amcebse  or  other  amoeboid  simple  protoplasmic  organisms.  These 
latter  swallow  up  bacteria  and  other  substances,  and  by  the  aid  of  ferments 
or  cytases  digest  them.  These  ferments,  he  says,  are  also  present  in  the 
wandering  cells  of  the  body,  and  differ  according  to  the  type  of  cell,  the 
small  neutrophile  leucocyte  possessing  a  so-called  microcytase,  while  the 
mononuclear  cells  or  macrophages,  which  eschew  bacteria,  except  such  as 
the  tubercle  and  leprosy  bacilli,  and  digest  with  avidity  cell  debris,  carry 
out  their  digestive  processes  by  the  aid  of  another  ferment  which  he  calls 
macrocytase.  Therefore  the  plasma  of  the  blood  is  scarcely  bactericidal 


156  TEXT-BOOK   OF   PATHOLOGY 

as  compared  with  blood-serum,  in  which  digestive  ferments  are  found,  owing 
to  the  disintegration  of  leucocytes  in  the  process  of  clotting.  He  does  not 
distinguish  sharply  between  such  ferments  and  the  complement  or  alexine 
of  the  serum,  but  does  sharply  separate  the  "fixateurs"  or  "  amboceptors " 
which  are  produced,  he  thinks,  by  the  phagocytes,  but  set  free  into  the 
plasma  as  specifically  adapted  substances  capable  of  preparing  the  bacteria, 
etc.,  which  stirred  up  their  production,  for  solution  by  the  complement. 
In  any  case  he  regards  the  phagocytes  as  the  great  source  of  these  ferments. 

Many  writers  have  recognized  the  power  of  certain  tissues  to  digest 
themselves  in  vitro  (autolysis),  and  have  observed  that  the  neutrophile 
leucocytes  produce  a  strong  proteolytic  ferment  capable  of  digesting  fibrin, 
gelatin,  etc.  Most  of  them,  however,  according  to  Wiens,  have  denied  the 
production  of  a  ferment  by  lymphoid  cells.  Opie  has  cleared  the  matter 
up  very  well  by  finding  that  the  ferments  of  different  cells  require  for  their 
activity  different  reactions.  He  states  that  the  polymorphonuclear  neu- 
trophile leucocytes  and  their  ancestral  granulated  cells  produce  a  trypsin- 
like  ferment  which  acts  best  in  an  alkaline  or  neutral  medium  to  digest 
proteins.  Its  action  is  often  combated  by  an  anti-enzyme,  which  is 
present  in  the  plasma  of  the  blood  and  in  other  body  fluids.  It  is  re- 
sistant to  heat  up  to  70°  or  75°  C.,  and  is  therefore  quite  different  from 
the  complement  of  the  serum,  which  is  destroyed  at  55°  C.  When  formed 
in  great  concentration  in  a  focal  area  of  inflammation,  the  enzyme  far  out- 
strips the  neutralizing  anti-enzyme,  and  brings  about  the  liquefaction  of 
dead  tissue,  as  in  the  case  of  an  abscess.  When  in  the  presence  of  a  great 
exudation  of  fluid,  as  in  the  pleural  cavity,  its  action  may  be  held  in  check. 
This  proteolytic  ferment  Opie  calls  leucoprotease.  Contrary  to  the  results 
of  other  workers,  he  finds  that,  if  the  correctly  feeble  acid  reaction  be  offered, 
the  mononuclear  cells  also  show  the  formation  of  a  proteolytic  ferment 
which  is  more  like  pepsin  in  its  character,  although  it  is  unable  to  act  in 
so  strong  an  acid  as  is  favorable  to  pepsin.  This  ferment,  which  he  calls 
lymphoprotease,  is  produced  in  the  lymph-glands  and  in  all  accumulations 
of  lymphoid  cells,  and  of  the  various  types  of  larger  wandering  mononu- 
clear phagocytic  cells  which  go  to  form  Metchnikoff's  group  of  macro- 
phages. 

While  these  ferments  are  evidently  used  inside  the  cell  in  the  case  of  the 
particles  which  have  been  ingested,  it  seems  certain  that,  in  the  formation 
of  pus,  as  in  the  abscess,  they  are  diffused  from  the  bodies  of  the  disin- 
tegrating leucocytes,  and  in  the  free  fluid  effect  the  solution  of  the  adjacent 
injured  and  dead  tissue.  This  function  of  the  wandering  cells  is,  of  course, 
of  immediate  importance  in  connection  with  their  task  of  cleaning  up  the 
injured  area  to  prepare  it  for  repair.  While  the  proteases  thus  produced 
are  active  in  the  solution  of  undesirable  material,  their  unbridled  action 
might  be  detrimental.  As  a  matter  of  fact,  it  is  shown  by  Jobling  and 
Petersen  that  the  anti-ferment  known  to  be  present  in  the  serum  and  to 
restrict  the  action  of  the  ferment  is  a  recognizable  chemical  substance, 


INFLAMMATION  157 

usually  a  soap  or  other  combination  of  an  unsaturated  fatty  acid.  It  is 
possible  to  remove  or  decompose  this  substance  or  to  saturate  the  fatty  acid 
with  iodine  and  thus  release  the  ferment  to  its  full  activity.  The  presence 
of  excess  of  such  soaps  in  the  tubercle  bacilli  seems  to  be  the  cause  of  the 
delay  of  liquefaction  of  tissue  brought  to  necrosis  by  those  bacilli.  It  is 
seen  from  this  that  we  are  at  the  beginning  of  our  knowledge  of  the  activi- 
ties of  the  wandering  cells.  What  other  ferments  they  produce  has  been 
as  yet  only  imperfectly  studied,  although  we  have  evidence  that  others, 
such  as  oxydases,  are  produced  by  some  of  them,  and  there  are  surely 
more. 

Pain  in  Inflammation. — Doubtless  the  cause  of  pain  in  inflamed  tissues 
is  different  in  various  parts  of  the  body,  for  in  certain  confined  places  it  is 
not  hard  to  imagine  that  the  accumulation  of  exudate  stretching  sensitive 
tissues  would  cause  suffering,  which  might  be  relieved,  as  is  so  often  the 
case,  by  an  incision  which  allows  the  exudate  to  escape.  Still  it  has  been 
objected  that  pressure  and  tension  on  the  nerve-endings  are  not  sufficient 
to  cause  pain,  since  local  anaesthesia  can  generally  be  produced  by  injecting 
some  indifferent  solution  into  the  tissues  until  they  are  distended.  There- 
fore it  has  been  thought  that  the  poisons  which  caused  the  inflammation 
also  irritate  the  nerve-endings.  Possibly  this  is  so,  but  an  inflamed  area 
following  a  burn  is  as  painful  as  one  resulting  from  bacterial  infection,  and 
in  sunburn  no  pain  is  felt  during  the  injury,  but  only  when  the  inflammation 
is  at  its  height.  Possibly  the  hypersemia  itself  renders  the  sensory  nerves 
hyperexcitable,  as  seems  to  be  true  in  the  case  of  non-inflammatory  hy- 
peraemias. 

LITERATURE 

The  student  should  particularly  consult  the  papers  of  Maximow  with  regard  to  the 
cells  concerned  in  inflammation  and  the  repair  of  tissue,  as  follows: 
Maximow:  Ziegler's  Beitrage,  Suppl.  5,  1902;  1905,  xxxviii;  1907,  xli.    Arch.  f.  mikr. 

Anat.,  1906,  Ixvii;  1909,  Ixxiii;  1910,  Ixxvi. 

Adami:  Inflammation,  Macmillan,  1909. 

Danchakoff:  Anat.  Record,  1916,  x,  397,  483.    Amer.  Jour,  of  Anat.,  1916,  xx,  255; 

1918,  xxiv,  1,  127. 

Jobling  and  Petersen:     Jour.  Exp.  Med.,  1914,  xix,  239,  etc. 
Lambert:  Jour.  Exp.  Med.,  1912,  xv,  510. 

Marchand:  Verh.  Deutsch.  path.  Gesellsch.,  1914,  xvi,  5.    (Lymphocytes.) 
Metchnikoff:  Lectures  on  the  Comparative  Pathology  of  Inflammation,  1893. 
Opie:  Harvey  Lectures,  1910,  192. 
Samuel:  Ergeb.  d.  allg.  Path.,  1895,  i2,  64. 

Weidenreich:  Arch.  f.  mikr.  Anat.,  1909,  Ixxiii,  793.     (Literature.) 
Wiens:  Ergeb.  d.  allg.  Path.,  1911,  xv:,  1. 
Ziegler:  Ziegler's  Beitr.,  xii,  152.     (Historical  and  critical.) 


CHAPTER  X 
DEFENCES  OF  THE  BODY  (Continued) 

Fever.  General  nature  of  the  reaction.  Its  chemical  characters  and  relation  to  immunity. 
Immunity.  Nature  of  injurious  agents.  Types  of  resistance.  Artificial  immunity. 
Phagocytosis.  Lysins,  agglutinins,  antitoxins,  etc. 

Maintenance  of  the  acid-base  equilibrium  in  the  body.  Mechanism  of  the  preservation 
of  neutrality — acidosis. 

FEVER 

General  Nature  of  the  Reaction. — It  is  common  knowledge  that  fever  is 
likely  to  accompany  inflammation,  and,  as  in  the  case  of  inflammation, 
the  efforts  of  physicians  and  healers  of  all  sorts  have  been  directed  toward 
cutting  it  short  on  the  idea  that  it  in  itself  is  the  harmful  process.  Only 
in  the  last  decade  has  it  become  vaguely  appreciated  that  there  is  real 
evidence  that  fever,  on  the  contrary,  is  a  reaction  elaborated  to  a  consider- 
able degree  of  perfection,  which  aids  in  the  defence  of  the  body  against  the 
advance  of  an  injurious  agent  by  facilitating  the  production  of  the  sub- 
stances which  are  formed  in  the  body  to  neutralize  poisons  or  kill  bacteria. 

From  this  point  of  view  it  would  seem,  to  say  the  least,  short  sighted  to 
give  a  patient  in  fever  an  antipyretic  drug  which  will  cut  short  the  febrile 
reaction. 

Fever  is  a  reaction  which  seems  to  be  carried  out  under  the  control  of 
the  nervous  system,  and  especially  of  the  vasomotor  mechanisms  which 
have  to  do  with  heat  regulation,  the  most  striking  feature  of  which  is  the 
elevation  of  the  temperature  of  the  body  above  the  normal.  This  is  not 
the  result  of  an  excessive  heat-production,  although  there  is  a  moderate 
increase  in  the  production  of  heat,  but  rather  of  the  retention  of  an  undue 
proportion  of  the  heat  produced.  In  the  course  of  fever  the  body  gives 
off  more  heat  than  it  normally  would  at  rest,  but  not  nearly  so  much  as  it 
would  during  active  exercise.  Indeed,  the  heat-production  during  exer- 
cise may  be  increased  200  or  300  per  cent.,  but  such  is  the  accuracy  of 
adjustment  of  heat  loss  to  this  increase  that  the  temperature  of  the  body 
remains  normal.  During  fever,  on  the  other  hand,  the  production  of 
heat  is  increased  only  20  or  40  per  cent.,  but  the  dissipation  of  heat  is  not 
proportional,  and  therefore  the  temperature  rises.  Heat  is  given  off,  but, 
as  Liebermeister  has  said,  the  regulating  mechanism  is  altered  to  react 
for  a  different  standard  of  body  temperature.  It  is  tuned  up  to  a  higher 
pitch,  so  that  it  begins  to  allow  of  the  escape  of  heat  only  at  a  higher  level, 
just  as  we  might  screw  up  the  thermoregulator  of  a  thermostat  so  that  its 
temperature  would  stand  at  40°  instead  of  35°. 

The  regulating  mechanism  is  found  in  the  vasomotor  apparatus  of  the 
vessels  of  the  skin,  in  the  secretory  activities  of  the  sweat-glands,  in  the 

158 


FEVER  159 

respiration  (especially  in  the  dog,  which  cools  itself  by  panting),  in  shiver- 
ing, and  partly,  in  human  beings,  in  conscious  changes  in  the  clothing.  A 
striking  instance  of  the  coordinated  working  of  all  these  arrangements  is 
seen  in  a  chill,  which  is  so  frequent  an  accompaniment  of  toxic  or  bacterial 
injuries  with  inflammation.  The  superficial  vessels  of  the  skin  are  con- 
tracted so  that  little  blood  is  carried  to  that  radiating  surface.  The  skin 
is  pale  or  livid.  The  sweat-glands  stop  secreting,  so  that  the  cooling  effect 
of  evaporation  of  the  sweat  is  held  in  abeyance;  the  smooth  muscles  in 
the  skin  contract  and  pull  it  into  gooseflesh;  the  person  feels  cold,  cowers 
together,  covers  himself  heavily  with  blankets,  and  shivers  violently,  thus 
turning  stored-up  energy  into  heat.  Every  available  mechanism  is  brought 
into  play  to  stop  the  dissipation  of  heat  and  to  warm  up  the  body,  and  in 
spite  of  the  sensation  of  cold,  the  temperature  of  the  interior  is  at  its  highest 
during  the  chill ! 

Later,  when  chemical  processes  are  under  way  to  produce  the  moderate 
excess  of  heat  which  is  observed  in  fever,  these  contractions  of  the  cutane- 
ous vessels,  etc.,  are  no  longer  kept  up,  and  the  skin  may  be  flushed  and 
even  moist,  but  still  the  balance  is  so  adjusted  that  a  little  less  heat  is 
dissipated  than  is  produced — enough,  at  least,  to  keep  the  temperature 
above  the  normal. 

Chemical  Characters  of  Fever. — Naturally,  since  fever  is  a  process 
concerned  with  heat-production,  the  most  painstaking  efforts  have  been 
made  to  ascertain  its  nature  by  the  study  of  the  changes  in  metabolism 
during  febrile  diseases,  but  so  varied  and  complex  are  the  conditions  that 
it  can  hardly  be  said  that  the  results  have  brought  out  any  very  definite 
and  characteristic  changes  peculiar  to  fever  as  such,  and  independent  of  the 
direct  effect  of  the  underlying  cause.  It  is  generally  agreed  that  oxidation 
is  increased  over  that  found  in  the  normal  individual  at  rest,  but  it  is  not 
so  certain  that  it  is  qualitatively  altered.  From  a  study  of  the  excretion 
of  nitrogen,  together  with  a  comparison  of  the  amounts  of  carbon  dioxide 
and  oxygen  in  the  expired  air,  it  has  been  thought  that  the  increased 
oxidation  affects  especially  the  nitrogenous  or  protein  constituents  of  the 
body,  and  indeed  not  so  much  the  labile  or  circulating  proteins  as  those 
which  actually  form  part  of  the  living  tissue.  It  is  known  that  the  store 
of  carbohydrate  is  rapidly  depleted,  but  it  was  thought  until  recently  that 
the  other  ordinary  fuel  used  in  the  production  of  heat  energy — the  fat — 
was  relatively  little  encroached  upon.  Now  May,  Grafe,  Coleman  and 
Shaffer,  and  others  state  that  in  fever,  too,  the  fats  form  a  particularly 
important  source  of  heat,  and  that  if  sufficient  carbohydrate  and  fat  be 
supplied  to  the  febrile  patient  the  waste  of  body  proteins  may  be  prevented. 
Indeed,  Grafe  thinks  that  this  attack  on  the  living  tissues  which  was  tradi- 
tionally emphasized  as  the  most  typical  feature  of  febrile  metabolism,  is 
due  altogether  to  inanition,  and  that  qualitatively  the  febrile  metabolism 
need  not  differ  greatly  from  the  normal. 

In  many  fevers,  especially  in  pneumonia,  there  is  a  curious  retention  of 


160  TEXT-BOOK   OF   PATHOLOGY 

sodium  chloride,  which  is  then  excreted  in  great  amounts  after  the  fever 
is  over.  Water  may  be  retained  in  the  same  way.  The  metabolism  of 
other  inorganic  substances  may  suffer  alteration  in  this  way  or  that  as  well, 
but,  on  the  whole,  it  is  difficult,  if  not  impossible,  to  put  one's  finger  on  any 
of  these  changes  and  say  that  this  is  characteristic  of  the  metabolism  of 
fever. 

In  all  these  studies  little  attention  has  been  devoted  to  the  anatomical 
changes  in  the  disease,  so  that  it  is  not  surprising  that  there  are  discordant 
results.  If  there  is  extensive  destruction  of  tissue  produced  by  the  poisons 
of  bacteria,  or  if  great  quantities  of  leucocytes  appear  in  the  tissues  and 
are  broken  down,  digested,  and  absorbed,  as  in  pneumonia,  there  must  be 
changes  in  the  nitrogen  output.  It  is  difficult,  too,  to  estimate  what  part 
of  the  increased  oxidation  is  due  to  the  heightened  temperature  itself, 
quite  aside  from  any  other  cause,  for  it  has  been  shown  that  artificial  over- 
heating produces  an  increased  oxidation. 

But  aside  from  the  mere  existence  of  dead  tissue  which  can  be  used  as 
fuel  and  appear  in  the  excreta,  and  the  later  result  that  heightened  tem- 
perature facilitates  further  burning,  there  must  be  some  original  cause  for 
the  intensification  of  the  oxidation  process,  even  if  it  prove  that  it  is  not 
qualitatively  but  only  quantitatively  altered. 

Relation  to  Immunity. — So  closely  has  attention  been  concentrated  on 
the  questions  of  disturbances  in  metabolism  that  the  biological  significance 
of  fever  has  been  somewhat  neglected,  but  recently  Roily  and  Meltzer, 
Loewy  and  Richter,  Fukuhara,  and  others  have  published  results  which 
show  it  in  a  clearer  light.  They  found  that  if  animals  were  artificially 
kept  at  a  high  temperature  in  a  thermostat  room,  they  were  able  to  develop 
a  much  more  effective  defence  against  intoxication  and  infection  than  those 
left  outside  at  ordinary  temperatures.  Briefly,  Roily  and  Meltzer  showed 
that  the  high  temperature  itself  had  probably  no  injurious  influence  on  the 
growth  of  bacteria  in  the  body.  Further,  that  if  a  fatal  dose  of  bacteria 
or  of  a  toxin  be  given,  no  special  difference  could  be  observed  between 
heated  and  unheated  animals.  But  this  sort  of  infection,  by  the  sudden 
introduction  of  enormous  quantities  of  bacteria  or  of  a  toxin  hardly  occurs 
in  nature.  Instead,  a  few  bacteria  get  into  the  tissues  and  then  gradually 
increase  in  number,  or  in  their  growth  produce  an  increasing  amount  of 
toxin,  so  that  time  is  given  for  the  appearance  of  a  defensive  reaction. 
If,  now,  the  experiment  be  arranged  in  the  same  way,  small  doses  of  bac- 
teria or  toxin  being  injected  at  intervals,  the  heated  animals  showed  a 
great  advantage  over  the  controls.  They  lived  longer,  and  many  of  them 
survived  doses  which  inevitably  killed  the  control  animals. 

When  they  studied  the  details  of  these  experiments  more  carefully,  they 
found  that  it  was  not  that  the  high  temperature  merely  prevented  the 
growth  of  bacteria — it  might  do  so  in  test-tubes,  but  in  the  body  the  bac- 
teria grow  well  enough  at  febrile  temperatures.  Phagocytosis  proved 
difficult  to  compare  in  the  two  sets  of  animals,  but  in  vitro  they  found  that 


IMMUNITY  161 

it  was  increased  by  temperatures  ranging  even  up  to  41°  C.,  so  that  prob- 
ably the  conditions  for  its  development  are  improved  by  high  temperatures 
in  animals.  When  they  studied  the  formation  of  specific  antibodies,  how- 
ever, they  found  a  great  difference.  Antitoxins  they  did  not  investigate, 
but  agglutinins  and  bacteriolytic  substances  were  produced  far  more 
quickly  and  in  much  greater  amounts  than  in  the  control  animals. 

New  as  these  results  are,  they  seem  to  open  the  way  to  a  more  fruit- 
ful study  of  fever  and  to  confirm  the  somewhat  vaguely  expressed  idea 
that  it  is  in  a  way  analogous  to  the  vascular  reaction  in  inflammation  in 
that  it  is  the  process  which  facilitates  the  more  essential  activities  of  the 
phagocytes  and  the  production  of  defensive  chemical  substances  in  the 
body. 

But  still  more  recent  discussions  of  fever  seem  to  lay  little  stress  on  this 
aspect  of  the  matter.  Instead,  they  are  concerned  more  especially  with 
the  mechanism  of  nervous  control  and  with  the  character  of  the  chemical 
substances  which  excite  this  nervous  mechanism  to  the  production  of  the 
disturbance  of  heat  regulation  which  we  have  described.  In  brief,  it  appears 
that  destruction  or  interruption  of  the  hypothalamic  region  of  the  mid- 
brain  throws  out  of  function  the  regulatory  mechanism,  so  that  the  warm- 
blooded animal  becomes  poikilothermic  and  makes  no  response  to  the 
usual  causes  of  fever.  This  merely  means  that  the  vasomotor  and  other 
changes  ordinarily  set  in  motion  by  the  " heat-regulating  centre"  are 
absent  because  their  connection  with  the  brain  is  interrupted.  As  to  the 
nature  of  the  regulating  centres  nothing  is  yet  known. 

In  anaphylactic  shock  the  temperature  falls  suddenly,  but  if  the  dose 
of  antigen  is  too  small  to  produce  this  collapse,  it  results  in  fever.  Fried- 
berger,  Leschke,  and  others  show  that  with  minute  doses  of  "anaphylatoxin" 
it  is  possible  to  produce  a  febrile  rise  in  temperature  at  will,  but  it  remains 
to  be  seen  whether  there  is  one  substance  responsible  for  this  or  many. 
One  gains  the  impression  that  it  is  the  product  of  injury  of  cells  and  con- 
sequent decomposition  of  protein  which  stimulates  the  heat-controlling 
centres.  In  this  sense  the  fever  may  still  be  purposeful,  although  it  is  less 
easy  to  discover  any  active  character  than  formerly  seemed  to  be  the  case. 
Antipyretics  and  baths  may  do  good,  not  so  much  by  allaying  the  fever 
as  by  calming  the  excitement  of  the  rest  of  the  brain. 


LITERATURE 

Loewy  and  Richter:  Virch.  Arch.,  1896,  cxlv,  49. 

MacCallum:  Archives  of  Internal  Medicine,  1908-09,  ii,  569. 

Meyer,  H.  H.,  Krehl,  Schittenhelm,  Friedberger,  Grafe,  Leschke:  Verb.  Congr.  f.  In- 

nere  Medizin,  xxx,  1913,  15-80. 

Richter:  Oppenheimer's  Handb.  d.  Biochemie,  1910,  iv2,  104. 
Roily  and  Meltzer:  Dtsch.  Arch.  f.  klin.  Med.,  1908,  xciv,  335. 
Vaughan:  Proc.  Assoc.  Amer.  Phys.,  1911,  xxvi,  191. 

Welch:  Cartwright  Lectures,  Boston  Med.  and  Surg.  Jour.,  1888,  cxviii,  333,  361,  413. 
12 


162  TEXT-BOOK    OF    PATHOLOGY 

IMMUNITY 

Nature  of  Injurious  Agents. — The  body  may  be  regarded  as  a  kind  of  tube 
with  thick  walls,  into  which  there  extend  cavities  open  to  the  exterior. 
These  cavities,  as  well  as  the  lumen  of  the  digestive  tract,  with  all  its  di- 
verticula,  are  outside  the  body,  and  poisonous  fluids  or  bacteria  can  exert 
their  influence  only  when  they  pass  through  the  lining  membranes  into  the 
real  interior.  An  injury  to  the  lining  membrane,  often  produced  by  the 
bacteria  themselves,  exposes  thennterior  of  the  body,  just  as  in  the  case  of 
an  abrasion  of  the  skin,  to  invasion,  but  many  poisons  can  be  absorbed 
without  such  cell  destruction. 

These  surfaces  then  constitute  the  portals  of  entry  of  all  the  injurious 
agencies  from  the  outer  world,  whether  in  the  form  of  inanimate  poisons 
or  live  creatures  which  can  live  and  multiply  in  the  interior  of  the  body,  to 
its  detriment.  Sometimes  entry  is  immediate,  but  it  is  well  known  that 
the  outer  and  lining  surfaces  of  the  body  may  and  do  swarm  with  living 
creatures,  many  of  which  are  permanently  innocent,  while  others  are  only 
waiting  an  opportunity  when  the  guard  is  weakened  to  force  their  way 
through  the  walls  and  attack  the  vital  organs  inside. 

Externally  the  impermeability  of  the  skin  acts  as  a  defence,  while  in  the 
case  of  the  lining  membranes,  fluid  secretions  tend  to  wash  away  noxious 
materials  or  annul  their  effects,  in  which  they  are  often  aided  by  phagocytic 
cells.  So  in  the  conjunctiva  bacteria  are  quickly  washed  down  into  the 
tear-duct;  in  the  upper  respiratory  tract  ciliated  cells  wave  back  every 
kind  of  particle,  and  from  all  the  adenoid  apparatus  leucocytes  are  ready 
to  emerge  on  alarm.  In  the  biliary  ducts,  as  in  the  genito-urinary  organs, 
bacteria  are  kept  in  check  by  the  stream  of  fluids,  often  aided  by  valvular 
arrangements  to  close  the  channels,  which  wash  away  the  bacteria  and  dis- 
infect the  lining  surfaces.  Nevertheless,  all  these  defences  are  often  over- 
come. Through  the  skin  the  attack  may  be  successful  not  only  by  way  of 
ordinary  wounds,  but  by  the  aid  of  biting  insects  and  other  animals,  or 
even  in  the  case  of  some  worm  larvae  by  their  own  penetrating  force. 
Through  the  mucosse  entrance  is  forced  by  the  destructive  action  of  the 
organisms  themselves,  though  this  is  often  aided  by  mechanical  factors 
which  protract  their  contact  with  these  tissues  or  by  the  failure  of  the 
phagocyte  guard  from  the  interior.  Thus  the  upper  intestine  or  the 
bladder,  which  normally  keep  themselves  practically  free  of  bacteria,  quickly 
become  perfect  hotbeds  for  their  growth  if  an  obstruction  prevents  the 
escape  of  the  intestinal  contents  or  the  urine. 

Aside  from  mechanical  or  physical  injury,  then,  the  body  suffers  from 
the  effects  of  destructive  chemical  substances  which  may  be  wholly  de- 
rived from  the  inorganic  or  inanimate  world,  or  may  be  produced  in  some 
way  by  living  beings.  Indeed,  the  greatest  danger  comes  from  the  latter 
when,  as  is  so  often  the  case,  these  living  beings  establish  themselves  in 
the  body  or  on  its  surface  and  manufacture  their  poisons  on  the  spot. 

A  word  should  be  said  here  about  the  rather  obscure  question  of  their 


IMMUNITY  163 

interfering  with  the  well-being  of  their  host  by  the  mere  abstraction  of  the 
materials  necessary  for  its  nutrition  and  metabolism.  Possibly  this  may 
occur  in  the  case  of  some  of  the  larger  parasites :  they  may  drain  away  the 
blood  or,  as  in  the  case  of  malaria,  eat  out  the  blood-cells,  but  probably 
even  in  the  most  obvious  of  such  cases  the  greatest  harm  is  done  by  the 
poisons  which  these  creatures  produce.  On  the  other  hand,  Dibbelt  has 
lately  maintained  that  in  the  fulminant  bacterial  infections  which  kill  in 
a  few  hours  death  is  not  due  to  the  formation  of  poisons,  but  rather  to  the 
wholesale  withdrawal  of  oxygen  from  the  tissues.  Such  a  result  might  be 
comparable  to  that  in  cyanide  poisoning,  in  which  metabolism  is  brought 
to  a  standstill  by  the  stoppage  of  oxidation  processes. 

Of  all  the  living  parasites  which  thus  insinuate  themselves  into  the  body, 
only  a  few,  such  as  the  diphtheria  and  tetanus  bacilli,  produce  a  soluble, 
diffusible  poison  or  toxin  which,  by  itself  circulating  through  the  organs, 
can  cause  the  symptoms  of  the  disease.  Such  bacteria  can,  therefore, 
live  and  grow,  even  in  a  very  small  spot  in  the  tissues,  and  yet  diffuse  enough 
poison  to  kill  the  animal.  Practically  all  the  rest,  whether  animal  or  vege- 
table, fail  to  do  this,  although  they  cause  the  most  intense  and  frequently 
fatal  diseases.  The  fluids  of  animals  dying  of  these  diseases  will  not  cause 
the  disease  in  other  animals  if  the  parasites  are  filtered  out,  and  the  fluids 
in  which  they  have  grown  are  found  not  to  contain  any  appreciable  amount 
of  poison.  Still,  if  their  bodies  are  ground  up,  a  poisonous  material  or  en- 
dotoxin  may  often  be  found  mixed  with  their  body  proteins  in  the  extract 
made  from  the  debris.  How  they  produce  the  disease  is,  therefore,  very 
difficult  to  learn,  and  generally  we  are  content  with  the  idea  that  they  be- 
come harmful  only  when  they  die  and  are  broken  up  in  the  tissues,  liber- 
ating their  endotoxin.  That  their  body  proteins  under  the  influence  of  the 
ferments  of  the  host  may  act  as  poisons,  too,  begins  to  seem  probable,  and 
will  be  referred  to  again. 

It  should  be  observed  that  the  harmful  effects  of  one  invader  are  often 
greatly  intensified  when  it  is  accompanied  by  another,  and,  indeed,  some 
bacteria  and  even  protozoan  parasites  seem  hardly  able  to  cause  an  in- 
fection without  the  help  of  others.  Such  mixed  infections  are  very  com- 
mon, and  may  be  simultaneous,  or  one  may  thrive  in  the  soil  prepared  by 
the  other. 

Types  of  Resistance. — Poisons  very  similar  to  those  produced  by  bac- 
terial and  animal  parasites  are  secreted  by  venomous  animals  and  plants, 
or  may  be  extracted  from  them.  Indeed,  it  is  quite  difficult  to  draw  any 
sharp  line  of  demarcation  in  the  long  series  of  poisons  beginning  with  the 
simple  inorganic  substances,  and  passing  by  way  of  the  complex  synthetic 
compounds  to  the  highly  intricate  combinations,  of  whose  nature  we  are 
generally  ignorant,  which  we  find  in  the  toxins  and  toxalbumins  and  other 
protein  substances  which  play  such  an  important  r61e  in  disease.  In 
general,  however,  it  is  found,  through  the  biological  test,  that  it  is  only 
toward  the  complex,  protein-like  poisons  that  the  body  can  elaborate 


164  TEXT-BOOK   OF   PATHOLOGY 

special  defensive  substances.  Even  though  the  others  may  finally  be 
tolerated,  it  is  through  some  other  mechanism.  Thus  it  is  well  known  that 
through  long  habit  animals  or  human  beings  may  become  able  to  swallow 
doses  of  such  poisons  as  arsenic,  morphine,  etc.,  which  would  be  far  more 
than  enough  to  kill  an  ordinary  being,  but  our  ideas  as  to  how  this  tolerance 
is  produced  are  very  vague.  Certainly  no  substance  is  produced  in  the  body 
which  will  neutralize  the  poison,  and  it  seems  that  it  must  be  due  to  some 
change  in  the  metabolism  of  the  cells  themselves. 

There  is,  even  without  any  such  gradual  case  hardening,  a  natural  in- 
susceptibility on  the  part  of  some  animals  to  injury  from  certain  poisons; 
thus  an  almost  unlimited  quantity  of  the  most  intensely  active  tetanus 
toxin,  a  milligram  of  which  would  kill  thousands  of  mice,  can  be  injected 
into  a  scorpion  or  an  alligator  without  producing  the  slightest  malaise, 
and  a  long  time  later  it  may  be  found  still  lodged  in  the  tissues.  Certain 
animals  are  equally  resistant  to  invasion  by  bacteria  which  can  produce 
the  most  deadly  disease  in  others,  apparently  because  their  defensive 
phagocytes  are  so  active  that  long  before  the  bacteria  can  gain  a  proper 
foothold  they  are  all  seized  upon  and  devoured.  Whether  this  is  an  in- 
herited character,  resulting  from  the  survival  of  those  thus  fitted  to  resist 
infection,  it  is  difficult  to  say.  The  immunity  is  not  absolute,  however, 
for  influences,  like  exposure  to  cold  or  heat,  great  fatigue,  or  other  illnesses, 
may  so  break  down  the  resistance  that,  after  all,  the  animal  succumbs  to 
infection.  Race  immunity  is  doubtless  an  example  of  this  kind,  and  race 
susceptibility  illustrates  its  opposite — the  South  Sea  islanders  succumbed 
in  thousands  to  measles  because  their  ancestors  had  never  had  to  contend 
with  it.  On  the  other  hand,  children  in  our  countries  sicken  with  such  so- 
called  children's  diseases  because  they  alone  have  not  acquired  immunity 
by  having  had  the  disease  themselves. 

In  all  the  ills  produced  by  living  invaders  there  exists  a  struggle  for 
supremacy — even  for  existence — between  the  host  and  the  parasite,  in 
which  the  stronger  prevails  and  in  which  defences  are  developed  not  only 
by  the  host,  but  by  the  invader  as  well.  It  is  doubtless  through  this  that 
the  bacteria  accustom  themselves  in  passing  from  the  body  of  one  animal 
to  another  to  the  action  of  the  defensive  reactions  of  the  host,  and  become 
thereby  more  virulent.  This  is  made  evident  in  some  cases  by  the  appear- 
ance, under  these  circumstances,  of  capsules  which  are  formed  in  the  bacillus 
of  anthrax,  the  pneumococcus,  etc.,  as  they  grow  in  the  animal  body  but 
not  in  cultures.  The  capsulated  forms  become  less  susceptible  to  phago- 
cytosis and  it  is  even  stated  that  infection  can  occur  only  when  capsules  are 
formed.  In  addition  to  this  protective  covering  such  bacteria  are  thought 
to  become  more  formidable  through  the  production  of  more  active  poi- 
sons which  injure  the  phagocytes  ("leucocidins,"  "aggressins").  Danysz 
found  that  bacteria  in  culture  may  be  accustomed  gradually  to  the  presence 
of  arsenic,  so  that  they  finally  grow  in  relatively  strong  solutions  and  in  the 
course  of  this  adaptation  acquire  a  capsule.  Indeed,  it  is  clearly  shown  that 


IMMUNITY  165 

certain  protozoa,  the  trypanosomes,  may,  like  the  Styrian  arsenic-eaters, 
become  so  used  to  arsenic  that  they  live  on  unhurt  in  the  body  through  a 
continued  bombardment  with  the  new  synthetic  arsenic  compounds,  if 
only  they  have  managed  to  survive  the  first  doses. 

We  know  so  little  about  the  defences  of  the  parasite,  however,  that  at 
present  we  must  exemplify  the  principles  by  reference  to  those  of  the  host. 
We  realize  that,  normally,  animals  have  well-developed  powers  of  defence, 
although  these  are  efficient  in  such  different  degrees  in  different  animals 
that  we  must  surmise  that  they  are  not  conferred  in  their  full  perfection 
on  all  at  their  creation,  but  have  been  gradually  acquired  through  the 
survival  of  those  best  provided,  who  in  turn  bequeathed  them  to  their 
offspring.  These  defences  may  guard  against  simple  poisoning  or  against 
the  inroads  of  living  parasites,  and  we  shall  see  that  they  do  not  lack  in 
variety  to  correspond  with  these  different  forms  of  injury.  Already  we  have 
found  that  certain  general  mechanisms,  inflammation,  and  fever  have  been 
developed  alike  in  all  animals,  but  we  have  been  forced  in  both  instances 
to  recognize  the  fact  that  these  reactions  are  mere  auxiliary  mechanisms 
designed  to  bring  into  play  to  the  greatest  advantage,  and  in  the  most 
opportune  concentration  during  sudden  emergencies,  other  more  profound 
and  more  subtle  processes,  phagocytosis,  and  the  chemical  neutralization 
of  poisons  which  we  admit  as  the  essential  agents  of  defence. 

For  a  time  there  were  those  who  maintained  that  the  activity  of  the 
phagocytes  constituted  practically  the  whole  defensive  armament,  while 
others,  enthusiastic  over  their  new  discoveries,  were  just  as  sure  that  the 
neutralizing  substances  in  the  body  fluids  were  all-important.  But  now 
a  reconciliation  of  these  cellular  and  humoral  doctrines  has  been  effected, 
because  it  has  been  shown  that  they  are  very  largely  interdependent, 
phagocytosis  depending  upon  the  presence  of  auxiliary  substances  in  the 
plasma,  while  in  turn  the  leucocytes  are  important  in  producing  other 
defensive  fluid  substances. 

Artificial  Immunity. — From  time  immemorial  it  has  been  known  that  a 
person  who  has  had  smallpox,  or  typhoid  fever,  or  yellow  fever,  or  any 
one  of  a  host  of  diseases  can  hardly  have  another  attack  of  the  same  dis- 
ease: he  is  immune.  On  the  other  hand,  there  are  certain  diseases,  such 
as  pneumonia,  diphtheria,  erysipelas,  furunculosis,  etc.,  which  seem  to 
predispose  to  a  repetition.  While  we  are  yet  far  from  clear  as  to  the 
reasons  for  this  latter  fact,  we  have  learned  a  great  deal  about  the  security 
conferred  by  the  immunizing  sort  of  diseases.  It  is  not  necessary  that  the 
illness  should  be  severe  to  give  this  lasting  protection,  and,  recognizing 
this,  it  was  the  habit,  many  years  ago,  to  court  mild  attacks  of  such  a 
deadly  disease  as  smallpox  in  order  to  be  safe  in  the  midst  of  an  epidemic 
where  the  disease  was  severe.  This  was  the  beginning  of  man's  inten- 
tional use  of  artificial  methods  of  providing  immunity,  a  plan  which,  under 
the  influence  of  the  phenomenally  intelligent  studies  of  such  men  as  Pas- 
teur, Ehrlich,  and  von  Behring,  has  extended  until  it  promises  now  to  be- 


166  TEXT-BOOK    OF    PATHOLOGY 

come  the  very  most  important  practical  achievement  of  medicine.  It  has 
proved  possible  to  devise  methods  by  which  security  from  parasitic  dis- 
ease can  be  attained  without  risking  any  serious  preparatory  illness,  and 
to  intensify  the  strength  of  this  defence  until  it  is  almost  absolutely  un- 
assailable. Further,  instead  of  thus  producing  an  active  immunity  by 
making  the  person  go  through  an  imitation  of  the  disease  himself,  it  is 
sometimes  possible  to  cause  an  animal  to  go  through  the  disease  and  then 
transfer  the  fluids  of  its  blood  to  the  body  of  the  person,  and  with  it  the 
immunity,  so  that  a  passive  immunity  is  conferred  which  may  even  stop 
the  disease  already  in  progress. 

Several  methods  are  thus  in  common  use:  (1)  The  parasites  in  full 
virulence,  but  in  very  minute  doses,  are  administered  so  that  the  person 
finally  overcomes  and  recovers  from  a  mild  attack  of  the  real  disease; 
(2)  the  same  thing  is  accomplished  by  a  larger  dose  of  weakened,  attenu- 
ated, or  non-virulent  parasites;  (3)  dead  bacteria  are  used  in  place  of  the 
living,  and  produce  a  feebler  but  similar  immunity;  (4)  the  isolated 
poisons  of  the  parasites  are  injected  in  gradually  increasing  doses  so  that 
the  power  is  developed  to  neutralize  the  poisons  or  (5)  from  such  an  animal 
this  neutralizing  power  is  transferred  to  another  which  thus,  without  effort, 
becomes  immune. 

Space  will  not  allow  more  than  the  merest  outline  of  these  processes. 
Details  may  be  read  with  the  help  of  the  general  references  given  to  the 
literature,  which  is  colossal. 

Phagocytosis. — As  has  been  stated  above,  bacteria  and  other  parasites 
are  in  normal  animals  taken  up  and  digested  by  the  phagocytes,  but  the 
help  of  the  serum  of  the  animal  is  most  important — without  it  the  leuco- 
cytes engulf  very  few  bacteria.  Denys,  Wright,  and  others  have  shown  that 
the  serum  contains  opsonins,  which  act  on  the  bacteria  and  prepare  them 
to  be  attacked  by  the  leucocytes.  Neufeld  found  that  in  the  serum  of 
animals  immunized  by  repeated  introduction  of  those  bacteria,  somewhat 
more  resistant  bodies  (bacteriotropins)  appear,  which  exercise  the  same 
function  in  making  the  bacteria  more  approachable  for  the  leucocytes. 
It  appears  that  cytotropins,  or  substances  which  prepare  foreign  cells  for 
phagocytosis,  may  be  produced  in  the  same  way  by  injecting  such  cells. 
Aided  by  these  substances,  which  bind  themselves  to  the  bacteria  or  for- 
eign cells,  but  do  not  affect  the  phagocyte  itself,  the  wandering  cells  exhibit 
a  great  phagocytic  activity.  Although  the  swallowing-up  of  a  bacterium 
does  not  necessarily  kill  it,  it  commonly  does  so,  and  at  any  rate  removes  it 
for  the  time  from  the  field  of  action. 

Cytolytic  and  Bacteriolytic  Reactions. — The  introduction  of  foreign  cells 
has  other  results  than  those  just  described.  The  serum  of  an  animal  which 
has  received  repeated  doses  of  a  certain  foreign  cell  acquires  the  property 
of  disintegrating  and  dissolving  those  cells.  This  reaction  is  highly 
specific,  so  that  if  red  corpuscles  of  a  dog  be  introduced  into  a  rabbit  there 
appears  a  hcemolytic  serum  which  will  destroy  only  red  corpuscles  and  only 


IMMUNITY  167 

those  of  the  dog.  Similarly,  with  inoculations  of  liver-cells,  kidney  cells, 
endothelial  cells,  etc.,  more  or  less  specific  hepatolytic,  nephrolytic,  or 
endotheliolytic  sera  have  been  produced.  Other  cells,  such  as  those  of 
animal  parasites  or  bacteria,  are  responded  to  in  the  same  way,  and  an 
intense  trypanolytic  or  trypanocidal  serum  can  be  produced  by  injecting 
the  bodies  of  trypanosomes,  just  as  bacteriolytic  (consequently  bactericidal) 
sera  result  from  the  introduction  of  the  dead  bodies  of  bacteria.  The 
fresh  serum  alone,  quite  free  from  phagocytic  cells,  has  then  the  power  to 
break  up  and  destroy  living  bacteria  brought  into  contact  with  it,  whether 
in  the  body  or  in  a  test-tube.  In  any  case  it  must  be  sharply  distinguished 
from  the  antitoxic  immunity  which  is  referred  to  later. 

Agglutination. — Another  sort  of  reaction  is  often  produced  at  the  same 
time,  the  effect  of  which  is  to  cause  the  special  bacteria  or  cells  which 
caused  its  production  to  stick  together  in  clumps  if  they  are  brought  into 
contact  with  the  serum  in  a  test-tube — and  to  some  extent  within  the 
animal  body.  This  is  the  so-called  agglutination,  which  is  so  specific  in  its 
relations  that  it  can  be  used  for  diagnostic  purposes.  Thus  the  serum 
of  a  person  suffering  from  typhoid  fever  or  one  who  has  had  the  disease, 
and  of  such  persons  alone,  will  cause  the  clumping  and  immobility  of 
known  typhoid  bacilli  suspended  in  a  culture. 

Precipitins. — It  is  not  even  necessary  to  inject  cells  for  the  production 
of  these  antibodies,  for  the  repeated  injection  of  any  foreign  protein  is 
responded  to  in  the  same  way  by  the  formation  of  a  new  substance  which 
will  specifically  and  exclusively  act  upon  that  protein  at  the  first  oppor- 
tunity. It  may,  when  a  new  quantity  of  the  protein  and  the  serum  are 
brought  together,  form  a  cloudy  precipitate,  or,  and  sometimes  coinci- 
dentally  with  this  effect,  it  may  break  down  the  protein  into  simpler  but 
still  complex  substances,  some  of  which  are  poisonous. 

The  first  of  these  phenomena  is  practically  useful  as  a  biological  test 
in  the  recognition  of  proteins.  Thus  it  may  be  necessary,  for  legal  pur- 
poses, to  say  whether  a  blood-stain  is  composed  of  human  or  ox  blood. 
The  clear  serum  of  a  rabbit  which  has  been  treated  with  human  blood- 
serum  will  become  clouded  if  a  trace  of  the  dissolved  blood-stain  be  added 
to  it  in  case  it  really  is  human  blood,  but  no  precipitate  will  appear  if  the 
blood  came  from  an  ox.  Conversely,  the  serum  of  a  rabbit  treated  with 
ox  blood  would  serve  to  recognize  that  blood.  Another  most  ingenious 
method  of  recognizing  human  or  other  blood  is  that  known  as  the  fixation 
of  complement  (see  paragraph  on  the  Side-chain  Theory).  This  method, 
developed -by  Neisser  and  Sachs,  depends  upon  the  fact  that  complement 
is  used  up  when  mixed  with  a  combination  of  human  protein  and  the  in- 
activated serum  of  a  rabbit  immunized  against  human  protein,  so  that  the 
subsequent  addition  of  inactivated  hsemolytic  serum  of  a  rabbit  immunized 
against  the  red  corpuscles  of  the  sheep  finds  no  complement  left  and  no 
haemolysis  occurs  in  added  sheep  cells.  A  principle  similar  to  this  is  the  basis 
of  the  well-known  Wassermann  reaction  for  the  recognition  of  syphilis. 


168  TEXT-BOOK   OF    PATHOLOGY 

The  second  phenomenon  which  is  probably  intimately  related  with 
the  precipitin  reaction  has  recently  come  into  prominence,  because  of  the 
observation  that  the  sudden  introduction  of  a  second  dose  of  a  certain 
protein  into  an  animal  already  immunized  to  that  protein  may  kill  it.  This 
effect,  which  is  accompanied  by  certain  characteristic  symptoms, — vaso- 
motor  paralysis,  fall  in  temperature,  inefficient  heart  action,  dyspnoea,  urti- 
caria, etc., — is  known  as  an  anaphylactic  shock,  and  the  condition  of  the 
animal  as  anaphylaxis.  Much  ingenious  experimentation  has  been  carried 
out  in  the  attempt  to  analyze  and  explain  this  phenomenon.  In  general  it 
was  thought  to  be  the  effect  of  poisoning  by  peptone-like  bodies  or  proteoses 
produced  by  the  partial  digestion  of  the  protein  of  the  second  dose  by  the 
combined  action  of  the  specific  antibody  developed  in  response  to  the  first 
dose  and  the  normal  alexin  or  complement  of  the  blood  plasma.  It 
seemed  that  all  of  this  might  occur  in  the  circulating  blood,  since  it  was 
sometimes  found  possible  to  mix  the  antibodies  and  protein  or  antigen  in 
vitro  and  to  produce  the  characteristic  symptoms  by  the  injection  of  the 
mixture,  and  since  passive  sensitization  of  a  normal  animal  might  be  pro- 
duced by  injection  of  the  blood  of  a  sensitized  animal,  after  which  injec- 
tion of  the  protein  would  give  anaphylactic  shock.  But  partly  because  it 
was  found  to  require  time  after  the  transfer  of  the  sensitized  blood  before 
the  injection  of  the  antigen  or  protein  could  produce  a  distinct  shock,  partly 
because  sensitized  animals  completely  perfused  with  normal  blood  were 
still  sensitized,  and  partly  because  strips  of  smooth  muscle  from  sensitized 
animals  were  observed  to  contract  on  exposure  to  solutions  of  the  antigen 
so  dilute  as  to  leave  unaffected  strips  of  muscle  from  a  normal  animal,  it 
has  been  decided  that  anaphylactic  sensitization  is  largely  an  affair  of  the 
tissue  cells  (Weil).  It  seems  that  the  antibody  upon  which  the  reaction 
depends  is  not  altogether  free  and  floating  in  the  circulating  blood,  but  that 
much  of  it  remains  sessile,  attached  to  the  cells.  It  is  for  this  reason  that 
the  effect  is  so  intense,  since  the  poison  is  produced  in  or  on  the  cells.  It  is 
even  suggested  that  possibly  the  presence  of  abundant  antibody  in  the 
blood  might  protect  the  cells  by  combining  with  the  antigen  before  it 
reaches  them.  Such  explanations  assume  that  the  poison  is  produced 
from  the  antigen  or  injected  protein.  As  a  matter  of  fact,  more  nitrogen 
is  excreted  as  a  sequence  of  the  anaphylactic  shock  than  could  be  accounted 
for  by  that  much  protein,  and  this  with  other  things  has  given  rise  to  another 
explanation.  Substances  such  as  kaolin,  agar,  bacterial  bodies,  etc.,  mixed 
with  normal  serum  produce  poisons  like  those  which  cause  symptoms 
of  anaphylactic  shock.  In  the  animal  body  the  increase  in  nitrogen  excre- 
tion shows  that  a  proteolytic  ferment  must  attack  the  proteins  of  the 
serum.  While  Friedberger  thought  that  the  poison  produced  from  bac- 
teria injected  into  sensitized  animals  was  due  to  cleavage  of  the  bacterial 
proteins,  Jobling  points  out  that  bacteria  as  well  as  kaolin  or  other  inert 
substances  can  absorb  anti-enzymes  (unsaturated  lipoids,  etc.)  of  the  serum 


IMMUNITY  169 

and  thus  release  proteolytic  ferments  which  effect  cleavage  of  the  proteins 
of  the  serum  into  poisonous  proteoses.  Whatever  the  nature  of  the 
mechanism  by  which  they  are  produced,  it  seems  clear  that  the  poisons  are 
the  cleavage  products  of  protein.  Even  if  it  be  true  that  after  the  injec- 
tion of  cells,  bacteria,  or  such  materials  as  kaolin,  the  poisons  may  be 
evolved  by  the  action  of  proteolytic  ferments  on  the  proteins  of  the  serum, 
the  evidence  in  other  cases  of  sensitization  in  animals,  as  by  foreign  serum, 
seems  to  support  the  idea  of  the  participation  of  a  specific  antibody  and 
the  complement  both  in  the  tissue  cells  and  in  the  blood. 

Dale  has  suggested  that  histamine-like  substances  may  be  the  poisons 
concerned,  and  the  work  of  Dr.  Abel  appears  to  show  that  the  poison  is 
actually  histamine  or  a  combination  of  histamme.  This  substance,  which 
can  be  obtained  from  any  tissue  by  acid  cleavage  and  extraction,  has 
precisely  the  same  physiological  effects  as  are  seen  in  the  anaphylactic 
shock. 

The  reaction  depending  upon  this  production  of  poison,  when  a  special 
protein  to  which  the  animal  has  been  spontaneously  (through  disease) 
or  artificially  immunized,  is  directly  or  parenterally  introduced,  is  made  use 
of  for  diagnostic  purposes,  as,  for  example,  in  the  tuberculin  and  luetin 
tests,  in  which  the  proteins  of  the  tubercle  bacillus  or  of  the  Spirochseta 
pallida  are  injected  into  the  skin.  Such  a  small  dose,  instead  of  overwhelm- 
ing the  nervous  system  and  producing  a  fall  in  temperature,  affects  it  only 
to  the  extent  of  stirring  up  a  febrile  reaction. 

Antitoxins. — In  those  cases  in  which  bacteria  produce  a  soluble  toxin, 
as  well  as  in  the  case  of  soluble  toxins  of  animal  or  vegetable  origin,  the 
body  will  respond  to  the  repeated  injections  of  the  toxin  by  the  production 
of  a  soluble  antitoxin  which  circulates  freely  in  the  blood  and  combines 
with  and  neutralizes  quantitatively  a  fresh  injection  of  the  same  toxin. 
This  will  happen  quite  as  well  in  a  test-tube  or  in  the  body  of  another 
animal  if  the  serum  of  the  immunized  animal  be  removed  and  mixed  with 
the  toxin  in  the  test-tube  or  injected  into  the  body  of  the  other  animal. 
In  the  latter  case  the  neutralization  of  toxin  already  introduced  will  take 
place  in  so  far  as  it  is  still  uncombined.  The  first  animal  has  acquired  an 
active  antitoxic  immunity,  while  a  passive  antitoxic  immunity  is  con- 
ferred on  the  second  one  by  the  injection.  This  is  the  basis  of  the  use  of 
the  well-known  diphtheria  antitoxin  of  von  Behring.  The  commercial 
preparation  is  nothing  more  than  the  serum  of  a  horse,  which,  by  repeated 
increasing  doses  of  diphtheria  toxin,  has  been  brought  into  a  state  of  active 
antitoxic  immunity.  It  is  quite  specific,  and  the  diphtheria  antitoxin  is 
therefore  useless  against  tetanus,  or  vice  versa. 

When  a  child  has  recovered  from  diphtheria,  antitoxin  is  found  circulat- 
ing in  the  blood.  Many  children  are  found  to  be  thus  protected  by  the 
possession  of  a  circulating  antitoxin  which  may  have  been  acquired  with- 
out any  severe  illness.  In  its  presence  the  intracutaneous  injection  of  a 


170  TEXT-BOOK    OF    PATHOLOGY 

minute  amount  of  diphtheria  toxin  produces  no  result,  while  in  its  absence 
such  a  test  leads  to  the  formation  of  a  minute  area  of  necrosis  with  a  rather 
wide  zone  of  reddening  and  swelling  of  the  skin  (Schick  reaction). 

The  participation  of  these  various  phenomena  in  natural  and  acquired 
immunity  is  not  always  perfectly  clear.  The  simplest  is  perhaps  the  anti- 
toxic immunity  in  which  the  poison  is  neutralized,  as  an  acid  might  be 
neutralized  by  an  alkali,  while  the  bacteria  causing  the  disease  are  left 
unharmed.  The  immunity  conferred  by  one  attack  of  the  disease  is  prob- 
ably a  combination  of  bacteriotropic  and  phagocytic  activity  with  bac- 
teriolytic  immunity.  So,  too,  the  immunity  produced  by  vaccines  of  dead 
and  attenuated  bacteria.  Bacteriolytic  sera  have  not  been  very  success- 
fully produced  except  in  the  case  of  a  few  bacteria,  such  as  cholera,  typhoid, 
etc.,  but  even  when  they  are  active  they  seem  unable  to  cut  short  the 
progress  of  the  infection  in  the  animal,  possibly  because  they  lack  the 
presence  of  sufficiently  active  bacteriotropins.  An  animal  may  be  able 
to  destroy  a  quantity  of  bacteria  injected  into  the  peritoneum,  but  still  be 
unable  to  withstand  infection  by  way  of  the  intestinal  tract.  Local  appli- 
cation of  these  sera  is,  therefore,  often  desirable  and  effective  in  conditions 
such  as  meningitis,  where  the  infection  itself  is  essentially  a  localized  one. 
In  all  cases  the  intense  specificity  of  the  reaction  makes  itself  felt,  so  that 
a  bactericidal  serum  or  bacteriotropic  substances  which  might  aid  in  the 
destruction  of  one  strain  of  streptococci  may  fail  of  all  activity  in  the  case 
of  another  hardly  distinguishable  except  by  such  a  biological  test. 

The  Side-chain  Theory. — To  explain  all  these  phenomena,  and  to  further 
the  discovery  of  others,  Ehrlich  has  constructed  a  hypothesis  known  as  the 
side-chain  theory,  which,  although  even  yet  not  proved  in  all  its  details, 
is  marvelously  perfect  in  its  agreement  with  new  facts  as  they  are  brought 
out  and  in  its  serviceability  in  showing  the  direction  in  which  new  facts 
may  be  sought.  He  conceives  of  the  cells  of  the  body  as  provided  with 
certain  molecular  arrangements  or  receptors,  by  means  of  which  they 
normally  anchor  and  bind  to  themselves  substances  which  they  require 
for  their  metabolism.  Such  substances  are  ordinarily  useful,  but  they  may 
be  injurious.  In  that  case  the  cell  may  be  destroyed.  If  not,  those  re- 
ceptors are  at  least  thrown  out  of  function  and  the  cell  is  to  that  extent 
injured  by  having  anchored  to  itself  the  toxin.  With  its  natural  powers  of 
repair  it  produces  new  receptor  groups,  and  since,  as  Weigert  has  expressed 
it,  the  process  of  regeneration  leads  to  the  production  of  an  excess,  the 
loss  is  more  than  made  up.  These  new  receptors  have  the  same  facility  in 
uniting  with  toxin  groups,  and  being  in  excess,  they  are  discharged  by  the 
cell  into  the  circulating  fluids.  There  they  by  themselves  anchor  toxin 
molecules  and  thus  prevent  them  from  reaching  the  susceptible  cells. 
Without  such  receptors  the  cell  is,  of  course,  insusceptible  of  being  affected 
by  the  toxin,  and  hence  perhaps  the  natural  immunity  of  some  animals. 

In  the  case  of  the  opsonins,  bacteriolytic  substances,  and  all  the  cyto- 


IMMUNITY  171 

lytic  and  antiprotein  reactions,  the  specific  antibody  is  produced  in  a 
similar  way  by  the  susceptible  cells  as  a  result  of  the  influence  of  the  foreign 
protein  or  cells  (antigens),  but  in  these  instances  it  is  found  that  the  specific 
group,  or  antibody,  thus  produced  cannot  act  alone  to  destroy  the  foreign 
cell  or  protein,  but  must  call  to  its  aid  a  ferment-like  substance  normally 
present  in  the  serum — the  so-called  alexin  or  complement.  There  are  many 
of  these  complements,  and  they  do  not  all  unite  equally  easily  with  the 
specific  immune  bodies.  They  are  easily  destroyed  by  relatively  low 
temperatures  or  by  any  other  injury,  such  as  drying,  the  action  of  chemi- 
cals, etc.  'The  fact  that  the  specific  immune  body  requires  the  aid  of  the 
complement  has  shown  that  it  itself  is  merely  a  link  specifically  able  to 
connect  or  introduce  the  non-specific  complement  into  combination  with 
the  special  cell  or  protein  against  which  it  has  been  developed.  It  is  for 
this  reason  that  Ehrlich  has  named  it  the  amboceptor  or  linking  body, 
although  Bordet  and  others  thought  of  it  as  a  mere  mordant-like  material, 
which  sensitized  the  cell  to  the  attack  of  the  alexin.  Amboceptors  or 
immune  bodies  are  resistant  to  heat,  drying,  etc.,  and  may  be  kept  in  good 
condition  for  years.  Their  characters  have  been  particularly  well  shown 
in  the  experiments  of  Ehrlich  and  his  school  on  haemolysis,  and  those  of 
Pfeiffer  on  bacteriolysis.  Left  in  contact  with  heated  immune  serum,  in 
which  all  complement  has  been  destroyed,  the  foreign  cells  bind  to  them- 
selves the  amboceptor,  but  no  destruction  of  the  cells  occurs.  The  ad- 
dition of  fresh  unheated  normal  serum  which  contains  the  non-specific 
complement  allows  hamolysis  or  bacteriolysis  to  take  place  at  once. 
Bacteriotropins,  agglutinins,  and  precipitins  appear  to  be  simpler  sub- 
stances not  composed  of  a  specific  resistant  and  a  non-specific  labile  por- 
tion. .Their  action  is  not  altogether  clear,  although  there  are  many  in- 
genious theories  for  which  the  student  is  referred  to  the  literature. 

LITERATURE 
Only  general  reviews  which  give  further  literature  references  are  cited. 

Aschoff :  Ehrlich's  Seitenketten-Theorie,  Jena,  1902.     (Zeits.  f.  allg.  Physiol.,  1902,  i.) 

Besredka:  Kraus  and  Levaditi,  Handbuch  d.  Immunitatsf  orschung :  Anaphylaxie. 

Biedl  and  Kraus:    Ibid.,  255. 

Dold:  Bakterien  Anaphylatoxin,  Jena,  1912. 

Ehrlich:    Gesammelte  Arbeiten,  Berlin,  1904. 

Friedberger  and  many  others:     Kolle  u.  Wassermann,  Handbuch  der  Bakteriologie. 

Metchnikoff,  E.:  Immunite  dans  les  maladies  Infectieuses,  Paris,   1901.     Lubarsch- 

Ostertag  Ergeb.,  1896,  ii,  298. 

Sobernheim:  Krehl  u.  Marchand,  Handb.  d.  allg.  Pathol.,  1908,  i,  417. 
Vaughan:  Proc.  Assoc.  Amer.  Phys.,  1907,  xxii,  268.     (Split  Products  of  Proteins.) 
Wassermann,  A.:  Volkmann's  klin.  Vortr.,  1902,  No.  331  (Chir.  No.  94). 

Consult  especially, 
Zinsser:   Infection  and  Immunity,  New  York,  1914;  Arch.  Int.  Med.,  1915,  xvi,  223. 

(Anaphylaxis.) 


172  TEXT-BOOK    OF    PATHOLOGY 

THE  MAINTENANCE  OF  THE  ACID-BASE  EQUILIBRIUM  OF  THE  BODY 
Mechanism  of  the  Preservation  of  Neutrality. — It  is  known  that  the  cir- 
culating fluids  and,  therefore,  the  tissues  depart  very  little  under  normal 
conditions  from  a  neutral  reaction.  The  fact  that  external  secretions, 
such  as  those  of  the  gastric  mucosa  and  kidney,  have  an  acid  reaction 
does  not  interfere  with  this,  but  is  in  some  degree  connected  with  up- 
holding it.  It  is  of  extreme  importance  that  this  constancy  of  reaction 
should  be  maintained,  inasmuch  as  many  of  the  functions  of  the  body, 
and  those  of  the  most  vital  importance,  depend  on  it.  Thus  the  respira- 
tory interchange  is  quickly  affected  by  the  excessive  production  of  acids, 
and  the  violent  gasping  for  breath  or  air-hunger  seen  in  such  cases  is  a 
symptom  of  the  disturbance  of  the  normal  balance. 

The  mechanism  of  the  preservation  of  this  approximate  neutrality  is  by 
no  means  easy  to  understand,  but  it  has  been  analyzed  by  Lawrence  Hen- 
derson, and  I  quote  chiefly  from  his  writings  and  those  of  Van  Slyke  and 
Bayliss  in  the  following: 

The  hydrogen  ion  concentration  of  the  arterial  blood  is  kept  at  a  very 
constant  level,  10  ~7'45  (PH  =  7.45),  and  does  not  change  except  in  the 
terminal  stages  of  some  disease  in  which  great  overproduction  of  acid 
is  taking  place.  It  is  the  expression  of  the  successful  functioning  of  the  reg- 
ulating mechanism,  the  factors  of  which  do  not  change,  although  they  con- 
tinue to  maintain  this  nearly  neutral  reaction. 

The  regulation  is  carried  on  by  two  groups  of  substances:  carbonic 
acid  with  various  bases,  of  which  the  predominant  one  is  sodium,  and 
phosphoric  acid,  in  its  combinations  with  sodium  or  other  bases.  For 
practical  purposes  we  need  only  consider  carbonic  acid  and  bicarbonates, 
on  the  one  hand,  and  monosodium  and  disodium  phosphate  on  the 
other. 

"Free  carbonic  acid  is  present  in  the  body  fluids  in  such  concentration 
that  it  automatically  converts  into  bicarbonate  all  bases  not  bound  by 
other  acids.  The  bicarbonate,  therefore,  represents  the  excess  of  base 
which  is  left  after  all  the  non- volatile  acids  have  been  neutralized  and  is 
available  for  the  immediate  neutralization  of  further  acids.  In  this  sense 
it  constitutes  the  alkali  reserve  of  the  body. 

Acidosis. — Acidosis  is  a  condition  in  which  through  rapid  production  or 
inadequate  elimination  of  acids  the  alkaline  reserve  of  the  body  is  reduced 
below  the  normal  level.  As  stated  above,  it  is  only  in  the  most  extreme 
examples,  in  which  the  overwhelming  production  of  acid  has  almost 
exhausted  the  alkali  reserve,  that  the  hydrogen  ion  concentration  of  the 
blood  is  changed. 

Until  then  the  organism  can  by  accelerated  respiration  maintain  the 

TT    f~^/"i 

ratio  -T  Tjnr.    in  the  arterial  blood  at  its  normal  value,  and  the  PH  being 
INarl^Us 

directly  proportional  to  this  ratio  is  thereby  also  kept  normal.  Whenever, 
either  by  increased  rate  of  CO2  production,  or  by  decomposition  of  NaHCOs 


MAINTENANCE    OF   THE    ACID-BASE    EQUILIBRIUM    OF    THE    BODY      173 

TT  r^r\ 

by  other  acids  the  ratio  .     TT^^   increases,  the  PH  of  the  blood  is  propor- 


tionately  increased  and  stimulates  respiration.     More  rapid  ventilation 

TT  r^r\ 

follows  until  the  H2CO3  of  the  blood  is  so  reduced  that  the  normal  ^T  *      * 

NaHCO3 

ratio  and  consequently  the  normal  PH  is  restored.  This  respiratory 
response  fails  when  the  acids  which  combine  with  sodium  are  in  great  ex- 
cess and  the  bicarbonates  are  almost  depleted,  and  there  arises  from  com- 
pensated acidosis  an  uncompensated  form. 

It  is  clear  from  this  that  the  natural  method  of  maintaining  this  ratio 
is  through  the  continuous  discharge  of  CO2  through  the  lungs.  The  amount 
of  CC>2  in  the  alveolar  air  is  directly  proportional  to  the  concentration  of 
free  carbonic  acid  in  the  blood,  and  this,  under  normal  respiratory  condi- 
tions, with  the  bicarbonate  concentration. 

While  this  respiratory  control  acting  upon  the  carbonic  acid  and  bicar- 
bonates is  perhaps  the  most  important,  it  is  not  the  only  influence  tending 
to  maintain  neutrality  of  reaction  in  the  body  in  the  face  of  abundant  pro» 
duction  of  acid.  It  is  known  that  blood  is  able  to  withstand  the  addition 
of  considerable  amounts  of  free  acid  or  alkali  without  much  change  in  its 
reaction.  This  is  chiefly  due  to  the  carbonates  and  phosphates  present. 
Henderson  has  shown  that  almost  any  mixture  of  monosodium  phosphate 
and  disodium  phosphate  is  neutral  to  indicators,  and  will  take  up  strong 
acids  or  alkalis  without  apparent  change  in  its  reaction. 

This  depends  upon  the  fact  that  strong  acids  and  bases  combine  quanti- 
tatively with  the  alkaline  or  acid  phosphate. 

HC1  +  Na2HPO4  =  NaCl  +  NaH2PO4 
NaOH  +  NaH2PO4  =  Na2HPO4  +  H2O 

Similar  properties  are  found  in  a  mixture  of  carbonic  acid  and  bicarbonates 
which  have  much  of  this  ability  to  absorb  alkalis  or  acids  without  apparent 
change  of  reaction.    The  systems  even  interact  as  follows: 
Na2HPO4  +  H2CO3  =  NaH2PO4  +  NaHCO3 

The  addition  of  acids  or  alkalis  to  such  mixtures  changes  the  proportions 
of  the  two  phosphate  salts  or  of  the  carbonic  acid  and  bicarbonates. 

The  readjustment  of  the  hydrogen  ion  concentration  in  such  mixtures 
is  an  expression  of  the  law  of  mass  action  affecting  solutions  in  which  electro- 
lytic dissociation  may  be  represented  as  taking  place  in  stages  as  follows 

(Bayliss): 

(1)  Na2HP04  ^=  -  Na-  +  NaHPO/ 

(2)  NaH2PO4  ^=^  Na'   +  H2PO4' 

(3)  NaHP04'  ^=^  Na*   +  HPO4" 

(4)  H2P04'  ^=^   H-    +  HP04" 

(5)  H20  <=^  H-  +  OH' 

(6)  HPO"  +  H20  ^=^  H2P04'  +  OH' 


174  TEXT-BOOK    OF    PATHOLOGY 

In  a  solution  of  NaH2PO4,  which  has  an  acid  reaction,  the  only  source 
of  H"  ions  is  the  stage  of  dissociation  numbered  (4)  in  the  list  above;  (2) 
must  precede  this,  so  that,  combining  the  two,  we  have: 

NaH2PO4   =    Na'   +  H*    +  HPO4" 

In  a  solution  of  Na2HPO4  we  have  also  HPO4"  ions  from  (1)  and  (3): 
Na2HPO4  =  Na-  +  Na'  +  HPO4" 

If  we  add  Na2HPO4  to  a  solution  of  NaH2PO4,  we  add  an  excess  of 
HPO4"  ions.  Therefore,  since  these  solutions,  as  weak  acids  and  bases, 
obey  the  law  of  mass  action,  we  reverse  the  dissociations  of  equation  (4), 

H2PO4'  ^=^  H-   +  HPO4", 

and  the  H*  ion  concentration  of  the  acid  phosphate  is  reduced. 

Similarly,  the  alkalinity  of  a  solution  of  Na2HPO4  is  due  to  the  OH' 
ions  derived  from  hydrolysis  of  HPO4"  ions,  according  to  equation  (6). 
Perhaps  it  would  be  more  correctly  expressed  by  saying  that  the  HPCV' 
ion  combines  with  H*  ions  of  water  to  form  H2PO4"  ions,  in  a  way  analogous 
to  that  in  which  acetic  anions  combine  with  hydrogen  ions  to  form  non- 
dissociated  acetic  acid.  In  any  case  the  result  is  an  excess  of  OH'  ions. 
If,  then,  NaH2PO4  is  added  to  Na2HPO4,  the  excess  of  H2P04'  ions  throws 
back  equation  (6),  and  the  alkalinity  is  reduced. 

The  monosodium  phosphate,  as  a  weak  acid,  gives  off  very  few  H*  and 
HPO4"  ions  by  (2)  and  (4),  so  that  a  very  small  amount  of  disodium  salt, 
which  as  a  sodium  salt  gives  many  HPO4"  ions  by  (1)  and  (3),  has  con- 
siderable power  of  diminishing  the  acidity  of  the  former.  Again,  the  di- 
sodium salt  as  a  weak  base  gives  rise  to  a  very  few  OH'  ions  by  (1),  (3), 
and  (6).  Hence  a  very  small  amount  of  NaH2PO4,  which  in  its  character 
as  a  sodium  salt  dissociates  with  the  production  of  many  H2PO4'  ions, 
diminishes  considerably  the  hydroxyl  ion  concentration  of  the  disodium 
salt  by  throwing  back  equation  (6). 

Similarly  in  the  case  of  carbonic  acid  and  bicarbonates  the  equations  of 
dissociation  may  be  written  to  correspond  with  those  of  the  phosphates: 

(3)  NaHCO3  ^=±  Na'  +  HCO3' 

(4)  H2CO3  ^=>  H-  -f  HCCV 

(5)  H2O  ^Z=±  H-  +  OH' 

(6)  HCCV  +  H2O  ^Z=>  H2CO3  +  OH' 

Since  carbonic  acid,  H2CO3,  is  a  very  weak  acid,  few  hydrogen  ions  are 
formed  by  equation  (4).  Sodium  bicarbonate,  as  a  weak  base,  produces 
few  hydroxyl  ions,  but,  as  a  sodium  salt,  produces  a  considerable  number 
of  HCO3'  ions.  Suppose  that  CO2  is  added  to  a  mixture  of  bicarbonate 
and  CO2.H2CO3  is  formed,  and  this  increases  the  concentration  of  HCOs' 
by  dissociation.  The  result  of  this  will  be  an  increase  of  non-dissociated 
NaHCOs  by  throwing  back  equation  (3)  (Bayliss). 


MAINTENANCE    OF    THE    ACID-BASE    EQUILIBRIUM    OF    THE    BODY      175 

"The  whole  physiological  equilibrium  may  be  concisely  summed  up 
(Henderson).    The  hydrogen  ion  concentration  of  the  body  has  been  seen 

TT    (~^(~\ 

to  depend  upon  the  ratio       z      *  .    Acid  reacting  with  this  system  causes 

a  diminution  of  the  denominator  and  an  increase  in  the  numerator  of  the 
fraction;  the  value  of  the  fraction  increases  and  with  it  the  hydrogen  ion 
concentration.  Hereupon  the  lung  reduces  the  value  of  the  numerator  by 
diminishing  the  concentration  of  carbon  dioxide  in  the  blood  and  alveolar 
air;  the  value  of  the  fraction  is  restored  more  or  less  exactly  to  its  original 
value  and  with  it  the  concentration  of  the  hydrogen  ion.  But  the  denomi- 
nator is  still  below  normal.  To  offset  this  there  occurs,  on  the  one  hand,  a 
production  of  ammonia  which  takes  the  place  in  the  urine,  of  alkali  exist, 
ing  as  salt  in  the  blood.  This  alkali  recombines  with  carbonic  acid,  forming 
bicarbonate,  and  thus  increasing  the  denominator.  On  the  other  hand, 
the  kidney  removes  less  alkali  in  combination  with  phosphates  than  exists 
in  this  state  in  the  blood.  This  alkali,  too,  helps  to  regenerate  sodium  bi- 
carbonate and  thus  to  increase  the  denominator.  Both  of  these  processes 
are  so  regulated  that  the  ratio  returns  to  normal." 

Excessive  production  of  acids  in  the  body,  depleting  the  alkali  reserve 
and  calling  into  activity  the  compensatory  mechanism  just  described,  occurs 
most  conspicuously  in  diabetes  where  the  imperfect  oxidation  of  fats  gives 
rise  to  beta-oxybutyric  and  other  acids.  Various  infectious  diseases  with 
extensive  destruction  of  tissue  are  accompanied  by  the  liberation  of  acids 
in  excess  in  the  tissues.  Destruction  of  the  liver,  the  extensive  metabolic 
disturbances  which  sometimes  accompany  pregnancy,  protracted  starva^ 
tion,  poisoning  with  acids  are  among  the  conditions  which  bring  about  an 
acidosis.  Chronic  nephritis,  inasmuch  as  the  excretion  of  acids  is  retarded, 
may  have  the  same  result,  while  cardiac  disease  with  decompensation  and 
dyspnoea  may  produce  a  similar  change  by. the  inadequate  removal  of 
carbon  dioxide. 

On  the  other  hand,  a  condition  which  might  be  referred  to  as  alkalosis, 
in  which  the  alkali  reserve  is  greatly  increased,  arises  with  pyloric  obstruc- 
tion when  there  is  vomiting  and  continued  loss  of  hydrochloric  acid  with 
the  gastric  juice.  Details  of  the  untoward  results  of  this  are  given  in 
describing  gastric  tetany. 

LITERATURE 

Bayliss:  Principles  of  General  Physiology,  2d  ed.,  1918,  195. 

Ewing:  Archives  Int.  Med.,  Nov.  and  Dec.,  1908. 

Frothingham. :  Ibid.,  1916,  xviii,  717. 

Henderson,  L.  J.:  Science,  1917,  xlvi,  73;  Ergebn.  Physiol.,  1909,  viii,  254. 

Van  Slyke  and  Cullen:  Jour.  Biol.  Chemistry,  1917,  xxx,  289. 


CHAPTER  XI 
DEFENCES  OF  THE  BODY  (Continued) 

New-growth  of  tissue.  General  characters.  Influence  of  various  agencies  on  growth. 
Growth  stimuli. 

NEW-GROWTH  OF  TISSUE  AND  REPAIR      . 

WE  ABE  very  ill  informed  with  regard  to  the  principles  which  underlie 
the  growth  of  tissues,  and  any  discussion  of  them  soon  leads  us  to  a  point 
beyond  which  we  cannot  go  without  invoking  the  deceptive  aid  of  such 
expressions  as  vital  force,  inherent  vitality,  etc.  There  have  been  many 
efforts  to  explain  the  manifestations  of  life  on  a  chemical  or  physical  basis, 
but  while  they  explain  very  well  what  happens,  they  leave  us  with  little 
notion  of  what  the  real  spark  is  which  starts  the  setting  free  of  energy, 
whether  its  result  be  a  functioning  of  the  cell  as  we  see  in  a  muscular  con- 
traction or  the  division  of  one  cell  into  two. 

We  do  know  well  enough  that  new-growth  of  tissue  occurs  when  tissue 
is  destroyed.  Much  of  this  compensatory  new  formation  may  take  place 
somewhere  quite  far  away  from  the  point  of  injury,  but  at  any  rate  there 
is  a  local  patching  which,  when  the  tissue  destroyed  is  a  highly  specialized 
one,  is  usually  carried  out  by  the  ubiquitous  connective  tissue.  The 
patch  is,  therefore,  not  likely  to  be  of  the  same  dignity  as  the  original  tissue, 
and  serves  mainly  to  reestablish  continuity. 

Since  injury  often  excites  the  inflammatory  reaction  also,  the  two  may 
become  inextricably  entangled,  so  that  there  has  long  been  confusion  with 
regard  to  "  inflammatory  new-growth."  This  is  especially  true  when,  on 
account  of  the  persistent  repetition  of  the  injury,  the  inflammatory  re- 
action continues  for  a  long  time,  and  attempts  at  healing  are  repeatedly 
partly  frustrated.  But  the  most  intense  inflammatory  reaction  may  occur 
with  hardly  any  new-growth  of  tissue,  as  in  pneumonia,  and,  on  the  other 
hand,  regeneration  and  repair  sometimes  take  place  with  no  visible  signs 
of  inflammation.  The  two  processes  seem  distinct  in  their  causes,  in  their 
aims,  and  in  the  cells  which  participate,  so  that  though  they  occur  to- 
gether they  should  not  be  confused.  If  we  reflect  upon  this,  even  though 
we  meet  with  difficult  and  questionable  cases,  we  must  realize  that  that 
process  which  we  call  inflammation  consists  essentially  in  the  flooding  of 
the  injured  tissues,  by  special  mechanisms,  with  an  excess  of  wandering 
cells  and  the  fluids  of  the  blood  which  tend  to  neutralize  the  injurious  agent 
and  clear  away  the  debris  and  then  to  fade  away  and  disappear,  having 
taken  part  in  no  new  formation  of  tissue.  Repair,  on  the  other  hand,  is 
the  new  formation,  from  neighboring  cells,  of  a  more  or  less  complex, 

176 


NEW-GROWTH    OF   TISSUE   AND   REPAIR  177 

permanent,  and  coherent  tissue  which  takes  the  place  of  that  which  was 
lost. 

It  seems  not  unreasonable  to  suppose  that  the  warmth  and  good  blood 
supply  which  are  so  characteristic  of  inflammation  might  favor  this  process 
of  repair,  or  even  that  the  irritant  itself,  when  it  becomes  diluted  in  its 
extension  into  the  tissue,  may  act  as  a  stimulant  to  cell  growth.  The 
conception  of  " inflammatory  new-growth"  or  " productive  inflammation" 
must  depend  upon  this  last  possibility,  and  there  will  arise  occasion  to 
discuss  it  further.  For  a  long  time  there  was  doubt  as  to  the  role  of  the 
many  kinds  of  wandering  cells  which  appear  in  old  areas  of  inflammation, 
and  as  long  as  they  were  thought  to  be  able  to  give  rise  to  connective  tissue, 
the  influence  of  inflammation  on  new-growth  seemed  very  great.  Now, 
however,  since  Maximow  and  others  have  shown  their  rather  specialized 
wandering  character,  and  it  is  admitted  only  grudgingly  that  they  have 
any  part  in  tissue  formation,  the  matter  becomes  clearer  and  we  have  to 
deal  with  wandering  cells  as  concerned  with  inflammation  and  fixed  tissue 
cells  with  repair. 

Nowhere,  however,  could  there  be  a  more  convincing  instance  of  the 
effect  of  a  chemical  stimulant  acting  to  excite  a  rapid  new-growth  of  tissue 
than  in  the  case  of  the  sudden  phenomenal  proliferation  of  leucocytes 'in 
the  bone-marrow,  and  the  flooding  of  the  blood  with  these  cells  when  some 
bacterial  poison  is  absorbed  from  an  area  of  inflammation. 

We  must  ask  ourselves  what  are  the  causes  which  lead  to  the  growth  of 
tissue  in  general,  and  the  new-growth  of  tissue  in  particular,  and  we  find 
that,  while  we  have  some  information  concerning  those  things  which 
influence  growth,  we  are  reduced  to  theories  when  we  attempt  to  explain 
the  actual  causes.  Underlying  it  all  we  must  recognize  one  essential  thing 
which  distinguishes  a  live  cell  from  a  dead  one,  namely,  the  ability  to  absorb 
and  assimilate  nutritive  substances,  building  them  up  into  its  own  pro- 
toplasm, and  then,  by  the  exercise  of  a  certain  amount  of  energy,  to  divide 
its  nucleus  and  protoplasm  in  such  a  way  as  to  form  two  new  cells  in  place 
of  the  old  one.  Given  this  power,  which  we  cannot  explain,  we  may  as 
well  go  on  to  discuss  the  conditions  and  influences  which  guide  this  growth, 
and  which  are  directly  chemical  or  physical  in  their  nature. 

The  materials  for  growth  must  be  supplied,  and  are  precisely  selected 
by  the  cell  in  quantities  to  suit  its  metabolic  processes.  Water,  protein, 
carbohydrate,  and  fatty  substances,  inorganic  materials,  and  oxygen  are 
absorbed,  and  carbon  dioxide  with  various  other  substances,  elaborated  or 
excreted  by  the  cell,  are  given  off.  We  realize  that  growth  is  inhibited  by 
faulty  nutrition  or  by  an  inadequate  blood  supply,  and  that  the  healing  of 
a  wound  is  slow  and  imperfect  in  those  whose  metabolism  is  impaired  by 
old  age  or  illness.  The  idea  that  increased  activity  in  growth  is  brought 
about  by  an  excessively  rapid  and  abundant  blood  supply  has  long  been 
held,  and  there  is  some  evidence  in  its  favor.  A  rabbit's  ear  kept  flushed 
with  blood  by  the  section  of  the  sympathetic  nerves  is  said  to  grow  more 

13 


178  TEXT-BOOK  OF  PATHOLOGY 

rapidly  than  the  other,  and  to  outstrip  it,  while  conversely  it  is  well  known 
that  rapidly  growing  tissue  makes  its  appearance  with  an  excessive  pro- 
vision for  blood  supply  in  the  form  of  numerous  wide  capillaries  which  dis- 
appear when  the  tissue  becomes  mature.  Still,  the  situations  in  which  we 
may  study  the  effect  of  an  excessive  blood  supply  in  comparison  with  an 
adequate  one  are  generally  complicated,  and  give  us  little  light  on  the 
subject. 

When  tissue  is  grown  artificially  in  a  hanging  drop  of  blood  plasma,  all 
these  influences  come  most  clearly  to  view,  and  it  is  quickly  apparent  that 
growth  stops  at  once  when  the  supply  of  nutriment  contained  in  the  drop 
of  plasma  becomes  insufficient.  The  effect  of  warmth  is  most  apparent 
there  also,  and  it  can  be  shown  that,  whereas  at  very  low  temperatures 
growth  does  not  occur  at  all,  it  begins  and  increases  slowly  in  rate  as  the 
temperature  is  raised  until,  at  a  certain  pqint,  it  finds  the  optimum  con- 
ditions. Higher  temperatures  than  this  are  unfavorable,  and  growth 
becomes  slower  and  slower  until  a  point  is  reached  at  which  it  is  com- 
pletely inhibited.  In  living  animals  this  can  be  demonstrated  to  some 
extent,  inasmuch  as  the  ear  of  a  rabbit  kept  warmer  than  normal  for  a 
long  time  is  said  to  grow  so  that  it  becomes  larger  than  the  other  ear,  which 
has  not  been  so  treated. 

In  this  last  instance,  as  in  the  case  of  the  influence  of  the  nervous  system, 
it  is  difficult  to  decide  which  of  several  things  may  be  the  real  cause  of  the 
growth,  for  in  such  a  rabbit's  ear  the  warmth  tends  to  widen  the  blood- 
vessels and  thus  bring  increased  supplies  of  nutrition  to  the  part.  Indeed, 
it  is  somewhat  doubtful  whether  the  nervous  system  has  any  direct  in- 
fluence over  growth,  even  though  we  speak  so  confidently  of  trophic  nerves. 
For  while  an  extremity  which  has  been  paralyzed  fails  to  grow  as  the  nor- 
mal one  does,  this  may  well  be  due  to  its  inactivity  and  the  consequent 
diminution  of  the  blood  supply. 

Mechanical  influences  play  a  considerable  part  in  determining  growth, 
although  it  is  well  known  that  in  plants  at  least  a  force  can  be  exerted  by 
growing  tissues  far  greater  than  that  which  might  ordinarily  be  used  to 
interfere  with  their  growth.  Here  again  there  enter  the  complicating 
factors  of  interference  with  nutrition  and  light,  which  are  most  powerful 
to  disturb  growth,  for  while  a  tree  growing  in  a  crevice  can  split  a  rock  and 
roots  can  lift  up  pavements,  one  may  apply  a  relatively  slight  pressure  so 
as  to  cut  off  nutrition  and  light,  and  growth  will  be  blocked. 

Continuous  pressure  applied  to  organs  or  extremities  in  the  animal 
body  interferes  with  their  growth  or  causes  the  cells  to  atrophy  and  dis- 
appear, as  we  see  in  the  deformed  livers  of  those  who  lace  tightly  and  in 
the  misshapen  skulls  of  those  Indians  who  bind  the  heads  of  their  children. 
But  intermittent  pressure,  as  that  of  a  shoe  which  pinches,  tends  rather  to 
cause  an  excessive  callous  growth  of  epidermis.  We  might  multiply  ex- 
amples of  the  growth  of  tissue  in  response  to  various  sorts  of  mechanical 
tensions  and  strains,  a  growth  which  forms  the  basis  of  the  wonderful 


NEW-GROWTH    OF   TISSUE   AND    REPAIR  179 

adaptation  to  function  so  generally  observed  when  tissues  or  organs  are 
subjected  to  changed  conditions.  Thus  the  arching  lamella?  of  bone  which 
are  precisely  calculated  to  meet  the  strain  at  the  upper  end  of  the  femur 
are,  after  a  time,  rearranged  to  suit  the  new  .conditions  with  equal  mechani- 
cal perfection  when  the  bone  has  healed  after  a  fracture. 

Probably  few  persons  who  survive  an  extensive  injury,  and  in  whom  this 
process  of  readjustment  to  new  conditions  is  going  on,  live  long  enough  to 
allow  it  to  be  quite  perfected,  but  there  are  frequently  found  in  such  per- 
sons the  most  extraordinary  adaptations. 

It  is  only  in  those  tissues  which  have  to  do  with  movement  and  support, 
however,  that  the  inciting  cause  of  the  new-growth  of  tissue  is  chiefly 
mechanical,  and  it  must  be  remembered  that  in  other  organs  whose  func- 
tion is  not  of  a  mechanical  nature  other  influences  are  at  work  to  bring 
about  the  readjusting  new-growth.  A  good  example  of  the  mechanical  type 
is  seen  in  the  establishment  of  a  collateral  circulation  when  an  important 
vein  or  artery  has  been  obstructed.  Numbers  of  channels  which  were  pre- 
viously insignificant  become  large,  thick-walled  vessels  and  give  passage 
to  the  pressing  stream  of  blood  in  a  roundabout  way,  so  that  it  may  re- 
join the  original  channel  beyond  the  obstruction.  A  remarkable  instance 
of  this  which  showed  a  complete  obstruction  of  the  superior  vena  cava  is 
described  by  Osier.*  A  bulky  mass  of  new  vascular  channels  was  so 
formed  as  to  convey  the  blood  from  the  upper  part  of  the  body  over  a  long 
detour  to  the  heart  (Fig.  8). 

Obstructions  placed  before  tissues  which  act  mechanically  in  such  a  way 
as  to  make  it  difficult  for  them  to  carry  on  their  function  nearly  always 
cause  a  growth  of  the  tissue,  so  that  it  becomes  stronger  and  forces  the 
barrier.  This  is  seen  in  the  heart  and  in  all  those  muscular  structures,  such 
as  the  intestine  and  the  bladder,  whose  duty  it  is  to  move  their  contents 
by  contraction.  Above  a  tumor  which  obstructs  the  colon  the  wall  be- 
comes enormously  thick  and  powerful,  and  so  does  the  wall  of  the  bladder 
when,  through  the  enlargement  of  the  prostate,  urine  is  evacuated  with 
difficulty. 

In  the  repair  that  follows  a  loss  of  substance  these  mechanical  influences 
are  not  quite  so  plain,  but  they  undoubtedly  play  a  part.  New  tissue  is 
formed  hurriedly  and  in  great  quantities  to  replace  that  which  was  lost, 
and  although  at  first  it  seems  to  grow  in  a  somewhat  disorderly  way,  it 
quickly  shows  an  adaptation  to  its  purpose.  All  this  is  probably  guided, 
at  least  in  part,  by  the  influence  of  the  solid  materials  with  which  the  cells 
come  in  contact,  for  while  the  young  connective-tissue  cells  and  blood- 
vessels can  grow  by  themselves  and  form  an  even  swelling  tissue,  the  more 
usual  and  natural  way  for  them  is  to  grow  upward  into  a  network  of  fibrin 
filaments  along  which  they  creep  and  which,  in  turn,  they  dissolve  and 
destroy  (Fig.  66).  Epithelium  grows  and  spreads  out  on  a  surface  when 

*  Johns  Hopkins  Hospital  Bulletin,  1903,  xiv,  169. 


180 


TEXT-BOOK  OF  PATHOLOGY 


that  is  offered,  but  scarcely  penetrates  into  a  feltwork  of  fibrin.  These  are 
differences  in  the  " inherent  vital  characters"  of  these  cells,  for  when  iso- 
lated from  all  connection  with  the  body  and  growing  in  the  hanging  drop 
of  plasma,  they  show  the  same  peculiarities  in  their  growth;  connective- 
tissue  cells  sprout  out  in  every  direction  so  long  as  they  may  follow  the 
course  of  a  filament  of  fibrin.  Epithelium  grows  in  a  sheet,  just  as  it 
tends  to  do  on  the  surface  of  a  healing  wound  (Figs.  67,  68,  69). 


=:••'•   •    •  i:<r->-f: 


Fig.  66. — Fibroblasts  growing  into  a  thrombus. 

Even  the  simplest  of  these  forms  of  tissue  proliferation  can  hardly  be 
ascribed  directly  to  any  mechanical  influence,  but  it  is  clear  that  the  cells 
in  their  growth  are  guided  and  directed  to  some  extent  in  this  way.  There 
must  be  remembered  always  the  underlying  tendency  of  the  living  cell  to 
assimilate  food  materials,  increase  its  substance,  and  divide. 

Functional  Equilibrium. — Is  there  then  some  stimulus  from  without 
which  accentuates  this  tendency,  or  is  the  tendency  merely  allowed  full 
play  by  the  withdrawal  of  some  restraining  influence?  This  has  been  the 


NEW-GROWTH    OF   TISSUE    AND    REPAIR 


181 


subject  of  debate  for  many  years,  for  while  Virchow  held  that  there  exist 
actual  growth  stimuli  which  might  indeed  act  through  the  injury  or  de- 
struction of  certain  cells,  Weigert  declared  that  cells  grew  because  the 
mutual  resistance  of  the  tissues  was  set  aside,  the  equilibrium  disturbed, 
and,  as  John  Hunter  before  him  had  thought,  the  cells  grew  impelled  by 
the  loss  of  the  physiological  limitations  which  one  tissue  element  opposes 
to  another.  John  Hunter  had  spoken  of  the  stimulus  of  incompleteness; 
Weigert  regarded  the  tissue  growth  which  occurs  with  inflammation  not  as 


Fig.  67. — Characteristic  growth  of  connective  tissue  cultivated  in  vitro. 

mitotic  figures. 


There  are  many 


the  result  of  a  stimulus,  but  only  as  the  consequence  of  the  tissue  defect. 
According  to  him,  it  was  quite  unproved  that  there  is  any  direct  idioplastic 
stimulus. 

The  existence  of  a  certain  equilibrium  among  tissues,  and  the  remark- 
able effects  of  its  disturbance,  have  long  been  recognized,  but  this  equilib- 
rium cannot  be  looked  upon  as  a  merely  mechanical  one.  Nor  is  it  to  be 
explained  on  any  simple  chemical  basis.  We  are  perhaps  nearest  to  the 
truth  if  we  say  that  it  rests  chiefly  upon  a  balance  between  the  functional 


182 


TEXT-BOOK  OF  PATHOLOGY 


activities  of  different  tissues.  If,  in  the  functioning  of  a  cell,  certain  ma- 
terial is  consumed,  the  cell  makes  this  up  by  its  assimilative  processes. 
If  functional  activity  is  maintained  at  an  extreme,  so  is  the  assimilation, 
and  the  cell  even  increases  its  size  and  functional  power,  or,  after  accumu- 
lating an  excess  of  cell  material,  divides  into  two  cells,  so  that  the  function 
is  better  maintained  (hypertrophy;  hyperplasia) .  But  no  mechanical  or 
chemical  disturbance  in  the  body  will  give  more  than  a  motive  for  this. 


Fig.  68. — Characteristic  growth  of  epithelium  in  culture. 

The  process  itself  depends  on  that  inherited  power  of  growth  by  which  the 
cell  adjusts  itself  to  the  new  conditions. 

When  they  reach  maturity,  the  bodies  of  any  one  kind  of  animal  have, 
as  we  know,  a  characteristic  form  and  a  recognized  average  size,  but  a  good 
deal  of  variation  from  the  standard  is  still  compatible  with  life.  Within 
the  body  the  interrelation  of  organs  seems  to  be  much  more  precisely 
calculated,  just  as  the  works  of  a  watch  must  be  calculated  throughout, 
although  the  case  may  have  any  form.  It  seems  probable  that  there  may 
even  be  an  actual  numerical  relationship  between  the  cells  of  different 


NEW-GROWTH    OF   TISSUE    AND    REPAIR 


183 


organs,  so  that  a  disturbance  of  this  balance  is  felt  if  cells  are  destroyed  in 
one.  It  is  known,  of  course,  that  each  organ  is  able  to  put  forth  in  an  emer- 
gency a  vastly  greater  functional  activity,  since  it  has  a  reserve  power 
which  constitutes  its  margin  of  safety,  but  this  effort  is  felt  at  once  and 
shortly  leads  to  the  multiplication  of  the  cells  and  the  increase  of  the 
functional  power.  This  is  true  whether  the  emergency  results  from  the 
destruction  of  some  of  the  cells  or  the  increase  in  the  demand  upon  the 
organ. 


•*.*/  ;* » •!:••»"  •«»  +  **  •*••  L*»if 

M$%M1i$ 

s&j^ggs*^ 


Fig.  69. — Epithelium  and  connective  tissue  growing  side  by  side  in  a  culture  made  from 

the  intestine  of  an  embryo. 

This  is  the  functional  equilibrium  of  the  tissues  which  is  maintained  very 
precisely  by  the  increase  and  reduction  of  the  various  functional  units. 
But  there  is  also  a  mechanical  equilibrium.  The  tissues  grow  in  certain 
arrangements,  and  the  organs  assume  certain  normal  forms  which  are  the 
result  of  the  action  of  various  tensions  and  strains  not  always  easy  to  recog- 
nize or  calculate,  and  the  end-result  is  the  recognized  normal  body  form. 
It  requires  a  very  extensive  disarrangement  of  the  tissues  to  obliterate 
the  trend  of  these  tensions  and  strains  and  allow  the  body  to  heal  into  any 
unusual  or  inappropriate  form.  Usually,  if  time  is  given,  the  healing  of 


184  TEXT-BOOK  OF  PATHOLOGY 

any  moderate  injury  goes  far  toward  restoring  the  normal  body  form  and 
thus  the  mechanical  equilibrium. 

When  an  injury  is  such  as  to  unbalance  for  a  time  this  mechanical 
equilibrium,  there  occurs  a  new  formation  of  tissue  to  replace  that  which 
was  lost,  and  in  time  the  original  mechanical  conditions  may  be  well 
restored  and  the  body  form  reinstated,  but  it  would  be  rash  to  state  that 
this  was  carried  out  solely  because  the  mechanical  equilibrium  was  dis- 
turbed or  that  the  cells  grew  because  pressure  relations  were  altered  on  one 
side  or  the  other.  There  is  always  the  other  factor  to  be  considered, 
namely,  that  the  loss  of  tissue,  even  when  it  is  merely  supporting  tissue, 
involves  an  unbalancing  of  the  functional  equilibrium,  so  that  the  growth 
occurs  also*  to  reinstate  that.  However,  even  with  these  two  reasons  it 
is  difficult  to  explain  the  purposeful  methodical  growth  of  tissue  which  so 
precisely  accomplishes  the  healing  of  a  wound,  but  in  its  detail,  in  which 
fibrin  plays  a  part,  guiding  the  direction  of  growth  of  the  new  cells  so  that 
they  stretch  across  from  one  side  of  the  wound  to  the  other,  a  plan  is 
doubtless  being  carried  out  which  has  become  a  routine  after  a  long  process 
of  evolution,  and  is  now  merely  the  common  means,  regardless  of  the  reason 
for  growth. 

That  the  unbalancing  of  the  mechanical  equilibrium  can  hardly  be  con- 
sidered the  main  reason  for  the  new-growth  of  tissue  becomes  clear  when 
we  consider  cases  in  which  it  can  be  practically  eliminated.  When,  for 
example,  some  poison  kills  a  part  of  the  liver-cells  in  each  lobule  of  that 
organ,  multiplication  of  the  remaining  cells  occurs  while  the  bodies  of  the 
dead  cells  are  still  in  position  and  little  change  in  the  pressure  relations  can 
have  arisen.  So,  too,  on  the  removal  of  one  kidney,  or  even  when  its 
function  is  annulled  by  obstruction  of  the  ureter  so  that  it  becomes  atro- 
phied or  enlarged  into  a  sac  of  fluid,  growth  occurs  in  the  other  kidney  until 
it  is  able  to  do  easily  the  work  of  both  (Fig.  70).  These  are  examples  of 
the  results  of  an  unbalancing  of  the  functional  equilibrium  which  seems, 
upon  due  consideration,  to  be  the  most  important  factor  in  this  question 
of  new-growth. 

Influence  of  Nutrition. — In  general,  growth  of  tissue  is  much  influenced 
by  the  character  of  the  food,  and  in  the  lack  of  certain  constituents  may  be 
greatly  retarded.  This  question,  obviously  of  great  importance,  has  been 
the  subject  of  extensive  studies  in  recent  years,  and  has  become  so  complex 
that  the  original  articles  of  F.  G.  Hopkins,  Osborne  and  Mendel,  and  others 
must  be  consulted.  Hopkins  showed  that  certain  substances,  often  vaguely 
referred  to  as  vitamines,  which  are  present  in  minute  quantities,  are  of 
fundamental  importance.  The  nature  of  these  substances  and  their  varying 
solubility  in  fats  or  in  water  have  been  much  discussed  without  any  definite 
conclusion.  It  is  realized  that  certain  of  the  constituent  amino-acids  are 
requisite  for  the  building  up  of  the  proteins  of  the  cells  and  that  growth 
is  retarded  by  their  absence,  but  the  absence  of  the  vitamines  brings  with 
it  profound  pathological  changes.  Whipple  and  Hooper  have  shown  that 


NEW-GROWTH   OF   TISSUE   AND   REPAIR 


185 


Fig.  70.— Atrophy  of  left  kidney  following  obstruction  of  the  ureter.     Corresponding 
enlargement  of  the  opposite  kidney. 


186  TEXT-BOOK    OF    PATHOLOGY 

regeneration  of  blood  by  the  bone-marrow  is  much  influenced  by  the  char- 
acter of  the  food,  and  Clark  found  that  the  healing  oi  wounds  begins  more 
promptly  upon  a  protein-rich  diet  than  upon  a  diet  composed  chiefly  of 
fats  and  carbohydrates,  although  when  once  begun  the  rate  of  healing  is 
the  same. 

Active  Stimuli  to  Growth. — Still  the  question  remains  whether  there 
exist  means  by  which  growth  can  be  directly  and  actively  stimulated. 
The  great  difficulty  in  answering  this  question  lies  in  our  being  unable  to 
eliminate  the  factors  of  the  unbalancing  of  the  mechanical  and  the  func- 
tional equilibrium  by  the  injury  which  these  stimuli  cause  in  the  cells,  and 
for  this  reason  we  may  await  with  interest  the  results  of  systematic  experi- 
ments with  the  application  of  such  supposed  stimuli  to  tissue  growing 
in  vitro  where  mechanical  conditions  c,an  be  controlled  and  functional  de- 
mands reduced  to  a  minimum.  Further,  in  those  frequent  cases  in  the 
animal  body  in  which  the  very  excess  of  the  new  tissue  produced  seems  to 
argue  the  existence  of  some  special  stimulus  to  growth,  we  must  eliminate 
the  possibility  that  this  new  tissue  may  represent  the  accumulated  product 
of  repeated  attempts  at  repair,  each  of  which  has  been  partly  frustrated 
by  a  new  injury,  so  that  even  the  repairing  tissue  is  injured  and  responds 
in  an  attempt  to  repair  itself.  It  is  readily  seen  that  this  process,  kept  up 
for  a  long  time,  would  end  in  the  formation  of  a  great  quantity  of  scar  tis- 
sue, or,  at  the  margin  of  a  chronic  ulcer,  of  a  greatly  thickened  and  irregular 
epithelial  growth. 

But  in  the  present  state  of  our  knowledge  it  is  impossible  to  deny  the 
existence  of  direct  stimuli  to  tissue  growth,  although  it  seems  that  this 
facile  explanation  ought  to  be  used  perhaps  a  little  less  freely  than  is  done 
in  most  text-books.  There  are  certain  substances,  such  as  the  stains 
Sudan  III  and  scarlet  red,  which,  when  injected  into  the  tissues,  provoke 
an  extraordinary  growth  of  epithelium,  cartilage,  etc.,  which  in  some  cases 
finally  looks  almost  like  a  tumor.  Similar  results  have  been  obtained  with 
skatol,  indol,  etc.,  and  even  with  ether  water.  It  is  not  quite  clear  how 
these  substances  act  nor  what  part  is  played  by  the  injury  they  produce  in 
the  tissues,  but  the  new-growth  is  far  in  excess  of  what  would  be  needed  for 
repair.  They  are  all  soluble  in  lipoid  substances,  and  it  is  possible  that  their 
effect  is  due  to  their  attacking  the  lipoid  membrane,  which  is  supposed  to 
envelope  each  cell,  thus  exposing  the  cell  to  outward  influences  from  which 
it  has  been  protected.  This  is  somewhat  allied  to  Loeb's  methods  of  stir- 
ring up  artificial  or  parthenogenetic  development  in  unfertilized  egg-cells, 
for  in  that  process  he  emphasizes  the  importance  of  lipolytic  substances 
in  their  action  upon  the  envelope  of  the  cell.  In  that  case,  however,  the 
segmentation  which  is  started  is  rather  a  process  of  the  development  of  a 
cell  endowed  with  great  energy  of  growth,  while  in  the  mature  cell  the 
latent  potential  energy  must  be  converted  into  an  active  form  and  greatly 
intensified. 

Very  vague,  too,  are  our  notions  about  the  substances  which  cause  the 


NEW-GROWTH    OF   TISSUE   AND   REPAIR 


187 


sudden  new-growth  of  tissue  at  the  onset  of  puberty,  and  especially  those 
which  produce  the  remarkable  changes  in  the  breasts  and  other  organs  in 
pregnancy.  Doubtless  these  are  chemical  substances  which  circulate  in 
the  blood,  as  has  been  shown  in  the  case  of  those  malformed  twins  which, 
being  fused  together,  have  a  common  circulation,  and  in  whom  preg- 
nancy in  one  affects  the  organs  of  the 
other  (Blazicek  sisters,  one  of  whom 
became  pregnant,  after  which  the 
breasts  of  both  secreted  milk). 

Other  instances  in  which  the  in- 
creased or  perverted  activities  of  the 
organs  of  internal  secretion  are  followed 
by  a  great  overgrowth  of  all  or  a  part 
of  the  tissues  are  well  known  (gigan- 
tism,  acromegaly),  and,  on  the  other 
hand,  the  extreme  stunting  of  growth 
from  the  failure  of  these  secretions  is 
equally  well  known  (myxcedema,  cre- 
tinism, etc.).  There  are  conditions, 
too,  such  as  the  pulmonary  osteo- 
arthropathy  of  Marie,  in  which  the 
absorption  of  poisonous  material  from 
the  widened  and  infected  bronchi  pro- 
duces a  great  overgrowth  of  the  ex- 
tremities— actually  a  sort  of  gigantism 
(Fig.  71). 

Infections  and  Foreign  Bodies. — Of 
daily  interest  in  regard  to  the  new- 
growth  of  tissue  is  the  influence  of  in- 
fections and  of  foreign  bodies,  among 
which  may  be  classed  dead  tissue  and 
fibrin. 

Many  infections  lead  to  inflamma- 
tory reaction  without  necessarily  re- 
sulting in  any  great  destruction  of 
tissue  or  any  very  evident  reparatory 
process.  But  this  is  doubtless  partly 
dependent  upon  the  situation  of  the 
infection,  for  while  the  pneumococcus 
may  produce  a  pneumonia  which  will 

disappear,  leaving  only  a  few  gaps  in  the  respiratory  epithelium  to  be  filled 
up  by  the  neighboring  cells,  the  same  organisms  in  the  pleura  or  pericar- 
dium are  likely  to  produce  an  exudate  the  replacement  of  which  by  new 
tissue  leads  to  the  permanent  binding  together  of  those  surfaces.  Never- 
theless, even  there  the  adhesions  may  be  slight  or  absent,  and  the  extent 


Fig.  71. — Secondary  hypertrophic 
osteoarthropathy  showing  enlarge- 
ment of  the  forearm  and  hand. 


188  TEXT-BOOK   OF   PATHOLOGY 

of  new  formation  of  tissue  appears  to  depends  upon  the  extent  of  the 
injury. 

The  result  of  the  destruction  of  tissue  by  bacteria  seems  to  differ  from 
that  produced  mechanically  chiefly  in  that  the  bacteria  persist  after  the 
repair  has  begun  and  repeat  the  injury.  This  is  notoriously  true  of  those 
resistant  bacteria  and  animal  parasites  which  remain  lodged  in  the  tissue 
for  a  very  long  time.  It  is  true  of  the  tubercle  bacillus  and  of  the  Spiro- 
chseta  pallida,  which  linger  after  completing  their  first  injury  to  the  tissue 
until  they  are  encased  in  a  nodule  of  new  tissue,  and  then  still  longer, 
until,  by  their  poisons,  they  cause  the  necrosis  of  the  cells  of  that  nodule, 
which  is  then  replaced  by  a  wall  of  cells  a  little  further  out.  The  first 
nodule  seems  far  in  excess  of  what  was  needed  to  repair  the  injury  caused 
by  the  bacilli,  and  the  question  arises  at  once  whether  its  abundant  cells 
have  not  grown  in  direct  response  to  a  stimulus  furnished  by  the  bacillus. 
Probably  so,  but  the  matter  is  so  complex  in  the  animal  body  that  it  seems 
possible  to  decide  it,  if  at  all,  only  by  recourse  to  experiments  with  isolated 
tissues  growing  in  vitro. 

All  the  factors  which  decide  the  inception  of  growth  are  at  work  when  a 
portion  of  tissue  is  left  dead  and  surrounded  by  living  tissues  in  the  organ, 
as  in  the  case  of  an  infarct.  Scavenging  leucocytes  attempt  to  remove  the 
coagulated  material,  but  before  they  can  make  much  impression  on  it  the 
gap  in  the  organ  is  patched  by  a  new-growth  of  tissue  and  the  dead  material, 
which  blocked  and  choked  this  gap,  is  replaced  by  the  new  tissue.  The 
functional  replacement  occurs  elsewhere,  and  at  this  point  there  is  only  a 
growth  of  fibrous  tissue  and  blood-vessels  to  restore  continuity  and  remove 
the  irritating  foreign  substance.  Perhaps  unbalancing  of  the  mechanical 
equilibrium  is  important,  but  it  seems  that  the  presence  of  the  fibrin-con- 
taining necrotic  tissue  offers  a  chemiotactic  attraction  which  guides  the 
growth  of  the  invading  blood-vessels,  and  it  may  be  that  it  is  really  a  chem- 
ical stimulus  to  growth.  An  exudate  of  fibrin  on  the  surface  of  the  peri- 
toneum or  pleura,  where  no  unbalancing  of  mechanical  or  functional 
equilibrium  can  be  caused  by  its  presence,  exerts  the  same  influence  on  the 
underlying  tissue  and  is  quickly  replaced  by  a  new  tissue.  So,  too,  a  clot  in 
the  course  of  the  blood-stream,  whether  it  obstructs  the  circulation  or  only 
lies  on  the  wall  of  the  heart. 

1  Inert  foreign  bodies  are  attacked  in  the  tissues  by  wandering  cells  of  all 
sorts,  just  as  the  fibrin  and  dead  cells  are  attacked  and  dissolved  or  sur- 
rounded ;  but  they  too  soon  find  connective  tissue  and  blood-vessels  flowing 
in  about  them,  so  that  they  are  quickly  encapsulated  or  permeated  by  these 
cells.  Indeed,  there  is  hardly  anything  which  sets  up  such  an  extraordinary 
new  formation  of  cellular  fibrous  tissue  as  a  suspension  of  foreign  par- 
ticles, such  as  the  diatom  shells  which  form  the  fine  dust  of  silicious  earth 
or  kieselguhr  (Podwyssotzky) .  Perfectly  insoluble,  these  particles  can 
hardly  act  through  any  chemical  stimulus,  nor  do  they  appear  to  cause  any 
great  injury  to  the  neighboring  cells  or  disturb  the  mechanical  equilibrium 


NEW-GROWTH   OF   TISSUE   AND   REPAIR 


189 


to  any  great  degree.  Perhaps  it  may  be  regarded  as  a  tactile  stimulus 
which  causes  cells  to  grow  around  them,  much  as  they  follow  threads  of 
fibrin  or  the  surface  of  the  cover-slip  in  cultures.  Indeed,  as  Lambert  has 
shown  by  the  aid  of  lycopodium  spores,  the  cells  in  a  culture  which  sur- 
round foreign  bodies  are  not  those  of  the  connective  tissue,  but  the  wan- 


5  S  tj^Cv,  ^^JW3*          *^        <f'3     ^X^B',1        ^ 
»       4    ^  '^      .-T      -t       '     ,«^ 


Fig.  72. — Tubercle-like  capsule  formed  around  a  lycopodium  spore  introduced  into  the 
liver  through  the  portal  vein. 

dering  cells.     Nevertheless,  in  the  body  the  actual  fibroblasts  appear 
in  time  and  form  an  outer  capsule  (Fig.  72). 

The  growth  of  tumors  exemplifies  in  a  singular  way  the  stimulation  of 
another  tissue  to  growth.  No  matter  what  may  eventually  prove  to  be  the 
reason  for  the  unbridled  growth  of  the  tumor-cells  themselves,  we  know 
that,  standing  as  they  do  in  close  relation  with  connective  tissue  and 
blood-vessels,  they  stir  up  a  growth  in  those  structures  which  leads  to  the 
production  of  a  most  complicated  and  extensive  organized  stroma,  which 
sometimes  assumes  forms  totally  unknown  in  the  body  and  reaches  a  bulk 
far  greater  than  that  of  any  new-growth  formed  in  the  process  of  repair. 


190  TEXT-BOOK   OF   PATHOLOGY 

Analogies  Between  Embryonic  Growth  and  Pathological  New  Forma- 
tion of  Tissue. — The  dividing  cells,  and  more  especially  the  products  of 
division  which  appear  in  the  course  of  the  new  formation  of  tissue,  are 
often  spoken  of  loosely  as  embryonic  cells;  the  tissue  has  returned  to  the 
embryonic  state,  and  the  ontogenetic  phases  are  being  reproduced.  This 
seems  hardly  justified,  since  these  new  cells  do  not  really  resume  the  char- 
acter of  embryonic  cells,  which  have  such  a  great  potential  energy  push- 
ing them  to  unfold  and  develop.  On  the  contrary,  they  are  merely 
young  cells  of  the  type  which  has  reached  maturity,  and  whose  growth 
energy  has  been  finally  reduced  to  a  point  which  leaves  them  able  to  main- 
tain the  integrity  of  the  organ,  but  not  to  develop  further  into  a  still  more 
highly  specialized  and  mature  tissue.  Even  in  those  situations  in  which 
normally  there  is  a  constant  active  production  of  cells,  as  in  the  Mal- 
pighian  layer  of  the  skin  or  in  the  bone-marrow,  the  cells  are  mature  in  the 
sense  that  they  do  not  tend  to  develop  further,  but  merely  produce  new 
ones  of  the  same  kind.  Even  the  fact  that  these  new  cells  become  much 
modified  does  not  affect  this  idea. 


LITERATURE 

Various  papers  of  Harrison,  Lambert,  Hanes,  Burrows,  and  others.     Summarized, 
Trans.  Cong.  Amer.  Phys.  and  Surg.,  1913,  ix,  63. 


CHAPTER  XII 
DEFENCES  OF  THE  BODY  (Continued) 

Repair.  Established  character  of  tissues.  Their  early  differentiation.  Metaplasia. 
Regeneration  as  exemplified  in  the  new  formation  of  various  tissue. 

REPAIR 

General  Phenomena  of  Repair.— When  the  body  has  reached  its  mature 
form,  cells  are  newly  formed  only  in  sufficient  quantity  to  make  up  for 
those  lost  each  day  in  the  ordinary  wear  and  tear.  Since  cells  are  being 
constantly  rubbed  off  the  surface  of  the  skin,  the  lower  layers  are  just  as 
constantly  occupied  in  producing  new  ones.  Since  the  red  corpuscles  of 
the  blood  are  short-lived  cells,  they  are  constantly  manufactured  anew 
in  the  bone-marrow.  These  processes  are  so  gradual  and  inconspicuous 
that  it  is  hard  to  be  sure  that  they  are  going  on.  But  if  a  piece  of  skin  be 
scraped  off,  or  a  few  ounces  of  blood  allowed  to  escape,  there  suddenly 
occurs  a  far  more  vigorous  new  formation  of  cells  in  the  skin  or  in  the  bone- 
marrow. 

Every  obvious  new  formation  of  tissue  in  the  grown  person  seems  to  occur 
as  a  result,  which  we  might  predict,  of  some  disturbance  which  impairs  or 
renders  inadequate  the  function  of  that  tissue.  It  is  a  response  so  appro- 
priate to  the  situation  and  carried  out  with  such  moderation  and  in  a  man- 
ner so  eminently  suitable  to  the  supposed  purpose  of  restoring  the  functional 
equilibrium  of  the  body  that  it  is  hardly  possible  to  doubt  that  it,  like  in- 
flammation, must  be  a  plan  evolved  and  elaborated  through  ages  of  natural 
selection  for  the  preservation  of  the  species.  It  is  complicated  and  makes 
use  of  subsidiary  mechanical  aids,  as  we  shall  see  (such  as  the  filling  of  the 
gap  across  which  tissue  is  to  grow  with  fibrin) ;  but  whatever  the  details 
may  be,  the  process  is  nicely  adjusted  to  the  purpose,  and  is  so  constant  that 
we  can  predict  with  absolute  certainty  what  will  happen  in  a  given  case. 

This,  as  every  one  will  recognize,  constitutes  a  striking  difference  between 
the  regenerative  and  reparatory  growth  of  normal  tissue  and  the  growth 
of  tumors,  in  which  one  cannot  foretell  with  certainty  what  will  happen  or 
where  the  growth  will  end. 

The  embryo  grows  according  to  an  inherited  plan,  almost  entirely  pro- 
tected from  outward  influences  until  the  body  form  is  reached.  Yet  then, 
too,  so  profound  is  the  impression  of  this  plan,  if  part  of  an  organ  or  tissue 
be  destroyed,  regeneration  and  repair  take  place  in  such  a  way  as  to  further 
the  original  plan  as  much  as  possible.  Indeed,  the  degree  to  which  this 
repair  may  proceed  is  greater  in  the  embryo  than  it  is  in  mature  life. 

191 


192  TEXT-BOOK   OF    PATHOLOGY 

Specificity  of  Tissues. — An  important  factor  governing  the  repair  or 
regeneration  of  tissues  lies  in  the  established  character  of  the  tissues  them- 
selves. According  to  the  plan  of  development  of  the  animal,  the  cells  of 
each  tissue  assume  at  an  early  stage  a  specialized  character  which  they 
retain  tenaciously.  When  these  cells  divide  and  multiply  after  that,  they 
breed  true,  as  it  were,  and  produce  new  cells  which  have  the  same  form  and 
function  as  themselves.  This  is  the  well-known  specificity  of  tissues,  which 
is  pretty  rigidly  maintained  in  mature  life.  In  the  embryo  we  may,  of 
course,  pass  back  to  stages  where  we  can  no  longer  recognize  the  character 
of  the  cell,  and  where  we  are  unable,  in  the  present  state  of  our  knowledge, 
to  say  that  this  cell  is  predestined  to  become  a  liver-cell  and  that  a  smooth 
muscle-fibre,  for  in  reality  the  cells  at  that  stage  have  not  divided  to  the 
degree  at  which  one  of  the  daughter-cells  takes  one  path  while  another 
follows  a  different  one.  They  have  not  yet  adopted  their  careers.  But  it 
is  further  clear  that  this  is  not  only  because  we  are  unable  to  recognize 
their  tendencies,  but  because,  at  a  very  early  stage,  these  tendencies  are 
not  absolutely  fixed.  The  original  fertilized  ovum  forms  by  its  segmenta- 
tion the  whole  body,  but  after  it  has  undergone  its  first  division,  each  of 
those  two  segmentation  spheres,  if  separated  from  the  other,  is  capable 
of  producing  a  perfect  individual,  as  we  so  frequently  see  in  those  so-called 
single  ovum  twins  which  are  of  the  same  sex  and  remarkably  alike  in  ap- 
pearance. At  later  stages,  when  the  segmentation  has  progressed  much 
farther,  the  destruction  of  one  or  more  of  the  segmentation  spheres  can  be 
compensated  by  the  adjacent  cells,  which  assume  their  function,  but  there 
must  come  a  stage,  and  that  quite  early,  when  such  compensation  can  no 
longer  be  carried  out;  if,  for  example,  all  the  formative  material  destined 
to  produce  the  heart  be  destroyed,  a  monstrous  foetus  would  be  formed 
without  a  heart.  We  cannot  say,  however,  when  this  specificity  is  estab- 
lished, nor  whether  it  is  at  very  different  epochs  in  the  development,  for 
different  tissues.  In  any  case  it  is  only  when  all  the  cells  are  destroyed 
that  the  production  of  that  tissue  is  made  impossible.  If  any  of  this 
formative  material  be  left,  the  processes  of  cell  multiplication  in  the  embryo 
are  so  efficient  that  even  that  remnant  may  be  able  to  reconstruct  as  much 
of  the  tissue  as  is  necessary. 

The  most  important  point  is,  however,  the  absence  of  differentiation  at 
a  sufficiently  early  stage,  so  that  from  an  indifferent  type  of  cell  quite  a 
variety  of  mature  cells  may  arise.  An  example  of  this  is  seen  in  the  primi- 
tive amoeboid  mesenchymal  cells,  which  may  develop  into  any  one  of  the 
various  sorts  of  connective  tissue,  or  form  the  endothelium  of  blood-  or 
lymph-vessels;  or,  on  the  other  hand,  remain  amoeboid  and  become  special- 
ized in  the  form  of  the  lymphoid  or  myeloid  cells  of  the  blood,  or  even  the 
red  corpuscles.  Such  a  variety  of  fates  is  not  reached  by  these  cells 
directly,  but  through  a  series  of  subdivisions  and  metamorphoses,  and 
where  once  entered  upon,  the  destiny  of  each  developing  cell  is  fixed.  A  con- 
nective-tissue cell  can  no  longer  give  rise  to  a  red  corpuscle,  nor  the  red 


REPAIR  193 

corpuscle  to  a  connective-tissue  element.  Nevertheless  the  whole  scheme  of 
the  elaboration  of  such  specialized  cells  as  those  of  the  blood,  from  simple 
amoeboid  mesenchymal  cells,  does  not  cease  to  exist  when  the  embryo  has 
grown  into  a  mature  individual,  and  amoeboid  mesenchymal  cells  are  no 
longer  scattered  everywhere  through  the  body.  Instead,  as  we  know  for 
that  particular  tribe  of  cells,  certain  places,  such  as  the  bone-marrow  and 
lymphoid  tissue,  are  set  aside  as  sites  for  the  continued  production  of  the 
elements  of  the  blood  by  exactly  the  same  process,  and  throughout  life 
we  can  find  in  those  places  this  progressive  differentiation  of  the  most 
elaborately  specialized  cells  from  undifferentiated  forerunners.  We  are 
not  informed  as  to  any  particular  site  in  which  such  a  differentiation  of 
the  other  tissues  occurs.  Rather  it  seems  that  they  merely  repair  their 
daily  losses  through  a  local  multiplication  of  the  differentiated  cells. 

While  we  know  that  most  tissues  are  so  specialized  that  they  can  assume 
only  one  form  and  one  function,  and  in  dividing  give  rise  to  no  other  type 
of  cell,  we  recognize  somewhat  different  degrees  in  this  specialization.  We 
cannot  imagine  the  case,  for  example,  in  which,  through  division  and  mul- 
tiplication of  liver-cells,  there  might  be  produced  pancreas  tissue,  although 
these  organs  arise  in  the  beginning  in  much  the  same  way,  but  we  are  quite 
accustomed  to  observe  the  alteration  of  one  type  of  connective  tissue  into 
another.  Here  the  specificity  appears  to  be  less  rigid,  for  while  we  know 
that  ordinarily  white  fibrous  connective  tissue  produces  only  that  type  in 
its  growth,  it  may  be  greatly  altered  in  character  by  metabolic  changes  or 
by  such  mechanical  influences  as  oedema  or  the  prolonged  action  of  a  ten- 
sion in  one  direction.  Mucoid  or  mucin-holding  tissue  apparently  arises 
in  one  way,  while  loose  connective  tissue  may  become  tendon-like  in  the 
other. 

Adipose  tissue  is  specific  in  its  appearance,  and  especially  in  infants  or 
emaciated  persons,  in  which  the  tissue  is  not  entirely  distended  with  oil- 
droplets,  it  can  be  seen  in  the  form  of  lobules  sharply  marked  out  from  the 
surrounding  areolar  tissue  and  supplied  with  a  peculiar  and  abundant 
capillary  circulation.  Whether  all  fat,  even  in  the  most  obese  persons,  is 
lodged  in  this  special  tissue  only  it  is  difficult  to  say  with  certainty. 

It  is  in  the  complicated  changes  which  go  to  the  formation  of  bone  that 
we  see  the  most  varied  interrelations  and  modifications  of  connective-tissue 
structures.  Both  from  cartilage  and  fibrous  tissue,  bone  may  be  formed 
by  the  activities  of  certain  specialized  connective-tissue  cells,  the  osteo- 
blasts.  In  so  far  as  bones  are  formed  in  the  normal  positions,  we  might 
believe  that,  at  an  early  stage,  this  specialization  of  certain  connective- 
tissue  cells  to  the  character  of  osteoblast  formed  the  essential  basis  upon 
which  bone  formation  is  possible,  but  we  are  frequently  confronted  with 
the  formation  of  perfectly  typical  bone  in  places,  such  as  the  wall  of  the 
aorta,  where  no  osteoblasts  could  normally  occur,  but  where  areas  of 
necrotic  tissue  had  become  encrusted  with  lime  salts.  It  is  for  this  reason 
that  we  must  think  that  the  specialization  among  connective-tissue  cells 

14 


194  TEXT-BOOK    OF    PATHOLOGY 

is  not  so  rigid  as  in  more  highly  developed  tissues,  because  it  is  obvious  that 
in  those  cases  some  neighboring  mesoblastic  cells  assume  the  function  and 
form  of  osteoblasts,  and  then  produce  bone  in  the  regular  way. 

Endothelial  cells,  both  of  the  blood-vessels  and  of  the  lymphatic  vessels, 
have  a  rather  high  degree  of  specificity,  marking  them  off  from  other  types 
of  mesoblastic  cells,  and  yet  it  is  precisely  with  regard  to  these  cells  that 
the  most  extraordinary  powers  of  assuming  other  forms  and  functions  have 
been  described.  They  are  known  to  act  as  phagocytes,  in  some  organs, 
and  Mallory  regards  them  as  especially  important  in  giving  rise  to  the 
wandering  phagocytic  cells  found  in  many  infectious  processes.  In  most 
places  they  act  as  a  mere  lining  of  the  channel,  but  in  some  organs,  as  in 
the  spleen,  they  are  greatly  modified  in  form,  and  appear  to  have  more 
complicated  functions.  There,  as  in  the  liver,  they  are  actively  phago- 
cytic, and  it  is  said  that  they  do  separate  themselves  from  the  wall  and 
pass  in  the  blood-stream  into  the  liver.  (This  I  have  never  been  able 
to  observe.)  In  the  bone-marrow,  too,  they  are  concerned  closely  with 
the  formation  of  the  new  cells  of  the  blood,  just  as  they  were  in  the 
early  stages  of  embryonic  life,  when  an  endothelial  cell  arose  from  the 
amoeboid  mesenchymal  cell  merely  because  it  came  to  be  the  border  of 
a  space  which  contained  blood,  or  in  which  blood  was  formed  from  changes 
in  some  of  the  endothelial  cells  themselves.  But  while  all  this  was  true 
in  that  early  embryonic  state  and  may  remain  true  in  the  bone-marrow 
and  other  sites  of  blood  formation,  there  comes  a  period  in  the  develop- 
ment of  the  embryo  at  which,  at  any  rate,  most  of  the  endothelial  cells  are 
specialized  to  their  function  of  lining  blood-  and  lymph-channels.  They 
grow*  as  distinct  sprouting  strands  which  later  become  hollow,  among  the 
other  less  differentiated  cells.  In  later  life  this  specificity  prevails,  at 
least  for  most  of  the  endothelial  cells  which  line  the  vessels  outside  of  those 
special  blood-forming  sites,  and  for  them  function  remains  the  successful 
lining  of  the  vessels.  Even  when  a  thrombus  fills  the  vessel  and  becomes 
replaced  by  fibrous  tissue,  the  endothelial  cells  take  no  part  in  the  formation 
of  that  tissue,  but  confine  their  growth  to  the  production  of  a  new  lining 
membrane  which  will  cover  all  the  surface  of  the  clot  and  extend  into  every 
crevice,  so  that  the  blood  is  kept  from  contact  with  the  fibrin  or  the  new 
fibrous  tissue. 

These  examples  have  been  cited  to  show,  in  a  general  way,  the  importance 
of  the  specificity  of  tissues  and  the  different  degree  to  which  this  holds  good 
in  different  tissues.  More  will  be  said  about  it  in  connection  with  those 
more  highly  specialized  structures  in  which  it  is  held  to  far  more  strictly. 

Metaplasia. — Metaplasia  is  a  term  used  rather  loosely  to  express  the 
conversion  of  one  tissue  into  another,  but  more  accurately  defined  by  Orth 

*MacCallum:  "Relation  of  Lymphatics  to  Connective  Tissue,"  Johns  Hopkins 
Hosp.  Bull.,  1903,  xiv,  142. 


REPAIR  195 

as  the  transformation  of  a  well-characterized  tissue  into  another  equally 
well  characterized,  but  morphologically  and  functionally  different.  For- 
merly such  processes  were  thought  to  be  very  wide-spread,  and  even  Virchow 
did  not  hesitate  to  derive  cancerous  or  epithelial  tumors  from  a  matrix  of 
connective  tissue,  but  now  different  explanations  are  available  for  most  of 
the  puzzling  conditions  in  which  a  tissue  is  found  in  a  position  totally  ab- 
normal for  it,  and  replacing  the  type  which  should  occupy  that  place. 

Metaplasia  is  not  meant  to  include  the  morphological  changes  produced 
by  mechanical  means,  such  as  the  keratinization  of  the  mucosa  of  a  pro- 
lapsed vagina.  Nor  does  it  include  such  displaced  embryonal  tissues  as 
develop  normally  in  a  wrong  situation,  islands  of  gastric  mucosa  in  the 
oesophagus  or  of  squamous  epithelium  in  the  stomach,  bronchi,  or  gall- 
bladder, nor  those  which  are  mechanically  displaced  in  later  life,  such  as 
traumatic  epidermal  cysts,  bone  formation  from  displaced  periosteum,  etc. 
Another  thing  which  lies  outside  the  boundaries  of  this  term  is  the  growth 
of  one  tissue  in  such  a  way  as  to  push  back  the  normal  and  replace  it. 
This  happens,  for  example,  when  the  skin  about  a  healing  tracheotomy 
wound  grows  through  the  opening  and  extends  so  as  to  line  the  trachea  for 
a  short  way. 

Metaplasia  does  not  include  the  ordinary  processes  of  differentiation 
which  take  place  in  the  development  of  the  embryo,  nor  those  quite  similar 
processes  which  continue  in  certain  sites  in  adult  life,  such  as  the  con- 
tinuous differentiation  of  the  tissue  of  the  bone-marrow  and  the  continuous 
destruction  and  new  formation  of  bone  by  the  action  of  the  osteoblastic 
cells.  It  is  difficult,  therefore,  to  say  just  where  the  term  will  apply,  for  it 
is  difficult  to  show  that  any  well-characterized  tissue  is  produced  from  an- 
other well-characterized  tissue  which  is  already  differentiated.  The  ten- 
dency is  rather  to  assume  that  when  such  a  transformation  does  occur,  it 
is  through  the  mediation  of  cells  which,  like  the  bone-marrow  in  other 
cells,  are  not  completely  differentiated. 

Such  examples  as  we  have  to  illustrate  true  metaplasia  lead  one  to  this 
opinion,  and  they  are  very  limited  in  number  and  practically  confined  to 
epithelial  and  connective  tissues. 

Epithelial  Metaplasia. — Under  pathological  conditions,  such  as  the  forma- 
tion of  an  ulcer  with  subsequent  healing,  one  may  find  that  typical  squa- 
mous epithelium  appears  to  cover  the  gap,  although  the  ulcer  may  be 
formed  in  a  dilated  bronchus  or  a  gall-bladder,  or  even  in  the  intestine. 
So,  too,  in  eversion  of  the  mucosa  of  the  bladder  in  the  so-called  ectopia 
vesicse,  the  mucosa  is  altered,  sometimes  to  epidermal  tissue,  sometimes 
to  a  high  cylindrical  form. 

Connective-tissue  Metaplasia. — Among  mesoblastic  tissues  there  are  so 
many  examples  of  the  persistence  of  groups  of  cells  undergoing  continuous 
differentiation  that  the  appearance  of  the  results  of  such  differentiation  in 
unusual  places  need  cause  little  surprise.  If  we  ligate  the  arteries  of  the 


196  TEXT-BOOK   OF    PATHOLOGY 

kidney  in  a  rabbit,  the  organ  becomes  necrotic  and  quickly  calcified,  after 
which  true  bone  may  develop  about  the  edges  of  the  mass.  In  precisely 
the  same  way  the  presence  of  necrotic  material  which  becomes  calcined 
may  be  observed  in  the  sclerotic  walls  of  the  blood-vessels,  in  degenerated 
tumors,  especially  such  as  occur  in  the  thyroid  and  in  the  uterus,  in  old 
caseous  tubercles  in  the  lung,  in  old  adhesions  in  the  pericardium  or  pleura, 
and  in  many  other  places.  Apparently  we  must  assume  that  undifferen- 
tiated  connective-tissue  cells  exist  near  by  which  become  specialized  in  their 
differentiation  as  osteoblasts,  for  these  calcified  necrotic  areas  become  the 
basis  upon  which  true  bone  is  formed.  In  exactly  the  same  way  new  sites 
of  progressive  differentiation  are  established  in  cavities  left  in  such  bone, 
in  the  form  of  a  definite  bone-marrow  producing  myelocytes,  erythroblasts, 
and  all  the  other  characteristic  cells.  Is  this  to  be  defined  as  metaplasia? 
Certainly  one  tissue  has  been  replaced  by  another,  but  hardly  by  a  direct 
transformation.  At  most,  connective-tissue  cells  serving  some  function 
unknown  are  transformed  into  osteoblasts.  Doubtless  the  same  thing 
occurs  in  the  larynx  or  bronchi  or  in  the  costal  cartilages,  when  in  time 
they  become  ossified.  Whether  the  bony  metaplasia  is  of  this  sort  in-the 
case  of  tendons  and  muscles  in  the  so-called  myositis  ossificans  is  uncertain. 

REGENERATION 

Regeneration  of  lost  parts  occurs  with  great  readiness  in  the  lower  and 
simpler  animals,  and  it  is  well  known  that  their  life  can  continue  after  the 
most  profound  mutilations  by  the  simple  expedient  of  forming  anew  what- 
ever is  found  to  be  lacking.  Details  of  the  extraordinary  experimental 
studies  of  these  phenomena  may  be  read  in  the  books  of  T.  H.  Morgan, 
J.  Loeb,  and  many  others.  As  has  been  stated,  something  of  this  power 
of  regeneration  prevails  in  the  embryo  of  higher  animals  and  man  up  to  a 
certain  stage  of  its  development.  It  may  be  expressed  once  more  by  say- 
ing that  the  fertilized  ovum  and  the  first  segmentation  spheres  are  toti- 
potent.  The  cells  produced  in  the  course  of  later  segmentations  are  multi- 
potent,  but  the  cells  of  the  differentiated  tissue  are  highly  specialized,  as  a 
rule,  and  potent  to  produce  others  of  the  same  type  only.  Quantitatively 
also  the  power  of  regeneration  diminishes  with  the  advance  of  develop- 
ment and  cell  specificity,  but  even  in  the  mature  human  individual  the 
latent  power  of  these  specialized  cells  for  regeneration  is  often  astonishing. 
While  we  recognize  this  decrease  in  the  versatility  of  the  cell  in  so  far  as  its 
offspring  are  concerned,  we  must  also  recognize  a  very  great  difference 
among  the  mature  tissues  in  their  power  to  regenerate  themselves,  for 
although  such  slightly  specialized  tissue  elements  as  those  of  the  ordinary 
connective  tissue,  the  periosteum,  the  epidermis,  etc.,  regenerate  very 
rapidly  and  extensively,  those  which  are  more  highly  specialized,  such  as 
the  central  nervous  system,  heart  muscle,  and  striated  muscle  in  general, 
regenerate  themselves  hardly  at  all,  and  any  gap  made  in  their  substance 


REGENERATION  197 

must  be  filled  by  some  inferior  tissue  which  can  grow  fast  and  restore  the 
continuity  quickly.  It  need  hardly  be  said  that  the  tissue  most  commonly 
employed  is  the  ordinary  fibrous  tissue.  Over  and  over  again  we  find  this 
principle  exemplified.  In  the  heart  there  may  be  energy  enough  to  form 
new  muscle  tissue  in  time,  but  when  an  area  is  destroyed,  it  is  healed  by 
fibrous  tissue  and  not  by  muscle.  In  the  liver,  although  the  liver-cells  can 
divide  fast  enough,  the  same  thing  prevails,  and  each  gap  left  by  their 
destruction  is  stopped  up  with  fibrous  tissue. 

Thus,  owing  to  the  different  powers  of  regeneration  shown  by  various 
tissues,  local  repair  is  carried  out  sometimes  by  the  injured  organ  substance 
itself,  but  more  often  by  an  inferior  material,  such  as  connective  tissue. 
But  even  though  such  patching  may  occur  there  is,  with  few  exceptions, 
some  attempt  made  there  or  elsewhere  to  restore  the  original  specialized 


Fig.  73. — Growth  of  epithelium  over  a  granulating  surface.     Irregular  downgrowtns 
of  epithelium  are  an  index  of  the  delay  in  the  healing. 

tissue  unless  it  has  been  destroyed  to  the  last  cell.  Before  discussing  this 
process  of  local  repair  we  may  pass  in  review  the  phenomena  which  appear 
in  the  case  of  each  type  of  tissue. 

Epithelium. — All  sorts  of  epithelium  possess  a  quite  remarkable  ability 
to  grow  again  and  make  up  for  that  which  was  lost.  As  is  so  well  known  to 
every  one,  the  surface  epidermis  will  quickly  grow  out  to  cover  again  any 
abrasion  or  to  heal  over  the  granulating  surface  of  an  open  wound  (Fig.  73). 
This  is  so  clearly  visible  in  the  case  of  a  healing  ulcer  where  the  thin,  pearly 
blue  edges  of  the  epidermis  advance  slowly  from  the  margin  toward  the 
centre  until  the  whole  area  is  covered,  that  it  seems  strange  that  there  could 
ever  have  been  doubt  as  to  the  source  of  the  epithelium.  Yet  for  a  long 
time  it  was  questioned  whether  the  epithelium  might  not  be  produced  by 
the  granulation  tissue.  More  careful  studies  have  shown,  though,  that  the 
regeneration  is  strictly  specific,  and  that  all  new  epidermal  cells  are  pro- 


198  TEXT-BOOK    OF    PATHOLOGY 

duced  through  division  of  those  still  alive  about  the  margin  of  the  wound. 
Apparently  many  of  them  move  and  stretch  out  to  spread  themselves  over 
the  uncovered  area  before  any  division  occurs,  because  the  karyokinetic 
figures  are  found  a  short  distance  back  of  the  edge,  and  especially  in  the 
lower  layers  of  cells.  These  less  specialized  cells  seem  to  take'  a  greater 
part  in  the  new  formation  than  those  which  have  progressed  some  way 
toward  the  keratiniz'ation,  and  have,  therefore,  lost  to  some  extent  or 
completely  their  power  of  division.  Groups  or  masses  of  new  cells  are  thus 
formed  and  furnish  the  material  for  the  further  spreading  of  the  whole 
layer,  but  if,  as  is  so  often  the  case,  that  spreading  is  constantly  prevented, 
they  accumulate  and  extend  downward  in  rapidly  thickening  and  very 
irregular  interpapillary  growths  (Fig.  73) .  It  is  generally  stated  that  direct 
or  amitotic  division  plays  a  great  part  in  this  new  formation  of  epithelium, 
but  this  statement  receives  very  little  support  from  the  direct  observation 
of  growing  epithelium  in  vitro. 

Since  such  a  conclusion  is  dependent  upon  finding  distorted  or  constricted  nuclei, 
or  up'on  the  failure  to  find  mitotic  figures,  it  seems  hardly  convincing.  No  one  can  fail 
to  accept  the  evidence  concerning  the  growth  by  mitosis,  but  there  seem  to  be  very  few 
instances  in  which  the  appearance  of  a  cell  with  its  nucleus  constricted  in  'the  middle, 
and  a  corresponding  constriction  of  the  protoplasm,  must  be  accepted  as  showing  that 
two  new  cells  of  normal  capacities  are  thus  being  formed.  The  appearance  may  so 
readily  be  due  to  pathological  conditions,  and  the  chance  of  abnormalities  in  the  amount 
and  arrangement  of  chromatin  in  the  new  cells  is  so  great,  that  I  hesitate  to  accept  the 
process  of  amitotic  division  as  a  normal  method  of  reproduction  and  growth  in  the  organs 
of  the  higher  animals.  Of  course,  we  have  abundant  observations  of  this  sort  of  division 
hi  simpler  forms,  and  one  may  not  deny  its  existence  or  its  importance,  but  at  least  it 
seems  clear  that  such  a  process  should  be  more  closely  investigated  rather  than  so  un- 
questioningly  accepted.  If  there  is  any  truth  in  the  theory  of  Hansemann  that  tumor 
growth  may  be  imitated  by  the  unequal  or  irregular  separation  of  chromosomes  in 
dividing  cells,  then  amitotic  division,  where  the  separation  of  chromatin  material  into 
two  nuclei  is  guided  by  no  such  precise  mechanical  process  as  in  mitosis,  may  well  be  the 
source  of  such  inequality. 

The  regeneration  of  surface  epidermis  produces  a  smooth  layer  of  cells 
without  any  reformation  of  such  specialized  epidermal  structures  as  sweat- 
and  sebaceous  glands  and  hairs.  Yet,  as  Minervini  points  out,  the  inter- 
papillary  downgrowths  and  the  fine  markings  of  the  palm  are  formed  again 
after  years.  Of  course,  if  the  abrasion  be  so  superficial  that  these  glands 
and  hair-follicles  are  not  completely  destroyed,  they  may  regenerate  them- 
selves from  the  remnants,  and  may  also  produce  the  less  specialized  sur- 
face epithelium. 

The  epithelium  of  the  mucous  surfaces  behaves  in  exactly  the  same  way, 
growing  out  from  the  edges  to  cover,  with  a  smooth  layer,  the  denuded  area. 
Glands  are  regenerated  from  the  epithelium  which  remains  in  their  depths 
if  they  have  not  been  completely  destroyed.  This  is  the  common  result 
in  superficial  ulcerations  of  the  intestinal  tract,  and  indeed  one  receives 


REGENERATION 


199 


the  impression  that,  even  though  the  whole  rnucosa  be  destroyed  over  a 
small  area  of  the  intestine,  as  in  the  deep  typhoid  ulcers,  it  may  be  restored 
to  a  semblance  of  the  original  much  more  rapidly  than  in  the  case  of  the 
skin.  After  all,  the  production  of  crypts  or  villi  is  a  rather  simpler  matter 
than  the  new  formation  of  sweat-  and  sebaceous  glands  and  hair-follicles 
from  the  epidermis. 

In  the  epithelial  organs  new  specialized  and  perfect  gland  tissue  is  pro- 
duced essentially  by  subdivision  and  multiplication  of  the  remaining  spe- 


Fig.  74. — Formation  of  new  liver-cells  at  the  ends  of  sprouting  bile-ducts  in  cirrhosis  of 

the  liver. 


cialized  cells.  It  is  true  that  an  elaborate  effort  toward  their  regeneration 
is  made  by  the  less  highly  specialized  cells  which  constitute  the  lining  of  the 
ducts.  From  the  very  fact  that  they  are  less  highly  specialized,  and  there- 
fore more  resistant,  these  cells  survive  in  places  where  all  the  gland  epi- 
thelium is  destroyed,  and  remain  alone  in  that  area  as  a  possible  source  for 
new  gland  tissue.  They  multiply,  and  the  ducts  bud  out  and  ramify  in  all 
directions,  but  generally  end  in  forming  new  connections  with  the  gland 
tissue  which  remained  alive  after  the  injury,  and  whose  duct  connections 
may  have  been  disarranged.  Occasionally  one  may  find,  in  a  cirrhotic 


200  TEXT-BOOK   OF   PATHOLOGY 

liver,  a  definite  formation  of  new  specialized  liver-cells  at  the  end  of  a 
growing  bile-duct  (Fig.  74) .  The  cells  are  seen  to  be  fresh  young  liver-cells 
from  their  characteristic  staining  and  their  lack  of  pigment,  but  such 
things  are  rare  and  can  play  no  very  important  part  in  the  restitution  of 
the  functional  liver  tissue  as  compared  with  the  profuse  multiplication  of 
the  already  differentiated  liver-cells  which  remain  in  the  fragments  of  the 
liver  lobules  which  have  not'  been  destroyed. 

In  the  kidney,  in  the  same  way,  the  increase  in  the  specialized  secreting 
cells  comes  from  the  multiplication  of  survivors  which  have  reached  that 
stage  of  differentiation,  and  not  from  the  cells  lining  the  conducting  tubules. 
If  all  the  cells  of  a  convoluted  tubule  are  destroyed,  that  tubule  collapses 
and  compensation  occurs  through  the  enlargement  of  another  tubule.  It 
is  by  no  means  denied  that  differentiation  of  less  specialized  tissue  occurs 
in  the  course  of  regeneration  in  adult  life,  but  it  seems  that  the  repair  of 
highly  specialized  tissue  is  more  readily  and  more  commonly  assumed  by  the 
remnants  of  tissue  which  has  already  reached  that  stage  of  differentiation. 

Connective  Tissues. — These  tissues  are  preeminently  capable  of  regen- 
erating themselves  rapidly  and  in  profusion,  so  that  they  form  the  bulk  of 
the  new  material  used  for  local  repair.  In  nearly  all  their  modifications 
they  are  resistant  to  injuries,  and  will  survive  and  grow  readily  after  treat- 
ment which  would  kill  more  delicate  tissues  in  a  short  time. 

The  character  of  their  specificity  has  been  discussed  already,  and  it  has 
been  shown  that,  although  in  places  undifferentiated  cells  persist  and  fur- 
nish the  specific  differentiated  cells  of  the  blood  throughout  life,  most  of  the 
connective  tissues  of  the  body  are  differentiated,  and  in  their  multiplication 
reproduce  the  same  type  of  cell.  Nevertheless,  the  assumption  of  osteo- 
blastic  functions  by  connective-tissue  cells  quite  away  from  the  original 
osteoblasts  is  sometimes  seen,  and  certain  other  lapses  from  strict  specificity 
may  be  observed. 

Ordinarily,  white  fibrous  or  areolar  tissue  produces,  by  the  division  of  its 
cells,  other  cells  of  exactly  the  same  character.  The  elongated  cell,  poor 
in  protoplasm  but  with  prolongations  in  all  directions  among  the  dense 
fibres  in  which  it  lies  embedded,  swells  before  division  and  retracts  some  of 
its  processes.  It  becomes  somewhat  rounded  and  denser  than  the  adjacent 
cells,  and  by  division  gives  rise  to  two  young  cells  which  are  temporarily 
rounded,  but  quickly  put  forth  pseudopods  and  acquire  an  elongated  form. 
A  great  variety  of  forms  may  be  found,  but  the  vesicular  nucleus  and  the 
elongated  form  generally  suffice  to  distinguish  these  cells  from  the  more 
rounded  mononuclear  wandering  cells. 

Occasionally,  when  newly  formed  connective  tissue  arises  to  constitute 
the  lining  of  a  cavity  in  the  body  or  to  form  a  bursa,  the  superficial  cells 
which  form  the  actual  lining  become  flattened  and  assume  the  appearance 
of  endothelium.  This  is  exemplified  in  Fig.  75,  which  is  from  the  granu- 
lation tissue  lining  an  infected  space  left  after  an  operation,  among  the 


REGENERATION 


201 


muscles  of  a  dog's  neck.  The  cavity  was  filled  with  turbid  fluid  full  of 
leucocytes.  The  new  tissue  is  of  the  ordinary  type,  with  distinct  project- 
ing granulations,  but  everywhere  covering  this  nodular  surface,  and  ex- 
tending down  into  the  crevices  between  them,  there  is  a  layer  of  cells 
resembling  endothelium,  although  much  stouter.  These  cells  are  often  in 
two  layers  for  a  small  space,  and  pass  over  by  insensible  gradations  into 
the  fibroblasts  underneath.  Evidently  this  is  a  mild  kind  of  metaplasia 
analogous  to  that  which  occurs  in  the  first  formation  of  endothelium,  but 
it  is  not  to  be  believed  that  these  cells  ever  play  the  part  of  real  endothelial 
cells  or  are  to  be  identified  with  them. 

TT 


Fig.  75.— Granulation  tissue  lining  a  cavity  showing  endothelium-like  flattening  of  the 

innermost  cells. 

While  at  first  these  new  cells  lie  loosely  about  so  that  the  spaces  between 
them  accommodate  fluid  and  wandering  cells,  they  later  produce  in  the 
marginal  parts  of  their  cytoplasm  the  fibrils  which  stain  differently  from 
the  general  protoplasm,  and  which,  increasing  in  number  and  in  thickness, 
become  arranged  in  roughly  parallel  form,  so  as  to  produce  a  dense  fabric 
in  which  the  cells  themselves  finally  become  rather  inconspicuous.  This 


202  TEXT-BOOK   OF   PATHOLOGY 

process,  so  carefully  studied  by  Minervini,  Maximow,  and  many  others, 
constitutes  the  formation  of  scar  tissue.  The  early  stages  are  seen,  how- 
ever, to  especial  advantage  in  cultures  of  connective  tissue  in  which  the 
fibroblasts  are  seen  to  grow  out  separately  from  the  margin,  showing  in  the 
most  beautiful  way  their  long,  sheet-like  processes,  and  dividing  actively 
by  mitosis  beneath  the  observing  eye  (Fig.  67). 

Elastic  Tissue. — The  regeneration  of  elastic  fibers  is  to  be  observed  after 
the  lapse  of  time  in  newly  formed  connective  tissue,  but  perhaps  especially 
in  those  places,  as  in  the  lung  or  in  the  vessel  wall,  where  those  fibers  play 
a  particularly  important  part.  There  has  been  much  discussion  of  the 
possibility  that  they  may  arise  in  the  intercellular  substance,  but  the  work 
of  Jores,  Nakai,  and  others  seems  to  show  clearly  that  they  are  formed  by 
differentiation  of  the  protoplasmic  processes  of  the  cells.  Though  chemi- 
cally and  physically  different,  they  are  produced  in  much  the  same  way 
as  the  collagenous  fibres,  and  there  is  no  way  of  distinguishing  the  mother- 
cells  from  each  other.  Nevertheless,  although  Jores  thinks  the  collagenous 
and  elastic-forming  cells  the  same,  it  seems  probable  that,  with  finer  meth- 
ods, we  may  be  able  to  show  that  they  are  differentiated  from  each  other 
before  they  proceed  to  form  their  different  fibres.  Apparently  the  new 
fibres  do  not  grow  in  connection  with  the  old  ones,  but  increase  in  size  by 
accretion.  Sometimes,  however,  as  in  the  walls  of  blood-vessels,  we  may 
see  very  plainly  that  a  new  distribution  of  the  lamellae  or  fibres  is  brought 
about  by  the  splitting  and  separation  of  the  old  ones. 

Fat  Tissue. — There  is  much  evidence  that  the  adipose  tissue  of  the  body  is 
specialized  at  an  early  stage,  and  remains  distinct  from  other  forms  of 
connective  tissue.  In  the  infant  it  is  segregated  in  lobular  masses  in 
which,  in  the  beginning,  the  large,  round,  isolated  cells  which  are  to  become 
fat-cells  have  a  deeply  stained  granular  protoplasm,  which  later  becomes 
filled  with  globules  of  fat  until  it  is  stretched  out  into  a  thin  film  and  its 
nucleus  pressed  to  one  side.  In  wasting  disease  the  fat  may  disappear 
from  the  cell  and  be  replaced  by  fluid.  In  a  sense  regeneration  occurs 
through  the  refilling  of  these  cells  with  fat,  but  if  the  tissue  is  destroyed, 
it  must  probably  be  regenerated  by  the  methods  used  in  its  first  formation. 
In  the  neighborhood  of  old  inflamed  areas  one  may  often  distinguish, 
within  the  outline  of  an  empty  fat-cell,  many  polygonal  or  rounded  cells 
with  finely  vacuolated  protoplasm.  These  Marchand  regards  as  evidences 
of  regeneration  or  new  formation  of  several  fat-cells  in  place  of  one.  Others 
(Maximow)  have,  however,  thought  of  these  cells  as  invading  phagocytes 
which  have  taken  up  some  remaining  globules  of  fat. 

Cartilage  and  Bone. — Defects  in  cartilage  are  in  part  healed  by  the  forma- 
tion of  fibrous  tissue  scars,  but  regeneration  of  actual  cartilage  also  takes 
place.  According  to  Marchand,  this  is  brought  about  chiefly  by  the 
activity  of  the  perichondrium,  which  produces  a  callus-like  growth  of  new 
tissue  which  gradually  assumes  the  characters  of  cartilage.  Borst  and 


REGENERATION 


203 


certain  Italian  writers  maintain,  however,  that  the  cartilage  itself  takes 
part  in  this  new  formation,  a  method  which  certainly  prevails  in  such  ani- 
mals as  the  salamander;  and  that  the  defect  is  filled  largely  by  the  active 
division  of  its  cells. 

Bone  is  regenerated  by  methods  identical  with  those  concerned  in  its 
first  formation.  On  account  of  its  easily  recognizable  arrangement,  it  can 
be  seen  building-up  is  in  progress  throughout  life.  By  means  of  osteoblasts 
the  well-preserved  Haversian  systems  are  irregularly  eroded,  and  new  Ha- 
versian  systems  fitted  into  the  gaps  thus  left  through  the  activity  of  the 
osteoblasts.  The  cells  concerned  in  the  regeneration  and  new  formation 
of  bone  are  always  the  osteoblasts,  or  at  least  cells  which  have  assumed 


Fig.  76. — Early  stage  in  the  healing  of  fractured  bone,  showing  periosteal  new-bone  forma- 
tion, together  with  fibrous  and  cartilaginous  growth. 


the  function  of  osteoblasts.  Therefore  bone  can  be  formed  by  the  osteo- 
genetic  layer  of  the  periosteum  and  by  the  endosteum,  but  probably  not 
by  the  bone-corpuscles,  which  are  buried  in  the  rigid  bone.  If  all  the  cortex 
of  a  bone  be  removed  and  the  periosteum  left  intact,  a  new  bone  may  be 
formed  by  the  activities  of  that  membrane — it  can  even  be  transplanted 
into  some  distant  region  of  the  body,  where  it  will  begin  once  more  to  pro- 
duce bone,  provided  always  that  the  nutrition  be  maintained  and  that 
the  actual  osteogenetic  layer  be  not  destroyed.  Membranous  bone  is 
formed  anew  in  the  same  way  by  the  production  of  a  mass  or  sheet  of  spindle- 
cells,  some  of  which  assume  the  characters  of  bone-corpuscles  and  give  up 
part  of  their  cell-body  to  the  fibrillar  substance,  which  first  becomes  hya- 
line and  then  calcified. 


204  TEXT-BOOK   OF   PATHOLOGY 

In  fractures  the  broken  ends  of  the  bone  are  at  first  surrounded  by  a 
haemorrhage,  but  after  the  escape  of  blood  from  the  bone-marrow  is  stopped 
by  clotting,  regeneration  and  healing  begin  through  the  proliferation  of 
new  tissue  from  the  periosteum  and  endosteum.  These  produce  a  callus 
which  flows  in  between  the  separated  ends  of  the  bone  as  the  intermediary 
callus.  It  consists  at  first  of  cartilage  and  osteoid  tissue,  that  is,  tissue  with 
homogeneous  ground  substance  inclosing  the  newly  formed  cells,  and  hav- 
ing the  form  of  bone  without  being  calcified.  The  osteoid  tissue  may  be 
laid  down  as  a  solid  layer  on  the  surface  of  the  old  bone,  or,  through  the 
guiding  action  of  blood-vessels,  assume  a  spongy  form.  Solid  new  formed 
tissue  of  this  kind  may  be  transformed  later  into  spongy  bone  by  the  in- 
vasion of  blood-vessels,  and  that  in  turn  become  compact  by  later  growth. 
The  cartilage  which  is  formed  by  the  activity  of  the  periosteum  is  similarly 
invaded  by  osteoblast-carrying  blood-vessels  and  converted  into  osteoid 
tissue,  and  finally  into  bone,  exactly  as  in  the  intracartilaginous  bone  forma- 
tion of  the  embryo.  Great  defects  in  the  bone  produced  artificially  or  by 
disease  may  thus  be  made  good,  although  for  a  time  the  new  bone  thus 
formed  is  very  abnormal  in  its  arrangement.  Later  modifications  tend  to 
reduce  it  with  wonderful  accuracy  to  the  form  best  adapted  to  meet  the 
strain  put  upon  it. 

Smooth  Muscle. — Experimental  and  other  study  of  the  healing  of  defects 
in  smooth  muscle  seems  to  show  little  activity  in  this  regard — sometimes 
mitotic  division  has  been  described,  sometimes  a  new  formation  by  amitotic 
division,  but  more  recent  studies  tend  to  the  idea  that  there  is  in  higher 
vertebrates  very  little  regeneration  of  the  muscle  itself,  but  that  healing 
brought  about  by  scar  tissue  brings  together  the  muscle  edges  at  the  site 
of  the  defect. 

Striated  Muscle. — Two  distinct  methods  of  regeneration  occur,  as  pointed 
out  by  Volkmann,  Schminke,  and  others.  In  one,  new  separate  cells  are 
formed  from  the  remains  of  the  fibre  by  collection  of  the  protoplasm  about 
its  nuclei  within  the  sarcolemma  (sarcoblasts).  These  develop,  just  as  the 
embryonic  muscle-fibres  do,  by  the  gradual  appearance  of  striated  fibrils 
in  the  elongating  cell.  In  the  second  method  a  bulbous  end  is  formed  in 
continuity  with  the  remains  of  the  muscle-fibre  with  a  great  number  of 
nuclei,  and  the  elongation  and  differentiation  of  this  protoplasmic  mass  give 
rise  not  to  new  fibres,  but  to  increase  in  the  mass  of  the  muscle  substance. 
Many  authors  have  ascribed  all  of  this  to  amitotic  division  of  the  nuclei, 
but  many  mitoses  have  been  observed,  and  doubtless  play  the  usual  im- 
portant part  in  the  reproduction  of  this  as  in  other  tissues. 

Heart  muscle  has  been  thought  to  regenerate  itself  little,  if  at  all,  any  loss 
of  substance  being  made  good  by  a  patch  of  scar  tissue.  Indeed,  this  seems 
to  be  generally  the  case,  although  Heller  has  recently  described  clear  evi- 
dences of  regenerative  activity  in  the  heart-muscle  fibres,  and  we  have  seen 
one  case  in  which  a  condition  resembling  closely  the  formation  of  the  bul- 


REGENERATION  205 

bous  ends  in  the  skeletal  muscles  appeared.  The  fibers  could  be  traced  in 
the  scarred  areas  into  deeply  stained  swollen  masses  of  protoplasm,  with 
numerous  nuclei  which  seem  to  represent  growing  ends. 

Blood-  and  Lymph-vessels. — In  the  early  stages  of  embryonic  growth 
blood-channels  seem  to  be  formed  anywhere  in  the  mesenchyme  by  the 
mere  separation  of  the  cells,  with  later  alteration  of  the  innermost  cells 
adjoining  the  cavity  thus  formed  into  definite  flattened  lining  or  endothelial 
cells,  which  in  turn  may  produce  any  of  the  elements  of  the  blood.  Chan- 
nels formed  in  this  way  are  capable  of  obliteration  by  collapse  and  the  ad- 
hesion of  their  walls,  while  other  new  channels  are  being  formed.  Thus 
it  happens  that  in  a  network  of  such  spaces  there  is  finally  emphasized  one 
passage  which,  after  the  collapse  of  the  rest,  survives  because  it  is  best 
adapted  to  carry  the  blood  according  to  the  existing  needs  and  pressure  rela- 
tions. Thus  in  early  life  the  whole  process  is  very  labile,  and  the  relation 
to  the  connective  tissue  extremely  intimate.  It  is  maintained  by  some  that 
lymphatic  channels  are  formed  in  the  same  way,  becoming  secondarily 
connected  with  the  blood-vessels,  but  Sabin  has  shown  that  their  genesis 
may  be  traced  to  an  actual  sprouting  from  certain  points  in  the  well-formed 
vessel-wall,  of  blind-ending  canals  which  finally  ramify  in  all  directions  in 
the  tissue  and  constitute  the  lymphatic  system.  At  any  rate,  there  comes 
a  period,  somewhat  later  in  embryonic  life,  at  which  the  promiscuous  for- 
mation of  blood-vessels  or  lymphatics  from  spaces  in  the  mesenchyme 
seems  to  be  restricted,  and  thenceforth  the  endothelial  cells  become  per- 
manently specialized  to  carry  out  that  function  only  and  to  give  rise,  by 
their  division,  to  all  subsequent  endothelial  cells.  After  this  epoch  new 
vessels  are  formed  only  by  the  formation  of  an  endothelial  bud  from  the 
wall  of  a  vessel,  which  may  grow  out  as  a  mobile  strand  of  endothelial  cells 
moving  through  the  tissue  until  it  meets  another  such  strand.  Exactly 
the  same  process  is  carried  through  in  the  case  of  the  lymphatic  channels, 
which  are  quite  as  completely  walled  off  from  the  connective  tissue  by  endo- 
thelial cells  as  are  the  blood-vessels.*  When  such  strands  of  endothelial 
cells,  which  at  first  may  be  no  more  than  whiplash-like  protoplasmic  fila- 
ments, become  united  with  others  so  as  to  form  a  bridge  and  become  thick- 
ened into  a  double  row  of  cells  by  mitotic  division,  there  gradually  appears 
a  cleft  in  the  middle  through  which  blood-corpuscles  are  forced.  There 
has  been  much  discussion  as  to  the  part  played  by  connective-tissue  cells 
in  this  process,  but  the  evidence  seems  to  be  overwhelming  in  favor  of  the 
idea  that  when  connective-tissue  cells  take  any  part  they  act  merely  as 
supporting  cells,  applying  themselves  to  the  outside  of  the  new  tube,  of 
which  the  essential  lining  layer  is  composed  of  endothelial  cells  alone 
(Marchand).  Coffin  has  traced  carefully  the  formation  of  lymphatic 
vessels  in  newly  forming  granulation  tissue,  and  has  found  that  they  appear 
in  precisely  the  same  way  as  the  new  blood-vessels. 

*MacCallum:     "Relations  Between  Lymphatics  and  Connective  Tissue,"  Johns 
Hopkins  Hosp.  Bull.,  1903,  xiv,  142. 


206  TEXT-BOOK   OF   PATHOLOGY 

Bone-marrow,  Lymph-glands,  and  Blood. — Bone-marrow  regenerates 
itself  rapidly  after  destruction  through  injury,  disease,  or  poisoning,  by  the 
formation  of  a  new  connective  tissue  rich  in  vessels,  in  which  there  appear 
later  fat-cells  and  the  specific  blood-forming  cells.  As  to  the  source  of 
these,  some  authors  (Haasler,  Enderlen,  Marchand)  have  held  to  the  idea 
that  they  are  derived  from  the  division  of  those  which  remained  behind  or 
are  brought  to  the  marrow  cavity  by  the  blood-stream  or  by  wandering 
through  the  tissues.  Others  (Maximow,  Weidenreich)  regard  them  as 
derivatives  of  the  young,  undifferentiated  connective  tissue  formed  upon 
the  invasion  of  blood-vessels  with  their  periosteal  cells  into  the  cartilage. 
This  seems  well  enough  established  in  the  case  of  embryonic  marrow  forma- 
tion, but  is  more  difficult  to  accept  in  the  regeneration  of  marrow  in  the 
adult,  although  it  is  perhaps  supported  by  the  observation  of  the  new  for- 
mation of  marrow  in  bone  produced  in  such  organs  as  the  lung  or  aorta. 
Lymph-glands  and  nodules  of  lymphoid  tissue  reappear,  without  doubt, 
in  areas  where  they  have  been  destroyed,  but  the  mode  of  their  regenera- 
tion is  not  very  clearly  understood.  In  the  case  of  an  autopsy  assistant 
who  had  suffered  repeated  infections  of  the  hands,  after  which  infected 
lymph-nodes  had  been  dissected  from  the  axilla,  new  nodes  appeared  under 
the  skin  about  the  shoulder  as  well  as  in  the  axilla.  Similarly,  in  the 
intestine,  after  destruction  of  Peyer's  patches  and  solitary  nodules,  through 
ulceration  in  the  course  of  typhoid  fever,  repair  and  new  formation  of  these 
structures  are  in  time  very  complete.  Undoubtedly,  as  Ribbert  points 
out,  there  are  many  scattered  lymph-follicles  in  the  tissues  which  become 
evident  only  when  they  are  caused  to  swell  by  some  inflammatory  reaction, 
and  it  is  possible  that  these,  through  their  enlargement,  compensate  for  the 
loss  of  the  original  lymph-nodes  in  places  where  the  latter  have  been  de- 
stroyed or  removed.  In  the  spleen,  when  the  amyloid  has  occupied  the 
whole  of  each  Malpighian  body,  one  may  sometimes  see,  as  in  Fig.  42,  the 
counterpart  of  this  in  the  new  formation  of  lymphoid  nodules  all  through 
the  splenic  pulp.  Bayer  and  others  state  that  complete  lymph-nodes  may 
be  newly  developed  in  fat  tissue,  but  it  seems  probable  that  this  occurs 
rather  in  connection  with  preexistent  lymph-channels  than  with  relation 
to  the  fat  tissue  itself. 

The  Blood. — Constant  new  formation  of  these  cells  occurs  on  account  of 
their  brief  tenure  of  life  in  the  circulating  blood.  Lymphocytes  are  un- 
doubtedly produced  in  great  quantities  in  the  lymph-nodes,  wherever  they 
may  be,  and  are  turned  into  the  blood  either  by  way  of  the  lymphatic 
channels  or  more  directly  into  the  veins.  Bone-marrow,  spleen,  and 
possibly  thymus  also  play  a  part  in  their  production.  When  traced  to 
their  ultimate  source  in  the  undifferentiated  rounded  mesenchymal  cell, 
they  are  seen  to  have  the  same  origin  as  the  granulated  cells  and  the  red 
corpuscles,  although  for  the  granulated  cells  Naegele  and  Schridde  claim  a 
separate  ancestor  in  the  non-granular  myeloblast.  The  granular  mye- 
locyte,  which  is  formed  from  a  preceding  non-granular  cell  (whether  it  be 


REGENERATION  207 

the  specific  myeloblast  or  the  common  ungranulated  ancestor  of  all)  and 
which  gives  rise  to  the  granular  polymorphonuclear  leucocyte,  is  ordinarily 
found  in  greatest  numbers  in  the  bone-marrow,  but  it  may  be  formed  in  the 
spleen,  in  the  lymph-glands,  in  the  liver,  in  the  thymus,  and  in  various  other 
places,  so  that  the  regeneration  of  the  granular  polymorphonuclear  leucocytes, 
eosinophile  as  well  as  neutrophile,  may  take  place  almost  everywhere 
Nevertheless,  the  chief  site  of  this  formation,  and  in  normal  conditions  the 
only  site,  is  the  bone-marrow.  The  forerunner  of  the  red  corpuscle,  a  non- 
granular,  non-haemoglobin-holding  cell,  may  shrink  as  it  acquires  hsemo- 
globin,  and  thus  become  the  normoblast,  which,  on  losing  its  nucleus, 
becomes  the  ordinary  red  corpuscle.  Large  haemoglobin-holding  nucleated 
cells  which  are  possibly  forerunners  of  the  normoblasts  are  the  megalo- 
blasts.  They  are  sometimes  swept  into  the  blood  when  regeneration  is 
active  in  an  extreme  anemia. 

Leucocytosis.—  Infections  of  all  sorts  cause  regeneration  of  the  greatest 
intensity  in  the  blood-forming  tissues,  so  as  to  furnish  to  the  blood  the 
necessary  phagocytes.  Polymorphonuclear  leucocytes  may  be  produced 
there  with  rapidity  in  a  quantity  far  exceeding  that  ever  called  for  in 
ordinary  regeneration  to  make  good  a  loss.  It  is  not  uncommon,  then,  to 
find  the  leucocytes  chiefly  of  this  type,  numbering  50,000  or  60,000  per 
cubic  millimetre,  and  cases  are  described  in  which  this  outrush,  bringing 
with  it  the  myelocytes,  has  so  flooded  the  blood  as  to  produce  the  picture 
of  an  acute  myeloid  leucaemia.  Other  infections,  such  as  typhoid  fever, 
through  exerting  another  kind  of  chemiotactic  action,  attract  to  the  blood 
chiefly  the  mononuclear  cells.  It  is  even  difficult  to  produce  a  polymor- 
phonuclear leucocytosis  in  those  cases.  Similarly  in  tuberculosis,  syphilis, 
and  many  other  infectious  processes,  most  of  which  progress  slowly,  and  in 
malaria  and  other  protozoan  infections,  the  stimulus  produced  by  the  in- 
fective agent  calls  forth  the  production  not  of  polymorphonuclear  leuco- 
cytes, but  of  mononuclear  forms. 

Thus  there  is  a  certain  independence  among  the  cell  types  in  their  re- 
generation. Red  corpuscles  are  produced  in  great  numbers  when  those 
normally  present  have  been  destroyed,  and  generally  there  is  a  consider- 
able coincident  outpouring  of  leucocytes,  but  this  too  is  dependent  upon 
the  nature  of  the  destructive  agent  and  not  merely  upon  the  fact  that  re- 
generative activity  is  going  on  in  the  bone-marrow. 

When  blood  is  suddenly  removed,  as  by  an  extensive  haemorrhage,  regen- 
eration begins  in  the  bone-marrow  (often  very  slowly  after  an  extreme 
haemorrhage),  and  the  red-corpuscle  content  of  the  circulating  blood  is 
gradually  restored  to  normal.  Naturally,  immediately  after  the  haemor- 
rhage the  number  of  red  corpuscles  in  the  circulating  blood  per  cubic  milli- 
metre is  unchanged;  then  there  comes  quickly  an  absorption  of  fluid  from 
the  tissues  and  from  the  digestive  tract  to  make  up  the  necessary  volume  of 
blood,  and  with  this  dilution  the  red  corpuscle  content  per  cubic  millimetre 
rapidly  sinks.  It  is  not  until  after  the  third  or  fourth  day  that  the  regen- 


208  TEXT-BOOK   OF   PATHOLOGY 

erative  process  begins  to  overtake  this  diluting  process,  so  that  from  that 
time  on  the  red-corpuscle  content  steadily  rises.  It  may  be  observed  that 
this  new  formation  proceeds  rather  spasmodically,  as  indicated  by  the 
periodic  " crises"  of  normoblasts  which  are  swept  out  into  the  circulation. 
In  the  bone-marrow  during  this  process  evidences  of  most  active  growth  of 
these  cells  can  be  found,  and  although  they  are  present  in  such  great  num- 
bers, it  can  often  be  seen  that  they  are  arranged  roughly  in  groups  or  islands 
among  the  granular  and  other  cells. 

Chronic  anaemias  which  follow  long-continued  infection  or  intoxication, 
or  repeated  small  losses  of  blood,  as  from  bleeding  hemorrhoids,  cause  the 
same  regenerative  processes.  The  marrow  of  the  long  bones,  normally 
yellow  and  composed  chiefly  of  fat,  becomes  dark  red,  solid,  and  granular, 
and  is  found  to  be  made  up  of  compactly  crowded  formative  cells  and  their 
products.  In  many  cases,  of  course,  the  benefit  from  this  regeneration  is  as 
promptly  frustrated  by  the  continued  destruction  or  loss  of  the  cells  as  they 
appear  in  the  circulation.  There  are  a  few  cases  in  which,  in  spite  of  ex- 
treme anaemia,  no  sign  of  regenerative  processes  begins  in  the  bone-marrow 
("aplastic  anaemia "),  and  others  in  which  it  is  prevented  by  the  extensive 
destruction  of  that  tissue  by  tumor  growths  or  otherwise.  The  extreme 
anaemia  produced  by  benzol  poisoning  seems  to  depend  largely  upon  its 
coincident  destructive  effect  upon  the  bone-marrow  and  blood. 

Nervous  Tissue. — If  a  peripheral  nerve  be  cut,  the  proximal  portion 
remains  alive,  except  for  the  last  two  or  three  Ranvier's  segments,  but  the 
whole  peripheral  portion  degenerates.  The  myeline  sheath  loses  its  homo- 
geneous character  and  breaks  up  into  globules  which  now  stain  with  fat 
stains.  The  axis-cylinder  becomes  granular  and  disintegrated.  The  cells 
of  the  sheath  of  Schwann  or  neurilemma  increase  greatly  in  size  and  num- 
ber, and  become  actively  phagocytic,  engulfing  and  removing  the  debris  of 
the  myeline  sheath  and  axis-cylinder. 

Up  to  this  time  the  degenerating  fibres  show  the  presence  of  black- 
stained  globules  in  the  position  of  the  myeline  sheath  by  the  method  of 
Marchi,  but  after  the  phagocytic  activity  of  the  cells  of  the  neurilemma  is 
completed,  nothing  is  left  of  the  medullary  sheath,  and  such  degenerated 
and  emptied  fibres  can  now  be  made  out  best  by  their  lack  of  staining,  in 
contrast  to  the  neighboring  well-preserved  medullary  sheaths,  which  be- 
come blue  black  with  Weigert's  medullary  sheath  stain.  The  proliferated 
cells  of  the  sheath  of  Schwann  now  become  arranged  closely  together  in 
long,  tubular  strands — the  so-called t "  band  fibres. "  At  this  point  arises 
the  difference  of  opinion  upon  which  there  has  been  strife  for  many  years, 
v.  Btingner,  Bethe,  and  others  maintain  that,  inside  these  band  fibres, 
there  are  formed  new  axis-cylinder  fibres  without  any  connection  with  the 
ganglion-cell,  and  quite  independent  of  the  proximal  portion  of  the  fibre 
from  which  they  were  originally  separated.  The  weight  of  evidence,  how- 
ever, is  overwhelmingly  on  the  side  of  those  (Waller,  Ranvier,  Howell, 
His,  Ram6n  y  Cajal,  Perroncito,  Stroebe,  Harrison,  and  others)  who  have 


REGENERATION  209 

shown  that  new  fibres  appear  growing  along  in  these  tubular  band  fibres 
but  only  as  sprouts  from  the  axis-cylinders,  which  are  still  in  the  proximal 
part  of  the  healing  nerve  and  still  in  connection  with  the  ganglion-cell. 
It  is  shown  that  the  ends  of  these  axones  in  the  tip  of  the  proximal  stump 
become  bulbous  or  branched,  or  peculiarly  altered  into  a  basket-like  ar- 
rangement, and  that  when  the  peripheral  portion  is  brought  into  apposi- 
tion with  this  stump,  filaments  penetrate  into  the  guiding  canals  furnished 
by  the  Schwann's  sheath  tube,  and  grow  down  them  until  they  reach  the 
end-organs  and  reestablish  connections  there.  If  there  is  a  large  gap 
between  the  two  ends  of  the  nerve,  the  accomplishing  of  this  process  is 
delayed.  It  is  hastened,  on  the  other  hand,  by  the  accurate  suture  of  the 
cut  ends  to  one  another.  The  band  fibres  thus  form  merely  a  guide  for 
the  newly  sprouting  axone,  and  in  no  case  give  rise  to  new  axone  material 
themselves.  All  this  is  particularly  well  shown  by  Harrison's  experiments, 
in  which  he  showed  that  axones  could  grow  out  to  a  great  length  if  offered 
merely  a  suitable  moist  medium  upon  which  to  grow,  and  were  not  entirely 
dependent  upon  the  facilitating  and  guiding  influence,  of  the  band  fibre. 
Functional  capacity  of  such  nerves  is  restored  in  a  remarkably  short  time, 
and  seems  to  depend  largely  upon  the  character  of  the  nerve-endings  and 
not  upon  the  precise  rediscovery  by  the  axones  of  their  proper  band  fibres. 
Indeed,  a  nerve  accustomed  to  convey  one  set  of  impulses  may  be  arti- 
ficially united  to  a  peripheral  stump  which  had  been  used  to  act  as  the 
mechanism  for  a  quite  different  sort  of  activities,  but  the  old  impulses  will 
now  produce  the  new  function  characteristic  of  the  new  nerve  terminations. 
Such  a  person  has  to  learn  to  interpret  and  control  his  impulses — in  other 
words,  learn  again  to  do  the  right  thing  at  will. 

In  the  central  nervous  system  a  similar  type  of  regenerative  process  is 
attempted,  but  seldom  carried  far,  because  no  proper  paths  seem  to  be 
prepared  for  the  guidance  of  new  fibres.  At  the  scarred  edges  of  wounds  or 
defects,  either  in  the  brain  or  in  the  spinal  cord,  the  same  bulbous  or  branch- 
ing ends  of  fibres  are  to  be  found,  but  there  is  little  evidence  of  their  cross- 
ing the  scar  and  reestablishing  the  original  connections.  There  is  also 
little  positive  evidence  of  regeneration  on  the  part  of  ganglion-cells — mitoses 
are  sometimes  seen,  but  at  best  it  is  only  an  attempt  at  new  formation. 
Healing  of  a  defect  in  the  brain  takes  place  partly  by  scar-tissue  formation 
and  partly  later  by  the  production  of  a  rather  broad  zone  of  sclerotic  neu- 
roglia.  The  cleansing  of  the  area  is  carried  out  by  the  so-called  granule 
cells,  large,  rounded,  mobile  cells  filled  with  globules  of  fat  which  accumu- 
late in  great  numbers  in  areas  where  destruction  of  nervous  tissue  has 
occurred  (Fig.  15).  These  cells,  which  are  especially  abundant  in  areas  of 
softening,  infarcts,  etc.,  in  the  brain,  resemble  the  mononuclear  phagocytic 
wandering  cells  very  closely,  and  are  regarded  as  such  by  Borst  and  others. 
Although  this  view  seems  perfectly  plausible,  it  is  contended  by  others, 
including  Fr.  Marchand,  Morzbacher,  and  Tanaka,  that  they  are  really 
wandering  cells  of  neuroglial  origin. 
15 


210  TEXT-BOOK   OF   PATHOLOGY 

LITERATURE 

Coffin:  Johns  Hopkins  Hosp.  Bull.,  1906,  xvii,  277. 
Goldzieher  and  Makai:  Ergeb.  d.  allg.  Path.,  1912,  xvi2,  344. 
Jores:   Ziegler's  Beitr.,  1900,  xxvii,  381;    1907,  xli,  167.     (Elastic  Tissue.) 
Marchand:   Process  der  Wundheilung,  1901. 

Maximow:   Ziegler's  Beitr.,  xxxv;   Suppl.  v;   xxxiv;   xxxviii.     (Suppuration.) 
Minervini:  Virchow's  Arch.,  1904,  clxxv,  238.     (Scars.) 
Nakai:  Virchow's  Arch.,  1905,  clxxxii,  158.     (Elastic  Tissue.) 


CHAPTER  XIII 
DEFENCES  OF  THE  BODY  (Continued) 

Transplantation  of  tissues  and  organs,  its  limitations.  Healing  of  wounds— by  direct 
union,  under  a  crust,  by  granulation  tissue,  etc.  The  healing  of  an  open  ulcer,  of  inflamed 
wounds  and  abscesses.  The  healing  of  special  tissues. 

TRANSPLANTATION  OF  TISSUES  AND  ORGANS 

THE  result  of  attempts  to  transplant  tissues  or  whole  organs  from  one 
animal  to  another,  or  from  one  portion  to  another  in  the  same  animal,  is  a 
matter  of  great  surgical  interest,  and  also  of  importance  in  contributing 
to  our  knowledge  of  the  growth  of  tissue  and  the  function  of  the  organs 
themselves  thus  transplanted.  It  is  treated  in  detail  by  Marchand,  Borst, 
Stich,  Makai,  and  many  others,  to  whose  papers  the  reader  is  referred. 

To  graft  tissue  or  a  whole  organ  into  a  new  situation  is  a  matter  of 
technical  difficulty,  but  success  depends  not  only  upon  the  skill  with  which 
the  operation  is  carried  out,  but  also  upon  the  nature  and  age  of  the  animal, 
nature  of  the  tissue,  the  intimacy  of  relationship  of  the  new  host,  the 
efficiency  of  the  blood  supply  (often  the  restitution  of  the  nerve  supply), 
and,  finally,  in  many  cases,  the  functional  need  for  such  tissue. 

It  seems  possible  to  carry  out  successfully  far  more  extensive  trans- 
plantations in  the  lower  animals,  such  as  worms  and  ccelenterates,  than  in 
higher  forms.  Probably  this  is  because  of  their  greater  adaptability,  and 
is  quite  like  their  great  power  of  regenerating  tissue  and  organs.  At  any 
rate,  one  may  easily  transplant  half  the  body  of  one  of  these  creatures  by  a 
sort  of  grafting  on  to  half  the  body  of  another.  But  this  can  be  done  in 
embryos  of  much  higher  animals  also,  with  the  production  of  remarkable 
monsters.  Complex  organs,  like  the  eye,  may  be  implanted  in  unusual 
situations  with  a  certain  success  which  could  not  be  attained  in  adults. 

The  success  with  which  tissues  can  be  transplanted  is,  to  some  extent, 
parallel  with  their  degree  of  specialization  and  their  need  of  constant  and 
abundant  blood  supply.  Little  difficulty  is  experienced  in  transplanting 
epidermis  from  one  situation  to  another,  or  even  from  one  individual  to 
another.  The  so-called  Thiersch  grafts,  which  are  thin  films  of  epidermis, 
sometimes  including  the  upper  layer  of  the  corium,  are  used  daily  in  surgi- 
cal operating-rooms  to  cover  large  denuded  areas,  and  there  is  seldom  any 
question  about  their  success.  So,  too,  bone  with  its  periosteum  may  be 
made  to  fill  a  gap  in  another  bone.  With  more  highly  specialized  tissues 
transplantation  is  more  difficult,  probably  because  their  cells  will  not  sur- 
vive long  enough  to  allow  capillary  blood-vessels  to  grow  in  from  the  new 
site. 

211 


212  TEXT-BOOK  OF  PATHOLOGY 

Nevertheless,  pieces  of  thyroid,  parathyroid,  adrenal,  etc.,  have  been 
implanted  in  a  cavity  made  in  one  tissue  or  other,  and  have  grown  and 
functionated  generally  only  after  necrosis  of  the  central  part,  with  survival 
and  increase  of  the  marginal  layers.  It  is  important  to  observe  that  in 
some  cases,  as  in  the  transplantation  of  bone  or  nerves,  the  graft  may  sur- 
vive only  as  a  sort  of  splint  which  supports  and  guides  the  new-growth  of 
tissue  from  the  host,  which  finally  absorbs  and  replaces  it  entirely.  This  is 
always  true  with  nerves  whose  specialized  structures  invariably  degenerate, 
but  not  always  with  bone,  which  may  remain  active  and  itself  perma- 
nently occupy  the  new  site. 

Transplantation  of  whole  organs  by  anastomosis  of  the  blood-vessels 
has  been  carried  out  in  a  number  of  cases,  notably  by  Carrel,  and  often 
with  successful  functioning  of  the  transplanted  organ.  Thus  in  one  animal 
the  transplanted  kidney  was  able,  after  the  removal  of  the  other,  to  main- 
tain the  life  of  the  animal  for  a  long  time. 

The  reimplantation  of  an  organ  or  tissue  into  the  same  animal  is  an 
autoplastic  operation — its  transfer  to  another  animal  of  the  same  species 
is  a  homoplastic  operation,  while  a  heteroplastic  transplantation  involves 
its  growth  in  an  animal  of  another  species.  Transplantation  of  whole  organs 
has  succeeded  so  far,  only  in  autoplastic  operations,  although  homoplastic 
transplantations  of  extremities  or  peripheral  tissues  have  been  successful. 
Heteroplastic  transplantations  have  been  uniformly  failures.  It  is,  there- 
fore, necessary  to  have  the  most  favorable  possible  conditions  for  the  re- 
newed growth  of  the  more  sensitive  tissues,  although  those  less  dependent 
upon  an  uninterrupted  blood  supply  may  sometimes  be  transferred  to  other 
animals  of  the  same  species  with  success.  Evidently  the  foreign  biological 
character  of  the  blood  of  another  species  makes  life  impossible  for  the  graft. 
Mechanical  conditions,  too,  are  important  in  the  success  of  a  transplant, 
and  a  piece  of  skin  transplanted  into  the  peritoneum  or  between  the  muscles 
is  sure  to  act  merely  as  a  foreign  body  and  be  encapsulated. 

Another  influence  which  is  undoubtedly  of  great  importance  is  that  of  the 
nerve  supply.  As  though  one  were  to  cut  the  electrical  connections  in 
moving  an  electromotor,  and  expect  it  to  work  in  its  new  position,  we  look 
for  proper  renal  activity  or  thyroid  activity  in  a  tissue  deprived  of  all 
connections  with  the  nervous  system.  If  such  function  ever  does  recur, 
it  seems  that  it  must  be  accompanied  by  new  formation  of  nerve  connec- 
tions. This  is  a  problem  for  future  study,  and  is  complicated  a  little  by 
the  fact  that  some  autonomic  nervous  activity  can  go  on  for  a  short  time 
in  plexuses,  etc.,  severed  from  central  connection.  Thus  in  a  freshly  ampu- 
tated and  reanastomosed  leg  inflammation  proceeds  normally,  probably 
aided  by  axone  reflexes  in  the  autonomic  fibres.  Later,  when  these  have 
degenerated,  the  phenomena  of  inflammation  fail  to  appear  on  application 
of  irritants. 

Finally,  it  has  seemed,  especially  from  some  experiments  of  Dr.  Halsted, 
that  successful  implantation  and  growth  of  such  organs  as  the  parathyroid 


HEALING   OF   WOUNDS  213 

depend  upon  a  need  for  their  functional  activity.  In  animals  with  a  normal 
amount  of  parathyroid  substance  he  found  it  impossible  to  make  an  extra 
gland  grow,  while  he  succeeded  in  one  already  deprived  of  most  of  its 
parathyroid  tissue.  This  seems  a  plausible  suggestion,  and  has  been 
supported  by  others,  but  as  yet  it  is  hardly  possible  to  set  it  down  as  a 
general  law. 

LITERATURE 

Borst:    Proceedings  XVII.  Internal.  Congress,  London,  1913,  Sec.  3,  pt.  1   171. 
Halsted:   Jour.  Exp.  Med.,  1912,  xv,  205. 
Makai:  Ergeb.  d.  allg.  Path.,  1912,  xvi2,  344. 
Marchand:    Process  der  Wundheilung,  1901. 
Stich:  Ergeb.  Chir.  u.  Orthopadie,  1910,  1. 

HEALING  OF  WOUNDS 

While  the  principles  remain  exactly  the  same,  the  details  in  the  healing 
or  making  good  of  any  destructive  injury  to  the  tissues  vary  with  cir- 
cumstances, and  it  forms  a  great  part  of  the  skill  of  the  surgeon  to  be  able 
to  leave  the  tissues  upon  which  he  has  operated  in  the  most  favorable 
possible  condition  for  repair.  Neglect  of  these  precautions,  which  concern 
chiefly  the  mechanical  adjustment  of  the  tissues  which  should  grow  to- 
gether, their  proper  nutrition,  and  the  exclusion  of  infection,  will  readily 
defeat  his  object,  no  matter  how  ingeniously  he  has  planned  to  cure  his 
patient.  As  in  the  early  days  of  surgery,  the  wound  will  in  a  short  time 
break  open  and  discharge  a  flow  of  pus  and  fragments  of  dead  tissue,  blood- 
vessels may  burst  their  ligatures,  and  the  secondary  haemorrhage,  dreaded 
of  old,  will  follow.  All  this  depends  upon  the  malnutrition  of  tissue  from 
crushing  or  cutting  off  the  blood  supply,  and  the  infection  which  can  thrive 
in  such  dying  or  dead  tissue  or  in  the  material  accumulating  about  it. 
But  if  the  tissues  be  carefully  brought  together  by  light  pressure,  or  by 
sutures  so  arranged  as  to  leave  them  all  very  richly  supplied  with  blood 
in  rapid  circulation,  the  few  bacteria  which  are  always  to  be  found  in  every 
wound,  no  matter  how  carefully  made,  are  easily  overcome  by  the  living 
tissues,  and  healing  proceeds  apace. 

Healing  by  Direct  Union. — It  is  in  wounds  treated  with  this  careful 
attention  to  the  condition  of  the  tissues,  or  in  wounds  so  superficial  and 
limited  that  apposition  and  good  nutrition  of  the  tissues  are  secure  of  them- 
selves, that  healing  occurs  with  the  slightest  reaction  and  with  the  least 
requirement  for  new  formation  of  cells. 

If  a  clean  incision  be  made  through  the  abdominal  wall  and  the  tissues 
approximated  edge  to  edge  by  sutures  throughout,  they  become  glued  to- 
gether almost  at  once,  and  in  a  short  time  heal  together,  with  an  almost 
imperceptible  linear  scar,  with  never  any  very  evident  inflammatory  reac- 
tion and  no  sign  of  actual  suppuration.  In  such  an  incision  only  the  cells 
along  the  line  of  incision  are  killed, — some  bleeding  occurs,  and  between 
the  approximated  edges  a  little  blood  remains, — or  if  the  escape  from  the 


214 


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blood-vessels  has  been  stopped,  at  least  a  little  coagulable  fluid  oozes  out 
between  these  edges.  This  clots  about  the  severed  cells  and  cements  the 
surfaces  together  (Fig.  77).  A  few  leucocytes  appear  from  the  slightly 
widened  adjacent  vessels.  Mitoses  arise  in  nearby  epithelial  cells  of  the 
epidermis,  and  in  the  connective- tissue  cells  close  to  the  wound.  Blood- 
vessels sprout  from  those  on  either  side,  and  accompanied  by  fibroblasts 
grow  across,  absorbing  and  removing  the  fibrin  and  the  dead  cells  which  the 


Fig.  77. — Fresh  stab  wound  of  the  liver.     A  few  cells  have  been  killed  and  the  edges 

glued  together  by  the  clot. 

leucocytes  help  to  liquefy,  and  replacing  this  material  by  a  more  permanent 
bond.  Later  this  new  connective  tissue  matures  into  a  scar.  Epithelium 
has  by  this  time  been  pushed  across  to  cover  the  outer  surface  and  the 
peritoneal  lining  cells  to  close  the  interior,  and  the  wound  is  healed.  This 
is  healing  by  first  intention  (Fig.  78). 

Healing  Under  a  Blood- clot  or  Crust. — In  many  cases,  when  apposition 
has  not  been  so  exact  or  when  more  tissue  has  been  destroyed,  a  good  deal 
of  blood  and  serous  fluid  oozes  out  on  the  surface,  clots,  and  dries,  or  the 


HEALING    OF   WOUNDS 


215 


cavity  of  a  wound  whose  edges  are  not  brought  together  may  fill  up  with 
blood  which  clots  and  remains.  So  good  is  such  a  clot  as  protection  against 
infection  that,  at  times,  surgeons  have  intentionally  allowed  large  spaces  to 
fill  up  in  this  way  (Schede,  Halsted),  and  have  carefully  preserved  the  clot 
as  a  covering.  Not  only  is  it  a  protective  substance,  which,  on  account  of 


&. 


Fig.  78. — Scar  of  healed  surgical  incision  through  the  abdominal  wall. 


its  bactericidal  power,  does  not  decompose  or  become  further  infected,  but 
it  forms  a  nutritive  material,  and  at  the  same  time  a  scaffolding  for  the 
up-growth  of  blood-vessels  and  fibrous  tissue. 

When  there  is  only  a  little  blood  or  inflammatory  or  serous  exudate  which 
dries  on  the  surface  of  the  wound,  healing  proceeds  under  the  protective 


216  TEXT-BOOK  OF  PATHOLOGY 

crust  thus  formed,  and  is  found  complete  when  it  drops  off.  Quite  the 
same  process  goes  on  if  the  crust  is  formed  by  the  necrosis  and  drying  up 
of  the  superficial  tissue.  The  epithelium  works  its  way  beneath  this  dried 
mass  and  quickly  grows  over  the  surface  of  the  underlying  living  tissue, 
even  if  it  has  not  been  covered  by  any  thick,  new-formed  granulations. 
This  is  the  peculiarly  favorable  feature  of  healing  under  a  crust  that,  with 
such  perfect  protection,  the  new  epidermal  covering  is  completed  without 
the  previous  slow  and  tedious  formation  of  granulation  tissue.  It  is  true 
that. later  much  new  tissue  of  that  sort  is  produced  beneath,  but  at  least  it 
is  closed  in  from  the  air  and  goes  on  unnoticed,  the  process  being  essentially 
finished  and  secured  when  the  epidermal  covering  is  complete. 

Granulation  Tissue— Secondary  Healing. — When  a  wound  is  infected 
with  bacteria,  it  is  not  apt  to  heal  throughout  any  great  part  of  its  extent. 
Instead,  it  breaks  open  and  discharges  a  purulent  exudate,  and  heals 
finally  by  "second  intention,"  in  a  way  rather  different  from  those  just 
described.  It  builds  up  from  the  bottom  a  new  connective-tissue  layer 
which,  beginning  by  covering  and  masking  all  the  exposed  structures  with 
a  thin  gray  film,  heaps  itself  up  in  an  ever  thicker  nodular,  translucent, 
grayish-red  substance,  until  the  whole  space  may  be  filled  or  even  until 
the  granulation  tissue  projects  in  soft,  fungus-like  masses  above  the  level 
of  the  skin.  This  sort  of  reparatory  growth  is  by  no  means  limited  to 
infected  wounds — it  is  the  regular  method  of  filling  up  and  repairing  any 
and  every  gap  in  the  tissue.  It  is  inconspicuous  and  limited  in  the  two  sorts 
of  healing  already  described,  because  in  the  one  case  very  little  of  it  is 
needed  before  healing  is  complete,  and  in  the  other  because  the  epidermal 
covering  is  so  soon  finished  that  connective-tissue  growth  is  held  in  check 
and  covered  from  view. 

If  an  open  wound  or  ulcer  be  kept  clean  and  moist  and  therefore  unable 
to  cover  itself  by  a  crust,  it  must  heal  slowly  from  the  bottom.  In  the  same 
way  a  space  among  the  tissues  kept  open  by  the  presence  of  bacteria  and 
an  accumulation  of  fluid  will  close  itself  gradually  by  the  formation  of  a 
complete  wall  of  new  young  connective  tissue,  which  is  gradually  drawn 
together  by  the  absorption  of  the  fluid  (Fig.  79).  Any  foreign  body  em- 
bedded in  the  tissues  stirs  up  the  same  response.  About  it  on  every  side, 
as  though  it  were  a  space  to  be  filled,  there  develops  a  wall  of  new  tissue 
(Fig.  80).  A  portion  of  tissue  itself,  killed  by  any  means,  becomes  a  foreign 
body,  and  is  treated  in  the  same  way — hence  an  abscess  with  its  mass  of 
bacteria  and  surrounding  dead  tissue  is  in  time  encapsulated.  Any  group 
of  cells  in  an  organ,  such  as  the  liver  or  kidney,  on  being  killed  and  absorbed, 
leaves  a  gap  which  is  filled  up  by  a  new-formed  connective  tissue  not  limited 
exactly  to  their  site,  but  extending  a  little  into  the  neighborhood. 

Other  examples  of  this  same  tendency  are  seen  when  it  is  not  dead  tissue, 
but  fibrin,  that  acts  as  the  foreign  body,  and  the  replacement  of  a  fibrinous 
exudate  on  a  serous  surface  (Fig.  81),  or  of  a  thrombus  in  a  blood-vessel  by 
the  growth  of  granulation  tissue  (Fig.  82) ,  is  perfectly  well  known. 


HEALING    OF   WOUNDS  217 

In  all  cases  the  mechanism  is  the  same.     It  is  the  standard  method  of 


S^W 

•*::.'-  :-":v  £t^^M^  ~^&\':;:^'f 

:  i>^'£     /  -    -v^>\^:v  ».•*•?#  —  ,v^-  -  -•  -'  •  .O-^--v  >^&vx.v:v 
%^!  v  •>  >>  -r^v:''"*1"*  'v^L-?-/8!  ••'••*"-  v%""  •*  '•  -''  -'  v"  *  •••^O'-"**^.^9 


vp:  -  /  * ; ":>  X,:  -;;  :/>:-;  «^^M§^Sp*f S  'm 


<-  ,• 


Fig.  79. — Granulation  tissue  lining  a  space  left  between  the  muscles  in  a  dog's  neck. 

healing  adapted  to  deal  with  the  most  varied  types  of  injury,  but  always 
proceeding  on  the  same  principles  toward  the  patching  of  the  injured  area. 


218 


TEXT-BOOK  OF  PATHOLOGY 


The  degree  to  which  inflammation  is  mixed  with  it  depends  upon  the  sort 
of  injury,  and  the  nature  of  the  wandering  cells  found  in  the  new  tissue 
depends  upon  the  sort  of  injurious  material  and  debris  that  must  be  treated 
and  removed.  The  healing  of  an  open  ulcer  may  serve  as  one  example. 

Even  if  such  a  loss  of  substance  is  produced  by  actually  cutting  out  a 
piece  of  tissue,  bleeding  soon  stops,  and  the  cut  surface  is  found  moistened 
by  a  thin  layer  of  fibrinous  exudate.  Within  an  hour,  although  the  surface 


m&m,     •&?••• 

WM^^i&tXi*. 

*?',.\-  ««?         ^^*^*w^  L.  "^ 

H.*.'  7,  &&  ~..&^^    ^i.1  .^  '^-  * 


#:vJ        A4P  *v 


Fig.  80. — Granulation  tissue  with  giant-cells  developed  around  a  foreign  material  (para- 
ffin) injected  into  the  tissues. 

becomes  reddened  by  the  widening  of  the  capillaries,  it  is  found,  on  injecting 
the  blood-vessels,  that  none  of  the  colored  mass  oozes  out  on  the  cut  surface. 
The  cut  ends  of  the  vessels  are  closed  by  the  fibrinous  exudate,  and  by  con- 
traction, many  are  definitely  thrombosed.  The  exposed  surface  con- 
tracts somewhat,  the  skin  edges  tend  to  turn  inward,  and,  as  healing  pro- 
gresses, this  contraction  plays  a  considerable  part  in  forwarding  the  closure 
of  the  wound. 


HEALING    OF   WOUNDS 


219 


The  reparatory  process  begins  first,  in  all  probability,  by  the  amoeboid 
stretching  out  of  the  adjacent  connective-tissue  cells,  and  even  of  the 
epithelial  cells  at  the  skin  edge.  This  is  readily  observed  in  tissues  grown 


Fig.  81. — Organization  of  a  fibrinopurulent  exudate  on  the  pleural  surface  by  new  blood- 
vessels and  connective  tissue  from  the  pleura. 

in  vitro,  and  it  seems  probable  that  it  occurs  here  too,  since  the  mitotic 
figures  which  indicate  the  new  formation  of  cells  are  found  some  dis- 
tance back  from  the  actual  margin  of  the  wound.  Connective-tissue 


220 


TEXT-BOOK  OF  PATHOLOGY 


cells  reaching  out  their  pseudopods  from  among  the  intercellular  fibres 
find  guidance  in  the  filaments  of  fibrin.  Through  their  multiplication  and 
that  of  the  endothelial  cells  of  the  blood-vessels  a  recognizable  amount  of 
new  tissue  is  formed  in  the  course  of  a  day  or  two.  At  the  same  time  an 
acute  inflammatory  process  arises,  with  all  the  features  described  above: 
The  vessels  widen  and  pour  out  their  fluid  and  cellular  contents;  the  tissue 
becomes  cedematous  and  infiltrated  with  leucocytes  and  scattered  red 


Fig.  82. — Thrombus  formed  behind  a  valve  in  a  vein,  being  invaded  by  blood-vessels 

and  fibroblasts. 

corpuscles — on  the  surface,  more  exudate  of  leucocytes  and  fluid  is  poured 
out,  and  the  network  of  fibrin  becomes  thicker;  mononuclear  wandering 
cells  appear  in  numbers  from  the  blood-vessels  and  from  their  resting  places 
in  adjacent  tissues;  sprouts  of  endothelial  eels  spring  up  from  the  intact 
capillaries  and  stretch  forward  into  the  fibrin,  making  way  for  themselves 
by  their  mobility  and  digestive  power.  Spread  open  into  tubes  by  the 
pressure  of  the  blood,  they  become  complete  capillaries,  carrying  a  current 


HEALING   OF  WOUNDS 


221 


of  blood.  With  them  there  grow  upward  the  fibroblasts,  with  their  long 
branched  protoplasmic  processes,  supporting  and  surrounding  the  vessels. 
Growing  upward  in  this  way,  the  capillaries  anastomose  and  form  arches, 
and  it  seems  probable  that  it  is  this  arching  forward  of  the  vessels  which 
brings  about  the  granular  appearance  of  the  surface  of  the  new  tissue 
(Fig.  83) .  Thus  an  actual  new  tissue  is  formed,  and  continues  to  be  formed 
with  the  greatest  rapidity.  It  consists,  as  is  evident,  of  abundant  blood- 
vessels and  young  fresh  connective-tissue  cells,  all  spread  apart  by  fluid, 


^m^^^^S^M 

*•& ./^;^'/  .--•••^^r^' H-':<  v' t^"^/;::-'-^  -'sV.-..  ::1 
lK-;Sito:'il;^vl:fe^'  ?  $•  '^'••^&Ki:-: 

yM^i^fi;.  ii?i*>>  fi^S-^i 


Fig.  83. — Granulation  tissue  formed  in  the  healing  of  an  ulcer. 

a  large  portion  of  which  is  an  inflammatory  exudate.  Therefore  it  is  easy 
to  understand  that  this  tissue  should  appear  as  it  does.  It  is  a  soft  gray 
or  grayish-red,  gelatinous,  translucent  layer  of  irregular  nodular  surface, 
bleeding  at  a  touch,  but  quite  insensitive  to  pain.  When  it  is  found,  as 
it  often  is,  in  surroundings  abundantly  infected  with  bacteria,  the  inflam- 
matory reaction  becomes  more  intense,  and  the  purulent  secretion  oozes 
out  on  the  surface  (Fig.  84). 

Granulation  tissue  is  subject  to  the  same  circulatory  and  other  dis- 


222  TEXT-BOOK  OF  PATHOLOGY 

turbances  that  affect  other  tissue-it  may  be  congested  with  venous  blood 
or  become  very  cedematous  in  patients  whose  circulation  is  embarrassed 
Checked  in  its  growth  by  some  injury,  that  which  remains  becomes  compact 
and  forms  the  basis  for  the  growth  of  a  new  layer.     It  may;  therefore,  pre- 
sent very  different  appearances  in  different  cases,  although  in  its  essentials 

it  is  the  same  in  all. 

Having  grown  to  such  an  extent  that  it  fills  or  nearly  fills  the  gap,  one 
becomes  aware  of  the  fact  that  a  thin,  grayish-blue  film  of  epithelium  is 


Fig.  84. — Granulation  tissue  showing  acute  inflammation. 

spreading  out  from  the  edges  toward  the  centre  of  the  wound,  to  cover  the 
granulations,  much  as  ice  in  its  first  formation  spreads  out  from  the  edges  of 
a  pond.  One  can  also  plant  a  fragment  of  epithelium  in  the  form  of  an  island 
in  the  middle  of  the  surface  of  the  granulation  tissue,  and  if  successful, 
the  spread  of  new  epidermis  will  take  place  from  there  in  just  the  same  way, 
meeting  that  from  the  margin  and  completing  the  covering  of  the  granula- 
tions (Fig.  73).  Bluish  at  first,  the  new  epidermis  gradually  becomes 
thicker,  more  opaque,  and  white.  Naturally  this  process  occurs  most 
readily  when  the  granulations  are  clean  and  oozing  only  a  little  serous  fluid — 
it  is  often  frustrated  by  infection  and  the  consequent  inflammatory  process. 


HEALING   OF   WOUNDS  223 

The  influence  of  different  diets  upon  the  rate  of  healing  has  been  studied 
by  Clark  and  has  already  been  mentioned.  Other  studies  upon  the  rate 
of  healing  have  shown  that  it  may  be  expressed  by  a  formula  in  which 
the  original  size  of  the  wound  and  the  age  of  the  animal  must  be  taken 
into  account  (de  Noiiy). 

Finished  in  this  way,  the  site  of  the  original  wound  is  occupied  by  a 
highly  vascular,  purplish  looking  tissue,  hidden  under  a  smooth,  pearly 
layer  of  epithelium,  which  has  none  of  the  lines  and  markings  of  the  normal 
skin— no  hairs,  no  sweat-  or  sebaceous  glands,  and  no  nerves.  From  this 
time  on  a  process  of  maturing  of  this  tissue  begins,  which,  as  has  been  said, 
tends  to  mould  it  into  the  form  of  that  which  was  lost.  Much  new  con- 


Fig.  85. — Margin  of  abscess  in  fat  tissue  with  large  phagocytic  cells  containing  cell  debris. 

nective  tissue  is  formed.  The  new  cells  produce  abundant  new  inter- 
cellular fibrillar  substance.  Many  of  [the  too  abundant  blood-vessels  are 
pressed  shut  and  disappear.  Since  the  venous  side  is  first  compressed,  the 
new  scar  retains  for  a  time  its  congested  appearance.  The  purplish  healed 
area  grows  paler  and  firmer  until,  in  the  end,  it  becomes  very  white,  hard, 
and  tendon-like,  and  that  dense  connective  tissue  which  is  the  final  product 
of  the  growth  of  the  granulation  tissue  we  know  as  a  scar.  In  the  first 
healing  of  the  wound  and  in  the  course  of  formation  of  the  granulation  tissue 
a  good  deal  of  contraction  occurs,  and  if  it  is  an  extensive  superficial  wound, 
such  as  might  be  caused  by  a  burn  of  the  skin,  this  contraction  is  apt  to 
deform  the  person.  After  the  scar  is  definitely  formed,  it  tends  rather  to 


224  TEXT-BOOK   OF    PATHOLOGY 

stretch  out  again  (Minervini)  or  relax,  and  this  extension  is  accompanied 
by  a  development  in  which  nerves  grow  in,  so  that  the  place  again  becomes 
sensitive,  and  new  cutaneous  papillae  arise.  The  fine  lines  or  wrinkles 
reappear  when  the  scar  becomes  flexible,  and  on  the  palms  or  soles  the 
characteristic  fine  corrugations  develop  in  time  and  again  cross  the  scar 
by  which  they  were  interrupted.  Almost  every  one  may  test  the  truth  of 
this  in  his  own  hands. 

Abscesses. — In  an  abscess  which  has  existed  for  some  time  we  are  ac- 
customed to  find  the  dead  tissue  separated  from  the  living  by  a  wall  of 
this  same  granulation  tissue.  It  forms  all  around  in  just  the  same  way, 
but  it  is  peculiar  in  the  extraordinary  number  of  wandering  cells  that  haunt 
the  meshes  of  its  connective-tissue  network.  Inflammation  still  proceeding 
actively  insures  this,  and  such  a  wall,  from  this  character,  has  often  been 
called  a  pyogenic  or  pus-producing  membrane.  There  is  nothing  peculiar 
about  it  though,  and  the  point  of  greatest  interest  is  the  extraordinary 
array  of  very  large,  highly  phagocytic,  mononuclear  wandering  cells  which 
crowd  into  this  marginal  tissue  and  aid  in  the  cleaning-up  process.  They 
are  probably  free  wandering  cells,  members  of  Maximow's  group  of  poly- 
blasts,  although  some  writers  think  them  derivatives  of  the  fibroblasts,  and 
others  of  the  endothelium.  As  shown  in  Fig.  85,  they  are  often  loaded  with 
fat  and  the  debris  of  other  cells.  (See  Chapter  XIV  concerning  the  forma- 
tion of  abscesses.) 

Sinuses. — Sometimes  such  an  abscess  may  break  through  the  skin  and 
discharge  its  contents,  or  if  deep  seated,  it  may  burrow  a  long  way  and 
finally  burst  through  the  skin.  A  long  channel  or  sinus  results,  and  all 
along  its  course  a  lining  or  wall  of  granulation  tissue  is  formed.  As  long 
as  the  infection  persists  in  the  original  site  this  sinus  may  stay  open  and 
will  discharge  the  products  of  inflammation.  This  is  especially  likely  to 
be  true  if  dead  tissue,  such  as  a  fragment  of  necrotic  bone  or  a  foreign  body, 
remains  in  the  depths.  Such  a  process  is  common  with  deep  tuberculous 
lesions,  with  actinomycosis,  and  with  various  other  chronic  and  tenacious 
infections,  and  sometimes  the  granulation  tissue  itself  gives  us  a  clue  as  to 
the  nature  of  the  infection. 

Psoas  Abscess. — A  good  example  is  seen  in  the  tuberculous  destruction  of  the  cen- 
trum of  one  or  more  vertebrae,  which  reduces  the  bony  substance  to  a  soft,  creamy,  or 
mortar-like  fluid.  Inclosed  as  it  is,  this  fluid  seeks  a  way  of  escape  and  burrows  into 
the  psoas  muscle  and  down  along  its  course,  to  appear  as  a  bulging  sac  at  the  femoral 
ring.  Bursting  out  there,  a  sinus  is  established  which  leads  from  the  inner  side  of 
the  thigh  far  up  to  the  mid-dorsal  region.  It  is  only  its  great  extent  which  makes  this 
example  peculiar  though,  for  with  tuberculous  disease  of  the  hip-joint  or  tuberculous 
osteomyelitis  at  any  point,  the  same  thing  may  occur.  The  granulation  tissue  lining 
the  sinus  is  quite  like  any  other,  except  in  that  it  is  particularly  rich  in  mononuclear 
wandering  cells  and  contains  tubercles  and  tubercle  bacilli.  It  is,  therefore,  a  precarious 
material  for  healing,  since  it  itself  is  very  prone  to  become  completely  necrotic,  leaving 
only  a  basal  part  alive.  On  this  remnant  new  granulation  tissue  forms.  It  is  for  this 
reason  that  there  is  built  up  about  tuberculous  lesions  such  a  great  amount  of  scar 
tissue,  and  this  is  true  for  actinomycosis  and  other  infections  of  like  character  and  for 
syphilis. 


HEALING   OF   SPECIAL   TISSUES  225 

Fistulae  or  channels  leading  into  openings  in  hollow  organs  are  lined  in 
the  same  way  by  granulation  tissue,  which  is  often  partly  covered  by  epi- 
thelium, which  grows  inward  from  the  skin  or  outward  from  the  mucosa. 
Closure  of  these  channels  takes  place  partly  by  their  gradual  contraction, 
partly  by  their  being  choked  with  the  ever-thickening  lining  of  granulation 
tissue  which  finally  fuses  together  to  obliterate  the  lumen. 


HEALING  OF  SPECIAL  TISSUES 

The  healing  of  special  tissues  need  not  detain  us  beyond  the  description  of 
one  or  two  illustrative  cases,  since  they  are  merely  examples  of  the  regen- 
erative processes  already  described. 

Serosae. — The  flat  lining  cells  of  the  serous  cavities  are  peculiarly  active 
in  their  growth,  and  cover  with  amazing  rapidity  any  defect  in  their  con- 
tinuity. When,  for  example,  a  loop  of  intestine  is  brought  through  the 
abdominal  wall  and  sutured  there,  its  surface,  where  it  passes,  is  glued  to 
the  parietal  peritoneum  by  fibrin  after  the  briefest  interval,  and  in  a  very 
short  time  the  serosa  cells  become  continuous  from  the  abdominal  wall 
back  over  the  intestine. 

In  peritoneal  infections  and  inflammations  these  cells  are  much  injured. 
When  a  fibrinous  exudate  is  poured  out  upon  their  surfaces,  burying  them 
in  its  depths,  they  finally  disappear,  unless,  as  sometimes  happens,  the  exu- 
date arches  up  over  a  group  of  them — then  they  grow  round  to  line  this 
latter  space  and  form  a  sort  of  cyst  in  which  they  preserve  their  characters. 
Many  such  little  cysts  may  arise  in  this  way,  and  are  common  enough  in  the 
pericardium;  between  them  granulation  tissue  springs  up  into  the  exudate 
and,  uniting  with  that  from  the  opposite  layer,  finally  composes  itself  into 
a  fibrous  adhesion  or  synechia  (Fig.  86) . 

Exactly  the  same  sort  of  thing  is  seen  in  blood-vessels  in  which  thrombi 
have  formed — if  there  is  a  point  in  the  wall  upon  which  the  thrombus  has 
not  been  laid  down,  the  endothelium  persists,  and  through  multiplication  of 
its  cells,  relines  the  little  cavity  thus  left,  while  granulation  tissue  grows  in 
and  replaces  the  thrombus  from  the  exposed  tissues  between  these  cavities 
(cf.  Fig.  87).  Mucosce  heal  in  exactly  the  way  described  for  the  skin, 
although  the  healing  seems  to  take  place  more  rapidly.  Regeneration  of 
the  special  features  of  the  mucosa,  including  lymph-nodules,  villi,  etc., 
occurs  in  time,  so  that  the  scar  may  hardly  be  found. 

Wounds  and  Injuries  of  Parenchymatous  Organs.— Wounds  in  such 
organs  as  the  liver  heal  with  the  formation  of  a  scar,  exactly  like  wounds  in 
any  other  tissue.  More  interesting  is  the  healing  of  the  minute,  but  widely 
diffused  foci  of  destruction  of  cells  which  are  so  common  in  the  course  of 
intoxications  and  infections.  Different  cells  are  picked  out  for  destruction 
by  different  injurious  agents,  and  it  is  very  hard  to  tell  why.  Chromic 
salts  kill  one  set  of  renal  epithelial  cells,  uranium  salts  another;  the  poison 
of  eclampsia  destroys  the  cells  of  the  liver  lobule  nearest  the  portal  veins; 
16 


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that  from  the  streptococcus  peritonitis  produces  a  midzonal  necrossi  (Opie), 
while  the  circulatory  disturbance  in  chronic  passive  congestion  destroys 
the  cells  about  the  efferent  vein.  The  healing  processes  which  follow  each 
of  these  lesions  are  practically  identical,  but  are  modified  by  the  differ- 
ences of  their  situation. 


Fig.  86.-Chronic  adhesive  pericarditis  showing  small  spaces  in  the  connective  tissue 
which  represent  the  remains  of  the  pericardial  cavity. 

They  proceed  by  the  gathering  of  phagocytic  cells  which  dissolve  or 
carry  away  the  dead  bodies  of  the  specific  cells  of  the  organ,  whereupon 
the  connect.ve-t,ssue  framework  in  which  they  had  been  supported  col- 
lapses. As  in  other  places  where  tissue  has  been  destroyed,  a  heal- 


HEALING   OF   SPECIAL   TISSUES 


227 


mg  or  patching  process  ensues  which  consists  in  a  new  formation  of 
connective  tissue  and  blood-vessels— a  granulation  tissue  bounded  on  all 
sides  by  the  uninjured  organ  substance,  so  that  it  cannot  show  any  free 


Fig.  87. — Organized  thrombus  in  a  blood-vessel  canalized  by  clefts  which  are  relined  with 

endothelium. 

nodular  surface,  but  otherwise  is  quite  like  that  which  fills  up  a  healing  ulcer. 
In  the  course  of  time  such  tissue  settles  into  a  scar.  When  organ  cells  are 
destroyed  in  small  groups  or  singly,  there  may  be  a  very  fine  diffusion  of 
this  scar  tissue,  and  we  have  the  condition  known  as  cirrhosis  in  the  case 


228  TEXT-BOOK   OF    PATHOLOGY 

of  the  liver,  and  often  loosely  spoken  of  as  chronic  interstitial  nephritis, 
pancreatitis,  or  hepatitis,  as  the  case  may  be.  That  this  latter  term  is 
practically  always  misleading  may  be  shown,  however,  by  a  study  of  the 
development  of  the  lesion.  The  diffuse  scarring  and  shrinkage  of  the  organ 
is  not  due  to  an  inflammation  of  the  interstitial  connective  tissue,  with  the 
development  of  scars  which  contract  and  constrict  the  epithelial  cells  be- 
tween them.  On  the  contrary,  the  highly  specialized  epithelial  cells  are 
the  first  to  suffer  destruction  by  the  poisonous  substance  which  is  the  pri- 
mary cause  of  the  disease,  and  the  scar  formation  is  essentially  a  reparatory 
response  to  their  disappearance.  There  is  practically  no  evidence  that  the 
scar  tissue  causes  any  further  injury  to  the  epithelial  cells.  Of  course, 
it  is  true  that  the  scar  tissue  may  seem  to  be  in  great  excess  of  what  was 
necessary  to  repair  or  patch  the  gap  produced  by  the  loss  of  epithelial  cells, 
but  it  must  be  remembered  that  in  such  cases  the  process  of  epithelial 
destruction  and  patching  with  connective  tissue  has  been  repeated  fre- 
quently through  years,  each  new  scar  heaping  itself  upon  the  old  one  near 
by.  The  constant  regeneration  of  epithelium  from  remnants  makes  this 
possible,  but  there  is  also  the  possibility  that  the  new  connective  tissue 
itself  may  be  injured  and  later  repaired  in  voluminous  fashion. 

LITERATURE 

Clark,  A.  H.:  Johns  Hopkins  Hosp.  Bull.,  1919,  xxx,  117. 
de  Noiiy:  Jour.  Exp.  Med.,  1916.  xxiv,  451,  461;  1917,  xxv,  721;  1919.  xxix,  329. 


CHAPTER  XIV 
ILLUSTRATIVE  EXAMPLES  OF  INFLAMMATORY  PROCESSES 

Catarrhal  inflammation.  Seroflbrinous  and  flbrinopurulent  pericarditis,  pleuritis,  peri- 
tonitis, appendicitis,  endocarditis,  lobular  pneumonia,  puerperal  infection,  pyamia,  abscess 
formation,  diphtheritic  inflammation. 

THE  form  assumed  by  the  inflammatory  reaction  varies  somewhat  with  the 
intensity  and  concentration  of  the  irritant,  and  with  the  kind  of  tissue  in- 
volved, but  in  principle  it  is  the  same  throughout.  Names  are  rather 
loosely  applied  to  these  different  forms  which  indicate  in  some  degree  their 
anatomical  characters.  Thus  a  catarrhal  inflammation  is  an  affection  of 
a  mucous  surface  in  which  the  irritant  is  not  intense  enough  in  its  action 
to  kill  the  epithelial  cells.  The  same  irritant  applied  to  the  peritoneal  or 
pleural  surfaces  might  produce  an  exudation  of  fluid  with  few  leucocytes 
only.  A  somewhat  more  intense  injury  in  these  serous  cavities  or  in  the 
alveoli  of  the  lungs  may  occasion  the  exudation  of  a  layer  of  fibrin  on  the 
surface — a  croupous  inflammation.  If  the  irritant  is  such  as  to  cause  the 
necrosis  of  the  epithelium  and  the  underlying  tissue,  with  an  extremely  in- 
tense, often  hsemorrhagic,  inflammatory  reaction,  in  which  the  fibrinous 
exudate  infiltrating  into  the  dead  tissue  binds  it  together  into  a  membrane- 
like  layer,  we  speak  of  it  as  diphtheritic  or  pseudomembranous  inflamma- 
tion. Although  the  diphtheria  bacillus  gives  rise  to  a  good  example  of  this 
type,  it  must  be  remembered  that  the  term  merely  indicates  the  anatomical 
condition,  so  that  not  every  diphtheritic  inflammation  is  caused  by  the  diph- 
theria bacillus.  According  to  the  distribution  of  the  inflammatory  irritant 
in  the  tissues  the  inflammatory  reaction  may  be  diffuse  or  concentrated. 
In  the  first  instance,  if  it  be  very  intense  and  accompanied  by  a  fibrino- 
purulent exudate,  it  is  often  called  phlegmonous;  in  the  second,  in  which, 
on  account  of  the  concentration  of  irritant  and  exudate,  necrosis  of  the 
tissue  and  intense  digestive  liquefaction  ensue,  an  abscess  is  formed.  Putre- 
faction may  be  associated  with  the  more  extreme  necrotizing  injuries  if 
the  tissue  is  exposed  to  invasion  by  putrefactive  organisms,  and  this  char- 
acter, often  spoken  of  as  gangrenous,  is  added  to  the  inflammatory  reaction. 

CATARRHAL  INFLAMMATION 

Catarrhal  inflammation  is  well  represented  by  the  familiar  coryza,  which 
is  an  acute  inflammatory  reaction  following  the  invasion  of  a  variety  of 
bacteria  into  the  upper  air-passages.  It  is  probable  that  the  infection  is 
favored  by  exposure  to  cold,  by  drafts,  and  all  the  other  widely  credited 
causes  of  colds,  but  undoubtedly  the  main  factor  is  the  transmission  of  the 

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bacteria  from  some  infected  person.  Recurrences  may  well  be  due  to  the 
infection  of  pockets  in  which  handkerchiefs  are  carried.  The  Micrococcus 
catarrhalis,  influenza  bacillus,  pneumococcus,  or  one  of  many  other  organ- 
isms may  be  concerned.  The  infection  is  quickly  followed  by  dryness  and 
reddening  of  the  mucosse,  which  then  swell  up  and  secrete  a  profuse  flow 
of  clear,  mucoid  fluid  with  some  desquamated  epithelial  cells.  Later, 
from  the  advent  of  leucocytes,  the  mucus-containing  fluid  becomes  thick 


Fig.  88. — Catarrhal  inflammation  of  a  bronchus. 

and  yellow.  After  a  time  it  decreases  in  amount  and  dries  on  the  mucous 
surfaces,  producing  crusts.  The  mucosa  in  section  shows  great  hypera3mia 
and  oedema,  with  an  excessive  production  of  mucus  by  the  goblet-cells  of 
the  epithelium.  Between  these  cells  there  wander  leucocytes,  but  no  fibrin 
is  formed  on  the  surface  (Fig.  88).  Catarrhal  inflammations  appear  in 
every  mucous  surface,  with  characters  similar  to  those  just  described. 
When  it  is  the  affair  of  a  narrow  tube,  such  as  the  gall-duct  or  the  Eusta- 
chian  tube,  the  swelling  of  the  tissue  may  produce  obstruction. 


PERICARDITIS,    PLEURITIS,    PERITONITIS  231 

The  more  intense  serofibrinous  and  fibrinopurulent  inflammations  are 
well  illustrated  by  the  various  effects  produced  by  bacteria  in  the  serous 
cavities. 

PERICARDITIS,  PLEURITIS,  PERITONITIS 

The  general  characters  of  these  processes  are  similar,  and  they  differ 
chiefly  in  their  mode  of  origin,  or  rather  in  the  portals  of  entry  of  the  organ- 
isms which  cause  them. 

The  walls  of  all  these  cavities  are  richly  supplied  with  blood-vessels,  and  in  the  peri- 
toneal cavity  there  hangs  the  peculiar  omentum,  which  is  largely  composed  of  such 
vessels,  although  it  may  be  also  laden  with  fat.  In  each  of  the  spaces  there  is  normally 
a  little  clear  fluid.  Each  is  lined  with  flattened  cells  of  mesoblastic  origin,  which  are 
not  identical  with  the  endothelium  of  the  blood  and  lymphatic  vessels.  These  form  a 
complete  lining  without  any  orifices  or  stomata,  such  as  have  been  declared  by  so  many 
authors  to  exist.  The  relation  of  the  lymphatic  channels  to  pleura  and  pericardium  is 
very  inadequately  studied,  but  in  the  case  of  the  peritoneum  it  is  better  known.  In  the 
abdominal  surface  of  the  diaphragm  and  in  the  floor  of  the  pelvis  are  the  two  most  con- 
spicuous areas,  where  an  absorbent  mechanism  is  presented.  There,  there  project  be- 
tween the  connective-tissue  fibres,  which  are  spread  apart  in  lozenge-shaped  spaces, 
thin-walled,  sac-like  endothelium-lined  structures  which  connect  abundantly  in  the 
depths  of  the  tissue  with  lymphatic  trunks.  These  are  completely  lined  by  the  endo- 
thelium, and  separated  from  the  peritoneal  cavity  practically  only  by  this  cell  layer  and 
the  overlying  layer  of  serosa  cells.  Occasional  fibres  stretch  across  them  when  they 
are  distended  like  a  rope  across  a  full  sail.  There  is  no  direct  communication  with  the 
peritoneal  cavity,  but  fluids  enter  by  diffusion,  and  solid  particles  are  carried  through  by 
leucocytes  between  the  cells,  or  are  pressed  through  free  along  the  same  lines.  Bacteria 
injected  into  the  peritoneum  reach  the  retrosternal  lymph-glands  or  the  thoracic  duct 
by  this  route  very  quickly  indeed.* 

Many  leucocytes  and  mononuclear  wandering  cells  lie  in  the  omentum  and  elsewhere 
in  subserous  tissues,  and  the  serosa  cells  themselves  are  somewhat  phagocytic. 

Absorption  from  the  pleura  seems  to  occur,  in  part  at  least,  through  the  lung,  since, 
when  carcinoma  cells  are  scattered  in  that  cavity,  they  lodge  and  grow  on  the  surface 
and  later  invade  and  actually  inject  the  lymphatic  channels  running  toward  the  hilum. 

Pericarditis  may  be  caused  by  a  great  many  organisms,  among  which  the 
most  common  are  the  pyogenic  micrococci,  the  unknown  cause  of  rheuma- 
tism, and  the  tubercle  bacillus.  They  are  thought  to  be  brought  directly 
to  the  pericardium  by  the  blood-stream,  since  it  is  difficult  to  trace  a  direct 
extension  from  a  pleural  infection,  and  such  pleurisies  occur  so  often  with- 
out pericarditis.  It  seems,  however,  that  they  must  sometimes  enter  in 
this  way  or  from  adjacent  lymph-glands.  Endocardial  and  myocardial 
infection  may  also  extend  to  the  pericardium.  That  bacteria  may  be 
introduced  in  stab  wounds  or  other  forms  of  traumatism  is  obvious. 
Rather  curious  is  the  frequent  occurrence  of  pericarditis  in  the  terminal 
stages  of  chronic  nephritis,  and  in  those  cases  it  is  generally  difficult  to 
find  any  bacteria. 

*  MacCallum:  " Absorption  of  Granular  Materials  from  Peritoneum,"  Johns  Hop- 
kins Hosp.  Bull.,  1903,  xiv,  105. 


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Sometimes  only  a  thin  film  of  fibrin  is  exuded  on  the  pericardial  surfaces 
without  effusion  of  fluid  (dry  pericarditis).  In  that  case  a  loud  creaking 
or  rubbing  sound  is  made  by  each  movement  of  the  heart.  If,  then,  fluid 
appears  in  excess,  the  surfaces  are  held  apart,  and  the  sound  is  lost  or  cut 
short.  So,  too,  when  a  thick  soft  layer  of  fibrin  is  formed  on  the  surface 
the  sounds  may  be  greatly  muffled.  In  this  condition  (serofibrinous  peri- 
carditis), or  even  when  the  fluid  is  pus-like  (fibrinopurulent  pericarditis), 
one  may  observe  that,  through  the  motion  of  the  heart,  the  fibrin  is  beaten 


Fig.  89.— Acute  fibrinous  pericarditis.     There  is  also  a  similar  exudate  on  the  pleural 

surface. 

into  compact  ridges  which  run,  roughly  speaking,  in  certain  transverse  and 
oblique  lines  which  are  fairly  constant.  The  heart  is  given  a  very  shaggy 
appearance  by  this  process  (Fig.  89). 

If  a  very  great  deal  of  fluid  be  exuded  into  the  pericardial  cavity,  the  sac 
is  gradually  dilated  and  will  accommodate  a  large  amount— far  more  than 
could  be  forced  into  it  suddenly.  There  comes  a  time,  however,  when  the 
heart  is  greatly  embarrassed  by  this  fluid  because  it  can  no  longer  expand 
properly  to  receive  the  blood. 


PLEURITIS,    PERITONITIS  233 

This  condition  is  especially  well  seen  when  a  sudden  haemorrhage  occurs  into  the 
pericardial  sac,  and  may  be  imitated  experimentally  by  distending  the  sac  with  oil  or 
salt  solution  under  pressure.  The  arterial  pressure  falls,  the  venous  pressure  rises,  and 
the  heart  collapses  and  stops  beating.  If  the  pressure  is  removed  quickly  enough,  it 
will  recover,  with  restoration  of  normal  pressure  relations. 

In  other  cases,  as  so  often  happens,  when  little  or  no  fluid  is  exuded, 
or  if,  later,  the  fluid  is  absorbed,  the  pericardial  layers  covered  with  exudate 
come  together  and  adhere;  granulation  tissue  springs  up  from  each  sur- 
face and,  replacing  the  fibrin,  binds  the  pericardial  sac  to  the  surface  of  the 
heart.  Blood  capillaries  arising  from  opposite  layers  anastomose  with  one 
another  and  complete  the  organic  union  of  the  two  surfaces,  by  forming  a 
vascular  fibrous  tissue.  The  motion  of  the  heart  stretches  and  keeps  loose 
these  adhesions,  so  that  practically  always  the  heart  can  move  about  a 
little  within  the  sac.  Nevertheless,  if  dense  adhesions  exist  also  between 
the  outer  surface  of  the  pericardium  and  the  lung,  the  heart  in  contracting 
will  be  forced  to  pull  directly  upon  the  lungs  and  upon  the  diaphragm. 
This  shows  itself  in  each  contraction  by  a  drawing  in  of  the  diaphragmatic 
insertion,  which  visibly  retracts  the  chest-wall  along  that  line  in  children, 
and  is  followed  by  a  very  great  hypertrophy  of  the  whole  heart.  In  other 
cases  in  which  the  external  adhesions  are  absent  there  is  no  such  hyper- 
trophy. 

The  fresh  exudate  is  composed,  of  course,  of  outwandered  leucocytes, 
red  corpuscles,  and  fibrin,  beside  the  fluid.  Most  of  the  serosa  cells  persist 
for  a  time  in  an  indistinct  row  in  their  old  site  (Fig.  90),  while,  as  stated 
above,  they  remain  able  to  proliferate  actively  in  any  place  where  they  are 
not  covered  by  exudate,  and  quickly  reline  any  part  of  the  pericardial 
cavity  which  has  not  been  obliterated.  In  the  midst  of  the  fibrous  ad- 
hesions one  may  find  spaces  lined  with  such  cells  which  have  proliferated 
in  this  way.  The  adhesions  may  be  localized  in  certain  areas,  where  they 
are  usually  drawn  out  into  bands.  If  these  break  through,  the  stumps 
flatten  themselves  into  opposed  plaques  which  remain  for  a  long  time  on 
the  surface  of  the  heart  and  the  opposite  area  of  the  sac-wall  as  the  so-called 
tendinous  flecks  or  milky  patches.  Other  explanations  are  offered  for 
these  thickenings  of  the  epicardium,  and  will  be  referred  to  later. 

If  very  thick,  dense  layers  of  fibrous  tissue  are  formed— if  the  adhesions  are  firm  or 
tunneled  with  channels  filled  with  yellowish,  opaque  fluid,  or  if,  with  the  thickening  of 
the  sac  and  epicardium,  a  h^morrhagic,  fibrinous,  and  fluid  .exudate  accumulates,  the 
tuberculous  nature  of  the  affection  may  be  suspected,  and  close  inspection  will  usually 
show  little  nodular  tubercles  in  the  granulation  tissue  (cf.  under  Tuberculosis). 

Pleuritis  or  pleurisy  arises  in  a  similar  way,  although  there  are  more 
opportunities  for  the  advent  of  infection  into  the  pleural  cavity.  Every 
pneumonic  process  which  approaches  the  surface  of  the  lung  causes  at  least 
a  localized  pleurisy.  The  occurrence  of  a  sterile,  hsemorrhagic  infarction 
in  the  lung  is  equally  productive  of  a  localized  pleural  exudation  or  coagu- 


234 


TEXT-BOOK  OF  PATHOLOGY 


lation  of  fibrin.  The  types  of  exudate  and  the  method  and  results  of  its 
organization,  with  the  formation  of  adhesions,  are  exactly  as  in  the  case 
of  the  pericardium  (Fig.  91).  Great  accumulation  of  fluid  in  the  pleural 
cavity  relieves  at  once  the  pain  caused  by  the  rubbing  together  of  inflamed 
surfaces,  but  tends  to  cause  dyspnoea  through  the  compression  of  the  lung. 
There  are  also  direct  anatomical  changes  produced  in  the  lung  by  this 


Fig.  90. — Acute  pericarditis,  parietal  pericardium.  Cross-sections  of  compact  ridges 
of  older  fibrin  are  separated  by  a  network  of  fresher  fibrin.  The  serosa  cells  are  still 
visible. 

pressure,  consisting  essentially  in  the  collapse  of  the  alveoli,  with  the  ex- 
pulsion of  the  contained  air. 

Slight  inflammatory  processes  in  the  pleura  may  heal  completely,  leav- 
ing no  trace  behind.  More  severe  alterations  with  fibrinous  exudate  usu- 
ally cause  the  formation  of  granulation  tissue  to  replace  the  exudate,  which 
finally  binds  together  the  pleural  surfaces  with  adhesions.  Repetition  of 


PERICARDITIS,    PLEURITIS,    PERITONITIS  235 

the  infection  may  call  out  a  new  exudate  in  the  meshes  and  crevices  of 
these  fibrous  adhesions.  In  other  cases  an  abundant  purulent  exudate 
persists  for  a  time  and  becomes  walled  off  (empyema)  and  surrounded  by 
a  dense  fibrous  capsule  which  must  be  cut  into  and  evacuated  if  recovery 


;^  ^  ^~->Vr,-: •-'"''I/.';-}' " Y«;  .'V:',"1"'? /'         /*•'/'*:/ W^  -.--  "  '  A'*-v" 
^V  V  .*'?\?i''-;.  X^    ''-iVr'v/l'^ . ,  ;-''.'.  ^  /  ;V •? itir;^ -i\ 


Fig.  91.— Acute  fibrinopurulent  pleurisy.     The  serosa  ceUs  are  stiU  to  be  seen  covering 

the  lung. 

is  to  be  expected  in  a  reasonable  time  (Fig.  92).  Otherwise  a  long  time  is 
required  for  the  thickening  and  gradual  removal  of  the  exudate,  and  in  the 
meanwhile  the  pleural  tissues  about  it  become  enormously  thickened  and 
form  a  dense,  tendon-like  wall  as  hard  as  cartilage  and  sometimes  nearly 
an  inch  thick.  Great  deformity  of  the  chest  follows  such  protracted  em- 


236  TEXT-BOOK  OF  PATHOLOGY 

pyemas  for  if  the  accumulation  of  exudate  is  large,  the  lung  is  generally 
found  compressed  into  a  small  mass  retracted  against  the  vertebral  column, 
and  fixed  in  this  compressed  state  by  the  growth  of  fibrous  tissue  through- 
out it. 

Peritonitis.— Little  is  known  of  peritoneal  inflammation  produced  with- 
out the  agency  of  bacteria,  although  in  some  instances  in  which  bacteria 


Fig.  92. — Empyema  with  thick  fibrinopurulent  exudate  lining  the  pleural  cavity. 
Compression  and  atelectasis  of  the  lung  caused  by  the  large  amount  of  fluid  which 
was  in  the  pleural  cavity. 

have  not  been  actually  demonstrated  the  exudate  has  been  ascribed  to 
chemical  irritants.  Bacteria  may  enter  by  way  of  the  blood-stream,  by 
growth  and  spreading  from  an  adjacent  or  contained  tissue  which  is  dis- 
eased, or  by  being  directly  introduced  through  a  wound  in  the  abdominal 
wall  or  a  perforation  of  one  of  the  bacteria-laden  organs  which  lie  in  the 


PERICARDITIS,    PLEURITIS,    PERITONITIS  237 

peritoneal  cavity.  Naturally,  the  variety  of  organisms  which  may  be 
concerned  is  almost  unlimited,  but  in  the  ordinary  course  of  events  the 
pyogenic  micrococci  and  bacilli  of  the  colon  group  are  most  commonly 
found.  The  tubercle  bacillus  occupies  a  special  place  as  a  common  exci- 
tant of  peritoneal  inflammation,  and  the  gonococcus  is  occasionally  respon- 
sible. Of  other  organisms,  something  will  be  said  elsewhere. 

From  an  anatomical  point  of  view  peritoneal  inflammation  resembles 
closely  that  of  the  pleura  and  pericardium,  except  that  it  is  more  frequently 
seropurulent  in  character.  Nevertheless,  there  are  many  instances,  es- 
pecially when  the  inflammation  is  not  diffuse  but  confined  to  a  limited 
region,  in  which  it  appears  as  fibrinous  or  fibrinopurulent  exudate,  which 
glues  together  opposing  surfaces  and  is  soon  replaced  by  a  growth  of  blood- 
vessels and  connective-tissue  cells  which  form  fibrous  adhesions.  This  is, 
of  course,  the  most  favorable  type,  for  the  adhesions  prevent  the  further 
spread  of  infection  and  may  themselves  be  mechanically  harmless,  or  later, 
when  healing  is  complete,  even  become  attenuated  and  finally  disappear. 
On  the  other  hand,  a  general  diffusion  of  bacteria,  especially  if  there  be 
injured  tissue,  foreign  material,  or  a  considerable  accumulation  of  fluid  to 
favor  their  growth,  leads  to  hypersemia  of  the  whole  enormous  surface  of 
the  peritoneum,  with  the  pouring-out  of  quantities  of  fluid,  leucocytes, 
and  fibrin,  and  the  absorption  of  much  poisonous  material  and  many 
bacteria  into  the  blood-stream.  Naturally,  the  outcome  of  such  an  in- 
fection depends  upon  the  balance  between  the  power  of  resistance  of  the 
individual  and  the  virulence  of  the  bacteria,  and  this  balance  is  greatly 
affected  by  the  presence  of  injured  tissue  in  the  peritoneum.  The  normal 
peritoneum  can  annihilate  many  more  bacteria  without  the  appearance  of 
any  peritonitis. 

Primary  or  hsematogenous  peritonitis  is  often  produced  by  the  pneu- 
mococcus,  which  gains  entrance  to  the  body  by  way  of  the  tonsils  or 
some  similar  portal  of  entry.  In  a  case  recently  observed  at  autopsy 
no  distinct  lesion  which  could  have  played  this  part  was  discoverable  on 
most  careful  search,  and  yet  the  whole  peritoneal  surface  was  covered 
with  a  thick,  greenish-yellow,  fibrinopurulent  exudate  which  slipped  off 
easily  into  the  turbid  fluid  which  filled  the  cavity.  The  Pneumococcus 
mucosus  was  there  in  pure  culture.  Secondary  forms  of  peritonitis 
include  those  which  follow  gunshot  or  other  wounds  of  the  abdomen, 
among  which  surgical  operation  wounds  unfortunately  hold  a  high  place, 
because  they  are  so  frequently  concerned  with  infected  tissues  and  organs 
in  the  cavity.  The  seriousness  of  such  injuries  as  gunshot  or  stab  wounds 
lies  chiefly  in  their  opening  into  the  stomach  or  intestine  and  allowing  the 
escape  of  food  or  faecal  material  loaded  with  bacteria.  The  peritonitis 
which  follows  surgical  intervention  is  usually  the  result  of  unskilful  attempts 
to  anastomose  intestinal  loops  or  other  infected  organs  in  which  tissues 
are  left  stretched  and  badly  supplied  with  blood,  or  sutures  passed  through 
an  infected  area  with  constriction  of  too  much  tissue. 


238  TEXT-BOOK  OF  PATHOLOGY 

Secondary  peritonitis  resulting  directly  from  disease  of  the  organs  lying 
in  the  cavity  may  begin  in  several  ways.  Ulcer ation  of  stomach  or  duo- 
denum proceeds  often  to  perforation  and  discharge  of  their  contents. 
Were  it  not  for  the  food,  the  juices  of  these  parts  of  the  digestive  tract  are 
almost  sterile,  and  prompt  surgical  operation  with  closure  of  the  perfora- 
tion usually  cures  the  patient.  Typhoid  ulcerations  in  the  lower  ileum, 
tuberculous  ulcers,  amcebic  and  other  dysenteric  ulcers  and  the  phlegmon- 
ous  and  gangrenous  forms  of  appendicitis  rupture  and  perforate  in  the  same 
way,  with  discharge  of  bacteria  of  the  intestinal  contents,  as  well  as  those 
which  have  directly  caused  the  lesion.  Of  these,  the  typhoid  ulcers  are 
perhaps  least  likely  to  be  guarded  by  adhesions.  Even  without  actual 
perforation,  peritonitis  arises  when  the  wall  of  the  intestine  becomes  necro- 
tic,  so  that  bacteria  can  wander  through,  as  happens  in  strangulated  hernia, 
intussusception,  volvulus,  infarction  of  the  intestine  through  embolism  or 
thrombosis  of  the  mesenteric  vessels,  etc.  In  intestinal  obstruction  from 
whatever  cause  the  part  of  the  intestine  above  the  obstruction  becomes 
greatly  dilated  and  stretched,  and  its  mucosa  ulcerated,  so  that  the  passage 
of  bacteria  through  the  wall  is  easy,  even  if  not  precipitated  by  actual  rup- 
ture of  one  of  these  ulcers. 

Extension  of  the  infective  process  from  inflammatory  lesions  of  the  gall- 
bladder and  ducts,  from  renal  and  perirenal  abscesses,  from  the  Fallopian 
tubes,  or  even  through  the  walls  of  the  uterus  in  puerperal  infections,  occurs 
but  requires  no  special  explanation  here. 

Gonococcal  infection  by  way  of  the  Fallopian  tubes  may  produce  diffuse 
peritonitis,  with  rather  dry,  tenacious  exudate  of  fibrin.  It  is  not  common. 

APPENDICITIS 

The  extraordinary  frequence  of  appendicitis,  and  its  extreme  seriousness 
in  many  cases,  make  its  study  important.  It  will  serve  well  as  an  example 
of  bacterial  infection,  followed  by  inflammation  and  generally  by  healing. 

The  wall  of  the  appendix  is  composed  of  various  tissues  which  correspond  with  those 
making  up  the  rest  of  the  intestine.  The  lumen  may  be  stretched  into  cylindrical  form, 
but  in  general  collapses  into  a  narrow  space,  which  is  Y  shaped  on  cross-section,  one 
limb  of  the  Y  reaching  toward  the  mesenteric  attachment.  The  mucosa  sinks  into 
crypts,  as  in  the  colon,  but  has  no  villi.  It  is  peculiarly  rich  in  agminated  nodules  of 
lymphoid  tissue.  The  appendix  most  commonly  extends  inward  to  the  brim  of  the  pel- 
vis from  the  caecum,  but  great  variations  are  found  in  its  position,  as  well  as  in  its  size, 
its  mesenteric  attachment,  and  in  its  relation  to  the  folds  of  the  peritoneum.  These 
matters  of  surgical  interest  may  be  read  of  in  Kelly's  monograph. 

Appendicitis  is  an  acute  infectious  disease  produced  by  the  invasion  of 
bacteria  from  the  lumen  into  the  mucosa  and  other  walls.  The  hsema- 
togenous  infection  of  the  appendix  wall  by  bacteria  transported  from  in- 
fected tonsils,  which  Kretz  regards  as  a  common  origin  of  appendicitis,  has 
not  been  clearly  shown  to  take  place.  If  it  does  so,  it  must  be  considered  an 
exceptional  occurrence,  and  does  not  explain  the  majority  of  cases  in  which 


APPENDICITIS 


239 


infection  from  the  lumen  can  be  conclusively  demonstrated.  Appendicitis 
may  heal,  leaving  characteristic  scars  which  predispose  to  a  renewed  at- 
tack, and  it  is  usually  in  this  way,  that  is,  in  the  occurrence  of  repeated 
attacks,  that  one  is  justified  in  speaking  of  a  chronic  appendicitis. 

Strangely  enough,  there  is  still  much  question  as  to  the  bacteria  which 
cause  it,  and  probably  several  sorts  are  concerned.  Aschoff  and  his  stu- 
dents find  a  Gram-positive  diplococcus  and  Gram-positive  bacilli  as  the 
most  characteristic  organisms.  Apparently,  streptococci,  perhaps  accom- 


Fig.  93. — Acute  appendicitis  with  beginning  necrosis  of  the  mucosa. 

panied  by  the  colon  bacillus,  have  been  found  most  often,  but  a  great  many 
other  forms  are  also  described,  even  including  certain  anaerobic  bacilli. 
Mechanical  factors  favor  the  lodgment  of  the  organisms  in  the  mucosa, 
especially  the  kinking  or  sharp  bending  of  the  terminal  portion  or  the  pres- 
ence of  obstruction  caused  by  previous  inflammation  and  scarring.  In- 
fected foreign  bodies  of  a  sharp  angular  form  may  have  the  same  effect, 
but  the  prevalent  idea  that  foreign  bodies  are  commonly  present  and  the 
ordinary  cause  of  the  disease  is  quite  erroneous.  Nearly  all  the  cherry- 


240 


TEXT-BOOK  OF  PATHOLOGY 


stones"  and  " date-seeds"  or  " grape-seeds"  which  are  found  in  the  appen- 
dix are  really  not  seeds  at  all,  but  concentrically  laminated  masses  of  faecal 
material.  They  are  injurious  inasmuch  as  they  may  cause  obstruction  and 
allow  bacteria  to  accumulate  behind  them,  but  Aschoff  insists  that  they 
do  not  themselves  injure  and  infect  the  mucosa,  but  that  they  rather  pro- 
tect it. 
As  may  be  determined  from  the  study  of  the  very  early  stages,  infection 


Fig.  94.— Acute  appendicitis.     A  portion   of   Fig.   93  enlarged  to  show  the  earliest 

changes. 

begins  in  the  mucosa  in  the  bottom  of  one  of  the  grooves  which  form  the 
Y-  or  X-shaped  lumen  in  cross-section.  Starting  as  a  tiny  break  in  the 
epithelium,  with  an  underlying  accumulation  of  polymorphonuclear 
leucocytes,  the  inflammatory  reaction  spreads  outward  in  a  widening  area 
toward  the  outer  surface.  This  diffuse  inflammation  may  be  practically 
bacteria  free  in  its  outer  part,  but  nevertheless  reaches  the  serosa  and  ex- 
tends along  the  walls  of  the  appendix.  It  is  the  phlegmonous  type  of 


APPENDICITIS 


241 


Aschoff,  and  may  sooner  or  later  show  the  formation  of  small  abscesses 
anywhere  in  the  affected  region.  Such  abscesses,  causing  liquefaction 
of  the  wall,  bring  about  perforation  either  into  the  lumen  of  the  organ  or 
into  the  peritoneum.  Such  rupture  to  the  outside  is,  of  course,  the  origin 
of  an  acute  spreading  peritonitis,  unless  it  is  limited  by  adhesions  from  a 
previous  attack.  Even  without  actual  perforation,  however,  the  extension 
of  the  phlegmonous  inflammation  sets  up  an  acute  fibrinous  exudative 
peritonitis  over  the  wall  of  the  appendix  itself.  The  organ  is  swollen  and 
reddened,  and  roughened  by  the  presence  of  the  fibrin.  When  an  abscess 
approaches  the  surface,  it  is  recognizable  as  an  opaque  yellow  spot  in  the 
congested  wall  (Fig.  95). 

It  is  even  more  common  to  find  that,  instead  of 
remaining  as  a  minute  lesion  of  the  mucosa,  the 
infection  spreads  so  as  to  cause  rather  extensive 
patches  of  necrosis,  in  which  the  outlines  of  the 
crypts  can  still  be  made  out,  although  a  dense  fibrin- 
ous exudate  welds  the  dead  tissue  of  the  mucosa  into 
a  sort  of  false  membrane.  Numerous  haemorrhages 
accompany  this,  and  with  the  loosening  and  dis- 
charge of  the  false  membrane  deep  ulcers  are  left 
(Fig.  96).  Extension  into  the  depth  is  rapid,  and 
may  proceed  to  destruction  of  the  whole  thickness 
of  the  wall  and  perforation,  especially  since  the 
cavity  is  often  distended  to  bursting  with  the  exu- 
date. Such  extreme  lesions  are  not  likely  to  heal, 
and  unless  saved  by  operation,  the  patient  succumbs 
to  a  general  peritonitis.  If,  however,  there  have 
been  previous  attacks  of  milder  character,  the  ap- 
pendix may  have  become  adherent  to  the  surround- 
ing tissues  by  the  organization  of  fibrinous  exudate 
between  its  surface  and  that  of  adjacent  coils  of  in- 
testine. In  that  case  the  material  discharged  through 
the  perforation  may  not  pass  into  the  general  peri- 
toneal cavity,  but  only  into  contact  with  these  adhesions,  where  an  abscess 
is  then  formed.  Such  periappendiceal  abscesses  are  sometimes  quite  large, 
and  may  contain  the  necrotic  debris  of  the  appendix,  floating  in  pus.  They 
are  perhaps  not  so  common  now  as  formerly,  nor  so  common  as  they 
would  be  in  an  age  of  less  prompt  and  aggressive  surgeons. 

Slighter  lesions  which  stop  short  of  destruction  of  the  whole  wall  may 
heal  without  intervention,  and  such  a  person  is  then  liable  to  a  renewed 
acute  attack  unless  his  appendix  is  removed  by  operation  in  the  interval. 
The  mucosa  may  not  have  been  very  widely  destroyed,  especially  in  the 
suppurative  form,  but  even  when  it  is  Ulcerated  away  over  one  side  of  the 
lumen,  it  is  regenerated  from  that  which  remains  and  the  lumen  is  kept 
open.  If  it  be  destroyed  all  the  way  round,  the  cavity  usually  collapses 


Fig.  95. — Acute  ap- 
pendicitis with  per- 
forating ulcer. 


242 


TEXT-BOOK  OF  PATHOLOGY 


and  becomes  obliterated  by  a  continuous  growth  of  granulation  tissue 
(Fig.  97).     Even  when  the  destruction  has  been  very  slight  and  the  inflam- 


Fig.  96.— Acute  phlegmonous  appendicitis. 

matory  reaction  in  the  walls  moderate,  scars  are  left  which  indurate  the 
submucosa  and  which  persist  in  the  interstices  of  the  musculature.     The 


APPENDICITIS 


243 


elastic  tissue,  which  has  a  characteristic  arrangement  for  each  layer,  is 
partly  destroyed,  and  though  regenerated,  is  left  greatly  distorted. 

Various  complications  and  sequelae  occur,  among  which  is  the  general 
or  localized  peritonitis  already  mentioned.  This,  if  survived,  often  leaves 
adhesions,  which  may  later  cause  mechanical  obstruction  to  the  intestine, 
either  by  kinking  and  constricting  loops,  or  by  facilitating  the  occurrence 


•':^;'  •;'•'.'.'  y>:  "!v;  ':•  •'••'  - ; :  "£  -:.-v  'S  .'^ .-.;"'"'.  7§^ 


-  t? 


a 


V  .  v 


wr"  V?"' •'•  •'•'- 
&  \\fv-.    "V- 

t?ii;:" 


^•v:1feSliiiP^^ :  • ; .  •  ;J| 


Fig.  gy.—Sequel  of  old  healed  appendicitis.     Obliteration  of  lumen. 

of  internal  hernial  entanglements.  Extension  or  burrowing  of  the  peri- 
appendiceal  abscess  may  lead  to  the  accumulation  of  pus  in  extraordinary 
places,  among  which  the  subdiaphragmatic  region  about  the  liver,  in  front 
or  behind,  and  on  either  side,  is  conspicuous.  These  are  the  so-called  sub- 
phrenic  abscesses,  which  may,  of  course,  have  other  points  of  origin. 
Thrombosis  of  the  nearby  iliac  and  femoral  veins  may  follow  appendi- 


244  TEXT-BOOK  OF  PATHOLOGY 

citis,  but  more  serious,  and  even  more  characteristic,  is  the  formation  of  an 


Fig.  98.— Suppurative  pylephlebitis  arising  from  appendix  abscess.     Numerous  abscesses 

in  the  liver. 


infected  thrombus  in  the  branches  of  the  portal  vein  which  lead  away  from 
the  appendix  itself.     On  this  day  of  writing  a  case  has  been  observed  in 


ENDOCARDITIS  245 

which  the  branches  of  the  vein  leading  from  an  abscess  around  the  appendix 
were  found  filled,  not  with  blood,  but  with  a  purulent,  greenish-white 
material.  The  main  trunk  of  the  vein,  greatly  dilated  and  thickened,  was 
full  of  the  same  material.  The  splenic  vein  was  plugged  at  its  entrance  by  a 
firm  thrombus,  so  that  the  inferior  mesenteric  vein  which  joins  it  before 
that  point  was  reached  evidently  discharged  its  blood  by  way  of  the  splenic 
vein  and  anastomosing  channels  to  the  stomach  and  oesophagus.  In  the 
liver  every  branch  of  the  portal  was  full  of  soft,  purulent  thrombus  ma- 
terial, and  there  were  numerous  large  abscesses  and  groups  of  smaller 
ones.  This  is  the  so-called  suppurative  pylephlebitis.  In  this  case  the 
infection  extended  even  further,  and  there  were  abscesses  in  lungs  and 
spleen  (Fig.  98). 

LITERATURE 

Aschoff:    Wurmfortsatzentziindung,  Jena,  1908. 
Aschoff :  Ergeb.  d.  inn.  Med.  u.  Kinderh.,  1912,  ix,  1. 
Kelly  and  Hurdon:   Diseases  of  Vermiform  Appendix,  1905. 
Kretz:   Mitth.  a.  d.  Grenz.  d.  Med.  u.  Chir.,  1907,  xvii,  1. 
Kretz:   Verb.  Dtsch.  Path.  Gesellsch.,  1907,  x,  229;  1910,  xiv,  157. 
Noll:   Mitth.  a.  d.  Grenz.  d.  Med.  u.  Chir.,  1907,  xvii,  249. 
Oberndorfer:   Ergeb.  d.  allg.  Path.,  1909,  xiiii,  527. 
Watzold:  Ziegler's  Bsitr.,  1907,  xlii,  260. 


ENDOCARDITIS 

Bacterial  or  other  injury  to  the  heart  valves  or  to  any  other  part  of  the 
endocardium  is  like  injury  to  the  endothelium  of  the  blood-vessels,  and  is 
peculiar  in  its  results  inasmuch  as  any  reaction  must  occur  in  the  streaming 
biood.  The  common  effect,  just  as  in  the  case  of  a  vein,  is  the  formation 
of  a  thrombus  upon  the  injured  place.  This  generally  occludes  the  vein, 
but  in  the  wider  space  of  the  heart,  and  especially  on  the  valves,  where  the 
stream  is  rapid,  it  forms  an  irregular  cap  of  platelets  with  a  little  fibrin  and 
a  few  leucocytes  and  red  corpuscles.  It  is  rather  important  to  realize  that 
this  is  primarily  a  thrombus,  and  that  it  is  only  later,  in  response  to  the 
presence  of  active  bacteria,  that  an  acute  inflammatory  process  is  added 
with  exudation  from  such  capillaries  as  exist  in  the  valves.  Of  course, 
when  bacteria  settle  on  the  endocardium,  covering  the  musculature  of  the 
heart,  the  primary  thrombus  formed  by  the  passing  blood  is  far  more 
quickly  joined  by  an  acute  inflammatory  reaction  from  the  heart-wall 
(Fig.  99). 

It  seems  that  all  cases  of  thrombo-endocarditis  are  really  dependent 
upon*  the  invasion  of  bacteria  into  the  endocardium,  although  it  is  not 
always  possible  to  demonstrate  their  presence.  The  mild  and  beginning 
forms  that  produce  very  small  warty  or  verrucose  vegetations  are  the  ones 
in  which  it  is  most  difficult  to  find  organisms.  They  occur  very  often  with 
rheumatism,  of  which,  in  spite  of  the  persistently  repeated  claims  that  it  is 


246  TEXT-BOOK   OF   PATHOLOGY 

the  effect  of  diplococcus  or  streptococcus  infection,  we  do  not  yet  know  the 
cause. 


.-.-:. -;X-v.>  •&?.*•. 

/.:£~O  lv'V"ft.- 

'••     .'•     *!'o  -    .      .'    -        -.    '      ?:?>-. 


s 


Fig.  99. — Acute  endocarditis.     Vegetations  upon  the  wall  of  the  auricle  showing  great 
numbers  of  bacteria  and  an  intense  inflammatory  reaction. 

It  is  thought  possible  that  toxins  alone  might  produce  destructive  lesions  of  the  en- 
dothelium  of  the  valves,  and  numerous  experiments  have  been  made,  with  some  §uccess, 
in  producing  such  endothelial  injuries  because  it  seemed  possible  that  they  might  in  turn 
afford  a  foothold  for  bacteria.  There  are  thickenings  of  the  valves  which  occur  in  old 
people,  and  which  are  thought  to  be  gradually  produced  by  mechanical  strain,  and  there 
are  thickenings  and  distortions  brought  about  by  a  process  apparently  identical  with 


ENDOCARDITIS  247 

arteriosclerosis  (Beitzke,  Martino).  But  the  lesions  which  we  may  call  endocarditis 
seem  to  be  essentially  bacterial  in  origin.  The  syphilitic  alterations  of  the  valves  will  be 
discussed  separately. 

Many  organisms  are  concerned  in  the  production  of  endocardial  vege- 
tations, but  the  different  forms  of  streptococci,  the  Staphylococcus  aureus, 
the  pneumococcus,  and  the  gonococcus  are  by  far  the  most  important. 
The  influenza  bacillus  has  been  found  several  times,  and  various  other 
bacteria  in  single  cases,  but  such  organisms  as  the  typhoid  bacillus,  the 
diphtheria  bacillus,  the  colon  bacillus,  etc.,  are  probably  not  the  actual 
cause  of  the  lesion,  although  they  may  be  found  as  secondary  invaders. 

Clearly,  the  bacteria  reach  the  valves  by  way  of  the  circulating  blood, 
and  from  the  situation  of  the  vegetations  one  cannot  escape  the  impression 
that  they  lodge  directly  upon  the  surface  of  the  valve.  It  is  not  at  any 
indifferent  point,  but,  as  is  clear  from  the  inspection  of  any  large  series  of 
affected  hearts,  upon  the  so-called  line  of  closure,  that  they  produce  their 
first  effects.  It  is  easily  seen  that  the  valves  do  not  come  together  only  at 
their  very  edges,  but  rather  along  a  somewhat  thickened  or  fortified  line 
a  short  way  back  from  the  edge,  this  line  being  supported  in  the  case  of  the 
semilunar  valves  by  the  corpora  Arantii.  In  these  valves  the  delicate  film 
which  forms  the  actual  edge  accurately  completes  the  closure,  even  though 
it  is  often  perforated  by  many  fenestrations.  So,  too,  in  the  tricuspid  and 
mitral  valves,  upon  the  backs  of  which  the  insertions  of  the  chordae  ten- 
dinese  are  spread  out  in  several  rows,  the  filmy  edge  which  is  also  held  tense 
by  delicate  cords  accurately  completes  the  closure.  Thus,  it  is  not  on  this 
complementary  film  that  vegetations  first  appear,  but  definitely  along  the 
main  line  of  closure,  from  which  they  extend  so  as  to  involve  any  other  part 
of  the  valve,  the  heart-wall,  or  the  chordae  tendinese.  How  they  happen 
to  lodge  there  has  long  been  discussed,  and  it  has  generally  been  thought 
that  the  mechanical  beating  together  of  the  valves  at  this  point  catches 
them  up  from  the  blood  and  drives  them  into  close  contact  with  the  tissue, 
so  that  they  cannot  slip  by  as  they  do  over  the  smooth  walls  of  the  arteries. 
Nevertheless,  one  sometimes  sees  independent  lesions  of  the  same  kind 
on  the  endocardium  of  the  auricle  or  ventricle.  Rosenow  has  recently  re- 
vived the  old  view  of  Koester  that  bacteria  reach  the  valve  as  emboli  by 
way  of  the  capillary  blood-vessels.  This  idea  was  set  aside  by  Coen  and 
v.  Langer,*  who  found  that  the  semilunar  valves  contained  no  capillaries, 
and  the  atrioventricular  valves  were  supplied  only  at  their  base,  so  that 
such  embolism  seemed  impossible.  Rosenow  has  shown  that,  with  large 
injections  of  the  Streptococcus  viridans,  he  can  produce  bacterial  colonies 
in  the  substance  of  the  valves  beneath  intact  endothelium,  and  surrounded 
by  a  gross  haemorrhage.  Such  haemorrhages  are  best  seen  two  or  three  days 
after  the  injection,  and  before  any  obvious  vegetation  has  appeared  on  the 
valve.  Whether  they  offer  the  explanation  of  the  mechanism  of  the  first 

*  Arch.  f.  mikr.  Anat.,  xxvii;  Virch.  Arch.,  109. 


248 


TEXT-BOOK    OF    PATHOLOGY 


appearance  of  endocardial  vegetations  is  by  no  means  settled,  and  Rose- 
now  himself  states  that  they  can  be  most  easily  understood  in  those  cases 
in  which  previous  injury  of  the  valves  has  led  to  their  vascularization. 

In  the  first  edition  of  this  book  a  paragraph  was  devoted  to  the  description  of  injec- 
tions of  the  dog's  heart  valves  made  by  introducing  India-ink  into  the  circulation  after 
obstructing  the  aorta.  The  ink  penetrated  to  the  bases  of  the  valves,  but  not  to  the 
line  of  closure.  Bayne-Jones*  explains  this  as  the  result  of  insufficient  pressure  from 
the  dying  heart.  He  himself  produced  beautiful  injections  of  a  network  of  capillaries 
reaching  the  extreme  edges  of  the  auriculo ventricular  valves,  but  in  the  semilunar  valves 
ending  like  the  top  of  a  hedge  along  the  basal  part  of  the  valve.  These  injections  give 


Fig.  100.— Verrucose  endocarditis  of  the  mitral  valve  with  chronic  adhesive  pericarditis. 
(From  a  case  of  rheumatism.) 

an  anatomical  basis  for  Koester's  view  as  far  as  the  auriculoventricular  valves  are  con- 
cerned. 

While  cases  of  endocarditis  differ  among  themselves  in  detail  according 
to  the  bacteria  concerned  and  their  localization,  they  are  alike  in  principle 
allowing  rheumatism  show  the  smallest  thrombi  or  vegetations 

*  Bayne-Jones,  S.:  Amer.  Jour,  of  Anatomy,  1917,  xxi,  449. 


ENDOCARDITIS 


249 


along  the  line  of  closure,  although  with  time  these  may  be  added  to  until  a 
considerable  size  is  attained.  This  is  the  so-called  verrucose  endocarditis 
and  the  vegetations  in  which  it  is  often  impossible  to  find  any  bacteria 
become  organized  quickly,  so  that  they  are  firm  and  gray  and  no  longer 
easily  pulled  off  Even  with  fairly  complete  healing  they  may  be  recog- 
nizable by  their  form,  but  in  other  cases  the  scar  leads  to  thickening  and 
shortening  of  the  valve, 
which,  with  the  nodular 
irregularities  along  the 
edges,  make  the  closure 
inefficient  (Fig.  100). 

The    streptococcus    is 
likely    to    give    rise    to 
larger  vegetations,  which 
grow    rapidly    and    are 
found  in  a  crumbly,  soft 
state.    Occasionally  they 
are  so  massive  as  prac- 
tically   to    occlude    the 
whole    valvular     orifice 
(Fig.  101).     This  is  true, 
too,  of  those  produced  by 
the  gonococcus,  although 
there  a  hint  as  to  the 
nature  of  the   infection 
may  be  gained  from  its 
frequent    occurrence    in 
the  valves  of   the  right 
side  of    the   heart,   and 
from  the  rapid  destruc- 
tion of  the  valves  them- 
selves, so  that  one  fre- 
quently sees  great  throm- 
bus masses  flapping  back  and  forth  on  the  end  of  a  thread  of  tissue, 
which  is  all  that  remains  of  the  valve.     Naturally,  either  obstruction  or  an 
extreme  insufficiency  follows  such  events.     Naturally,  too,  emboli  of  in- 
fected thrombus  particles  are  scattered  into  the  circulation.     Such  ulcer- 
alive  endocarditis  may  be  produced  by  the  Staphylococcus  aureus,  which  is 
rapidly  destructive,  and  also  by  the  pneumococcus.     Every  position  may 
be  ultimately  assumed  by  the  vegetations;   they  grow  away  from  the  line 
of  closure  to  the  edge  of  the  valve,  and  down  into  the  sinus  of  Valsalva  or 
along  the  chordae  tendineae  (S.  viridans).     These  may  rupture,  since  it  is 
the  advance  of  bacteria  which  determines  the  extension  of  the  vegetations, 
and  the  necrotic  ends  of  the  broken  chorda?  flap  loosely  in  the  blood-stream 


Fig.  101.— Large  vegetation  upon  the  mitral  valve 
obstructing  its  orifice.  There  are  smaller  vegetations 
at  other  points. 


250 


TEXT-BOOK   OF   PATHOLOGY 


and  are  capped  with  thrombus  material  (Fig.  102).  Vegetations  extend 
along  the  auricular  wall,  covering  whole  patches  of  it  with  a  flattened,  rough 
mat  of  thrombus,  or,  where  the  broken  chordse  flap  against  the  endocardium 
there  are  sown  bacteria  which  rapidly  cover  themselves  with  new  thrombi. 
Loss  of  substance  through  necrosis  of  the  valve  itself  underneath  the  vege- 
tation often  leads  to  perforation,  so  that  blood  regurgitates  through  the 


Fig.  102. — Endocarditis  involving  the  mitral  valve  and  causing  rupture  of  the  chordae 
tendinese,  which  are  covered  with  vegetations. 

hole  thus  formed.  The  edge  of  such  a  perforated  valve  may  swing  loose 
in  time  as  a  thread  bearing  a  thrombus,  and  we  have  seen  such  a  thrombus 
still  attached  driven  into  the  orifice  of  the  coronary  artery,  blocking  it 
completely  and  causing  death.  Or  if  the  valve  is  not  at  once  perforated,  it 
may  bulge  at  the  weakened  part  into  a  sort  of  aneurysmal  sac  which  pro- 
jects into  the  ventricle,  or  in  the  case  of  the  mitral  valve,  into  the  auricle. 

In  some  cases  when  the  vegetation  extends  to  the  base  of  the  valve  the 
myocardium  may  become  involved,  and  a  burrowing  abscess  extend  far 
into  its  substance. 

Libman  has  studied  the  subacute  form  of  endocarditis  produced  by  the 


ENDOCARDITIS 


251 


Streptococcus  viridans,  and  finds  that  it  affects  the  aortic,  and  much  more 
commonly  the  mitral,  valve,  producing  large  yellow,  pink,  or  greenish 
vegetations,  rarely  with  actual  ulceration  of  the  valve.  Auricular  vegeta- 
tions (Fig.  103)  and  others  involving  the  chordae  are  common,  and  bacterial 
emboli  are  scattered  in  numbers,  producing  characteristic  embolic  glome- 
rular  lesions  in  the  kidney  and  gross  infarcts  in  other  organs.  Although, 
as  in  the  other  forms,  the  blood  is  infected  with  these  bacteria,  there  may 
come  a  bacteria-free  stage  in  which  the  vegetations  heal.  This  is  accom- 
plished by  the  calcification  of  the  thrombus,  together  with  its  organization 
and  the  great  distortion  of  the 
valve.  But  just  as  the  vege- 
tations in  this  infection  are 
found  to  have  developed  upon 
the  scars  of  older  lesions,  so 
upon  these  healing  vegetations 
new  bacteria  may  be  developed 
and  begin  the  process  anew. 

Probably  in  all  forms  of  bac- 
terial endocarditis  some  such 
healing  may  occur  if  the  pa- 
tient can  live  long  enough,  but 
such  roughened  valves  are 
very  susceptible  to  new  locali- 
zation of  the  bacteria.  At  best 
such  healing  is  advantageous 
only  in  that  with  it  the  danger 
of  succumbing  to  the  bacteria 
is  at  an  end,  but  the  disease 
cannot  be  said  to  be  healed 
when  a  large,  calcified  mass 
still  hangs  on  a  valve,  or 
when  the  valves  are  short- 
ened, thickened,  and  distorted 
by  the  scars  that  replace  the 
thrombi. 

The  anatomical  results  are  then,  as  may  be  gathered  from  what  has  been 
said,  as  follows:  Fresh  vegetations  are  produced  along  the  line  of  closure 
on  the  face  of  the  valve,  more  commonly  in  the  case  of  the  mitral  and  aortic 
than  in  that  of  the  tricuspid  and  pulmonary,  although  these  are  also  fre- 
quently affected.  The  bacteria  may  be  destroyed  before  they  produce 
any  greater  injury  to  the  valve  than  is  sufficient  to  cause  the  thrombus 
formation,  upon  which  organization  of  the  thrombus  occurs  exactly  as  it 
might  anywhere  else,  except  that  blood-vessels  must  grow  a  long  way  to 
reach  it  With  the  completion  of  this  process  the  valves  are  left  beaded 


X 


Fig.  103. — Mural  vegetations  on  the  left 
auricle  accompanying  vegetations  of  the  mitral 
valve  and  chordae. 


252 


TEXT-BOOK  OF  PATHOLOGY 


with  nodules  of  fibrous  tissue,  which  later  shrink  and  flatten  themselves, 
and  although  with  the  most  favorable  result  the  delicacy  of  the  valve  is  im- 
paired and  the  smoothness  of  its  closing  surface  lost,  still  no  great  degree 
of  insufficiency  may  result.  When  the  bacteria  are  not  so  easily  destroyed, 
they  grow  in  the  substance  of  the  valve  and  cause  more  or  less  necrosis, 
followed  by  loss  of  substance  not  only  from  the  overlying  thrombus,  but 
from  the  valve  itself.  The  ulceration  and  crumbling  of  the  larger  vegeta- 
tions afford  a  source  of  emboli,  and  by  eating  away  the  valve  give  rise  to  a 
more  and  more  extensive  insufficiency  with  regurgitation  of  the  blood. 
Even  without  ulceration,  large  heaped-up  thrombi  prevent  the  accurate 
closure  of  the  valves,  with  the  same  result.  They  in  their  turn  may  become 

organized,  and  the  eroded 
remnants  of  valves  may 
heal,  naturally  with  the 
production  of  extraor- 
dinary deformities  and 
distortions. 

Large  vegetations  may 
in  themselves  block  the 
passage  of  blood  through 
the  valvular  orifice,  pro- 
ducing a  kind  of  acute 
stenosis.  But  beside 
this  there  is  the  effect  of 
healing,  which  commonly 
thickens  the  whole  of  the 
valves,  welding  them  to- 
gether with  dense  plaques 
of  fibrous  tissue,  which 
form  in  the  place  of  the 
vegetations  and  extend 

Qn  ^  valves  toward 
£  . 

their  base  and  toward 
the  angles,  where  they 
adjoin  one  another.  The 

contraction  of  this  tissue  brings  together  into  a  narrow  slit  the  bound- 
aries of  the  valvular  orifice,  producing  the  well-known  stenosis  of  the  valves 
(Fig.  104).  In  the  case  of  the  mitral  there  is  commonly  a  great  thickening 
of  the  left  auricle  and  of  its  endocardium,  and  from  the  mitral  ring  down 
to  the  mitral  orifice  there  is  formed  a  dense,  rigid  funnel  at  the  bottom  of 
which  is  the  small  crescentic  slit  with  rough,  nodular  edges,  often  discolored 
by  yellowish  pigment  and  made  rigid  by  extensive  deposits  of  calcium. 
The  edges  of  this  orifice,  if  brought  together,  fit  pretty  well,  and  appear  as 
an  irregular  line  in  the  bottom  of  the  otherwise  smooth  and  rounded  funnel. 
From  that  line  down  to  the  actual  edge  of  the  valve  is  a  precipitous  surface 


Fig.  104. — Mitral  stenosis.  Great  narrowing  and 
scarring  of  the  mitral  orifice,  which  stands  open. 
Hypertrophy  of  the  right  ventricle  and  left  auricle. 
The  heart  is  viewed  from  the  apex. 


ENDOCARDITIS 


253 


representing  the  thickness  of  the  valve  and  fitting  the  opposite  one.  Often, 
however,  the  valve  is  so  rigid  that  this  orifice  stands  permanently  open' 
causing  insufficiency  as  well  as  stenosis.  The  chordae  tendinese  are  very 
much  shortened  and  thickened  into  dense  white  cords.  Sometimes,  as  in  a 
case  studied  recently,  the  stenosis  is  produced  by  scars  occupying  only  the 
edges  of  the  valves,  so  that  their  basal  parts  remain  delicate  and  soft,  and 
sometimes,  though  rarely,  there  remains  a  delicate  edge  on  each  valve 


Fig.  105. — Insufficiency  of  aortic  valve.     Hypertrophy  and  dilatation  of  left  ventricle. 
Thickening  of  endocardium  below  the  incompetent  valve. 


capable  of  completing  the  closure,  so  that  there  is  stenosis  without  insuf- 
ficiency. On  the  edges  of  the  stenosed  valves  it  is  common  to  find  fresh 
vegetations.  In  the  case  of  the  aortic  valves  exactly  the  same  things 
may  arise — the  valves  are  sometimes  thickened  and  stiffened  by  old  scars 
in  which  lime  salts  are  deposited,  or  their  edges  alone  may  be  thickened 
into  round  cords  which  interfere  with  accurate  closure  (Fig.  105).  When 
the  valves  are  greatly  thickened,  they  adhere  by  their  angles  and  fuse  into 
a  sort  of  triangular  orifice,  bounded  on  all  sides  by  rigid,  jagged,  calcified 


254  TEXT-BOOK  OF  PATHOLOGY 

walls  which  offer  great  obstruction  to  the  passage  of  the  blood-stream  and 
are  useless  to  prevent  its  eddying  back  when  systole  is  over. 

That  combinations  of  these  things  may  arise  is  often  exemplified,  as  in  a 
case  just  observed,  in  which  there  was  found  tricuspid  stenosis  with  ex- 
quisite minute  fresh  vegetations,  similar  fresh  vegetations  along  the  line 
of  closure  of  the  pulmonary  valves,  extreme  mitral  stenosis,  again  with  a 
fringe  of  minute  thrombi,  and  thickened,  insufficient  aortic  valves  with 
thrombotic  deposits  on  their  ventricular  surfaces.  The  effects  of  all  these 
changes  we  shall  discuss  elsewhere.  Here  it  suffices  to  show  them  as 
examples  of  the  processes  of  inflammation  and  repair. 

Although  it  has  been  said  that  endocarditis  is  essentially  a  bacterial 
disease,  distortions  of  the  valves  may  arise  (especially  in  the  case  of  the 
aortic)  through  syphilitic  infection  of  the  aorta  involving  the  valves,  and 
apparently  also  through  the  ordinary  arteriosclerosis.  Syphilitic  aortitis, 
involving,  as  it  does,  the  lodgement  of  the  spirochseta  in  the  adventitia  and 
media  of  the  vessel,  may  apparently  be  reproduced  in  the  aortic  valves 
themselves.  Its  early  stages  have  not  been  studied,  but  the  healing  proc- 
esses, like  those  in  the  aorta,  result  in  scars  and  retractions,  and  it  is  shown 
that  this  course  of  events,  never  at  any  time  accompanied  by  thrombotic 
vegetations,  may  shorten,  thicken,  and  distort  the  valves  in  such  a  way  as 
to  produce  a  marked  regurgitation.  Indeed,  a  very  large  proportion  of 
the  cases  of  aortic  insufficiency  develops  on  the  basis  of  a  syphilitic  in- 
fection, and  the  Wassermann  reaction  is  an  indispensable  clinical  procedure 
in  every  case. 

Whether  the  ordinary  arteriosclerosis  is  of  as  much  importance  as  was 
once  thought  in  encroaching  upon  these  valves  and  disturbing  their  func- 
tion is  questionable.  There  are  many  cases  in  which,  with  an  old  arterio- 
sclerosis, the  aortic  valves  are  found  united  at  their  angles  and  thickened, 
but  it  is  impossible  to  say  with  certainty  that  this  is  the  uncomplicated 
effect  of  the  sclerosis.  It  is  true  that  such  fatty  and  sclerotic  plaques  are 
found  on  the  back  of  the  mitral  valve,  but  the  part  they  play  in  actual 
disease  of  the  heart-valves  is  relatively  slight. 

LOBULAR  PNEUMONIA  OR  BRONCHOPNEUMONIA 

Focal  or  patchy  inflammation  in  the  lung  due  to  infection  beginning  in  the 
terminal  bronchioles  is  an  exceedingly  common  condition,  of  serious  import 
in  both  children  and  adults.  It  is  not  strictly  lobular  in  its  distribution, 
since  only  a  part  of  each  lobule  may  be  affected  or  several  lobules  at  once; 
nor  is  it  in  all  cases  caused  by  a  primary  infection  of  the  bronchi,  since  a 
practically  indistinguishable  condition  may  arise  through  distribution  of 
bacteria  into  the  lung  by  way  of  the  blood-stream.  In  most  of  those  cases, 
however,  the  bacteria  are  carried  in  emboli  of  thrombus  material,  and  the 
lesions  are  apt  to  assume  the  form  of  abscesses  in  the  lung  substance. 

In  spite  of  these  objections  the  names  bronchopneumonia  and  lobular 
pneumonia  will  remain  in  common  use. 


LOBULAR  PNEUMONIA  OR  BRONCHOPNEUMONIA       255 

Bacteria  exist  quite  commonly  in  the  respiratory  tract  in  small  numbers,  causing  no 
disturbance,  but  if  the  carrier  of  such  bacteria  be  weakened  by  another  disease,  by  in- 
jury, exposure  to  cold,  or  any  of  a  great  variety  of  things  that  seem  to  lower  resistance  to 
infection,  invasion  and  destruction  of  the  tissue  of  the  bronchioles  may  occur.  It  is 
doubtless  partly  for  this  reason  that  lobular  pneumonia  forms  such  an  extremely  common 
terminal  event  in  protracted  illness  from  chronic  nephritis,  rickets,  typhoid  fever,  chronic 
anaemias,  long-standing  tumor-growths,  etc.  It  is  partly  on  this  account,  too,  that  this 
form  of  pneumonia  is  so  very  common  in  the  course  of  certain  acute  diseases,  such  as 
measles,  scarlet  fever,  influenza,  and  diphtheria,  but  there  the  additional  reason  exists 
that  the  whole  upper  air-passages  are  usually  intensely  infected.  The  coryza  of  measles, 
the  sore  throat  of  scarlet  fever,  and  the  membranous  exudate  of  diphtheria  which  may 
extend  into  the  small  bronchi  are  well  known. 

Another  well-defined  group  of  cases  exists  in  which  foreign  material  infected  with 
bacteria  is  aspirated  into  the  bronchi  because,  for  some  reason,  the  ordinary  protective 
reflexes  fail.  This  is  seen  in  extremely  ill,  delirious,  or  unconscious  patients,  in  intoxi- 
cated people,  in  the  insane,  and  in  patients  anaesthetized  for  surgical  operations.  Vomit- 
ing gives  an  opportunity  for  the  aspiration  of  gastric  contents,  but  saliva  drawn  into  the 
bronchioles  is  also  laden  with  bacteria. 

It  is  evident  that  almost  every  sort  of  bacteria  may  be  concerned  in  one  or  other  of 
these  forms.  Especially  when  foreign  particles  reach  the  bronchi,  it  is  likely  that  many 
different  organisms  will  accompany  them.  In  the  cases  which  seem  to  begin  spontane- 
ously the  pneumococcus  is  very  common.  In  those  associated  with  exanthematic  dis- 
eases and  diphtheria  the  streptococcus  is  prominent,  but  other  pyogenic  microorganisms, 
as  well  as  the  influenza  bacillus,  Friedlander's  bacillus,  and  many  others  may  play  im- 
portant parts. 

The  lung  is  commonly  quite  glossy  on  its  pleural  surface,  but  if  any  foci 
of  consolidation  lie  very  near,  the  pleura  is  found  covered  with  a  thin, 
fibrinous  exudate  at  least  over  that  region.  On  section  the  consolidated 
parts  can  be  felt,  and  can  usually  be  seen  as  slightly  elevated  patches,  vary- 
ing in  color  from  a  dark  red  or  blackish  red  through  the  precise  color  of  the 
remainder  of  the  tissue  to  paler  and  paler  grayish  rose  or  yellowish  gray 
(Fig.  106).  It  is  hard  to  see  them  when  their  color  is  quite  the  same  as 
that  of  the  surroundings,  but  they  can  generally  be  made  evident  by  gently 
pulling  the  lung  tissue  this  way  and  that.  The  alveoli  stretch  out  into  long 
rhombs  as  though  one  stretched  diagonally  a  fine  silk  gauze,  but  those  which 
contain  exudate  resist  this  slightly  and  stand  out  by  contrast. 

They  vary  in  size  from  the  minutest  foci,  which  occupy  only  a  few  alveoli 
about  the  termination  of  a  bronchiole,  to  large,  confluent  areas  which 
stretch  over  a  considerable  portion  of  a  lobe  of  the  lung.  The  variety  in 
their  appearance  and  color  is  largely  due  to  the  fact  that  the  exudate 
changes  in  color  as  time  passes.  Red  corpuscles,  which  give  it  a  dark  or 
hsemorrhagic  hue  at  first,  fade  through  being  broken  up,  and  the  grayish 
color  of  the  increasingly  abundant  leucocytes  comes  into  view.  The  exu- 
date is  often  very  loosely  arranged-with  only  a  few  cells  in  each  alveolus 
and,  in  many  cases,  probably  most  of  those  in  children,  it  does  not  form 
such  rough  projecting  plugs  as  in  lobar  pneumonia.  From  the  bronchi 
there  may  usually  be  expressed  a  drop  of  purulent  fluid.  But  in  other 


256 


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cases  the  consolidated  patches  are  firm,  and  the  alveoli  filled  with  project- 
ing masses  that  are  in  every  way  like  those  seen  in  lobar  pneumonia. 

When  they  are  very  small  and  arranged  in  clusters  around  the  ends  of 
the  bronchial  branches,  their  relation  to  the  bronchi  can  be  easily  made  out, 
both  microscopically  and  on  inspection  of  the  gross  organ,  but  when  they 
become  confluent,  this  relation  is  no  longer  so  clear. 

Microscopically,  the  condition  is  equally  variegated  in  appearance. 
At  times,  when  a  sudden  aspiration  of  infected  foreign  material  has  occurred 


Fig.  106.— Lobular  pneumonia  in  adult  lung,  showing  patchy  areas  of  consolidation. 

shortly  before  death,  these  particles  can  be  seen  in  the  bronchioles  or  alveoli 
loaded  with  bacteria,  and  surrounded  almost  solely  by  red  corpuscles. 
Such  foci  are  soft,  impalpable,  and  deep  red.  In  other  cases  time  is  given 
for  the  growth  of  enormous  numbers  of  bacteria,  which  fill  the  bronchus  and 
every  alveolus,  but  which,  although  they  destroy  the  tissue,  seem  to  kill 
the  patient  without  rousing  any  inflammatory  reaction.  Such  patches  are 
soft  and  gray,  and  often  surrounded  by  a  zone  of  hemorrhage.  When  much 


LOBULAR  PNEUMONIA  OR  BRONCHOPNEUMONIA 


257 


gastric  juice  has  been  drawn  into  the  lung,  one  may  smell  it  and  distinguish 
yellowish,  green,  opaque  discolorations  about  the  bronchi  and  in  patches  in 
the  lung.  The  tissue  is  softened  and  disintegrated,  generally  without  much 
inflammatory  reaction.  It  is  probable  that  death  always  follows  rapidly, 
and  that  partial  digestion  of  the  injured  tissue  proceeds  after  death. 

But  ordinarily  the  infection  of  the  lung  is  produced  by  the  aspiration  or 
wandering  of  the  organisms  which  are  present  in  the  upper  respiratory 


Fig.   107.— Bronchopneumonic  patch  showing  infiltration  of  bronchial  and  alveolar 
walls  with  the  inflammatory  exudate. 

tract.  The  individual  when  weakened  by  disease  is  infected  by  bacteria 
of  which  he  is  himself  the  healthy  carrier,  or  by  breathing  in  the  bacteria 
from  other  infected  persons  his  lungs  are  invaded  by  some  new  bacterial 
strain.  The  occurrence  of  epidemics  of  bronchopneumoma  owing  to  the 
rapid  spread  of  some  virulent  bacterium  among  persons  predisposed  by 
measles  or  influenza  became  a  familiar  phenomenon  during  the  mobiliza- 
tion of  the  troops.  The  exact  nature  of  the  changes  both  general  and  1 
18 


258  TEXT-BOOK    OF    PATHOLOGY 

which  are  due  to  the  predisposing  disease  is  not  well  known,  since  it  is 
masked  by  the  supervening  bacterial  infection.  But  the  character  of  the 
pneumonia  itself  is  clearly  dependent  on  the  nature  of  the  bacterium  which 
predominates  in  the  secondary  infection,  and  this  becomes  much  more 
apparent  in  the  epidemic  occurrence  of  the  disease  than  in  the  daily  in- 
stances in  which  various  strains  of  organisms  from  every  source  are  con- 
cerned in  the  production  of  terminal  bronchopneumonia. 

The  latter  seem  never  so  extensive  or  intense  as  those  which  occur  in 
the  midst  of  an  epidemic,  probably  because  the  accidentally  invading  organ- 
ism has  not  acquired  the  extraordinary  virulence  developed  by  passage  In 
the  course  of  an  epidemic. 

It  will  be  best  to  consider  in  detail  the  anatomy  of  each  specific  form  of 
lobular  or  bronchopneumonia  in  connection  with  the  other  effects  of  those 
particular  organisms,  and  to  confine  ourselves  here  to  the  barest  outline 
of  what  may  happen  in  the  non-epidemic  forms. 

The  bacteria,  after  producing  an  intense  inflammation  of  the  larynx, 
trachea,  and  larger  bronchi,  extend  into  the  terminal  bronchioles,  where  in 
the  same  way  they  cause  the  outpouring  of  an  exudate  rich  in  leucocytes 
and  red  corpuscles.  This,  with  their  further  growth,  fills  the  terminal  and 
neighboring  alveoli.  Desquamated  epithelial  cells  and  a  network  of  fibrin 
are  added,  and  the  alveoli  thus  come  to  contain  plugs  of  exudate  more  or 
less  consolidated  by  the  filaments  of  fibrin.  The  old  distinction  between 
catarrhal  or  bronchopneumonia  and  croupous  or  lobar  pneumonia  has  never 
seemed  to  me  accurate,  since  there  is  commonly  a  great  deal  of  fibrin  in  the 
exudate  in  bronchopneumonic  patches,  particularly  in  their  more  distal 
portions.  The  walls  of  the  bronchioles  and  of  the  air  cells  themselves  are 
infiltrated  with  leucocytes  and  fluid,  and  the  lymphatics  in  the  walls  of  the 
bronchi  and  blood-vessels  and  in  the  interlobular  septa  are  commonly 
infected  and  contain  an  exudate  of  leucocytes  or  are  even  thrombosed. 

The  complete  occlusion  of  the  bronchioles  by  the  exudate  leads  quickly 
to  the  collapse  of  its  air-cells,  since  the  imprisoned  air  is  absorbed  or  dis- 
solved by  the  passing  blood.  This  atelectasis  is  often  evident  on  the  sur- 
face of  the  lung  in  the  form  of  patches  of  purplish,  pasty  tissue  sunken 
below  the  surroundings.  On  the  other  hand,  if  the  occlusion  is  incomplete, 
the  alveoli  may  become  overdistended  with  air,  in  the  manner  described  in 
another  chapter. 

The  healing  of  this  type  of  pneumonia,  brought  about  by  the  annihila- 
tion of  the  bacteria  and  the  complete  or  partial  liquefaction  of  the  exudate 
and  its  absorption,  occurs  rather  more  slowly  than  in  lobar  pneumonia, 
and  its  retardation  by  the  organization  of  the  exudate  into  fibrous  strands- 
is  more  common.  Occasionally  in  children  in  whom  bronchopneumonia 
has  lasted  for  some  time  and  is  rather  mild  one  finds  that  the  exudate  is 
largely  composed  of  desquamated  epithelial  cells,  with  leucocytes  and  fibrin, 
and  that  these  epithelial  cells  have  fused  to  form  syncytial  masses  of  proto- 
plasm, with  many  nuclei.  These  "giant-cells"  often  extend  from  one 
alveolus  to  another,  or  line  a  whole  air-space  while  inclosing  masses  of  fibrin 


PUERPERAL   INFECTION  259 

or  leucocytes.  In  severe  bronchopneumonia  the  walls  of  the  bronchi  and 
of  the  air-cells  are,  as  has  been  said,  much  infiltrated  by  the  inflammatory 
exudate,  and  their  destruction  and  the  formation  of  an  abscess-like  soften- 
ing in  place  of  the  focus  of  pneumonia  may  take  place.  On  the  other  hand, 
the  introduction  of  putrefactive  bacteria,  together  with  those  which  injure 
and  destroy  the  tissue,  may  set  up  a  condition  far  different  from  that  ordi- 
narily seen.  This  is  the  so-called  gangrene  of  the  lung,  which  leads  not  only 
to  the  death  of  the  lung  tissue,  but  to  its  softening  into  a  violently  foul- 
smelling,  greenish,  shreddy  mass,  semifluid  in  character,  which  is  usually 
fairly  well  marked  off  from  the  surrounding  tissue  by  a  zone  of  coagulated 
lung  substance.  Cavities  of  considerable  size,  lined  with  ragged,  floating 
shreds  of  dead  tissue,  discharge  part  of  their  contents  into  the  bronchus,  so 
that  a  foul  odor  is  given  off  with  the  breath.  Buday  and  others  find  in  this, 
as  in  other  examples  of  progressive  infectious  gangrene,  many  organisms, 
but  especially  frequently  a  combination  of  fusiform  bacilli  and  spirilla, 
which  they  regard  as  the  specific  cause  of  the  condition,  and  as  being  suf- 
ficient to  cause  the  necrosis  of  the  tissue  as  well  as  the  putrefaction. 

Around  such  an  area  the  alveoli  are  found  to  be  filled  with  a  dense 
exudate  composed  largely  of  fibrin,  with  many  leucocytes  and  red  corpuscles. 

LITERATURE 

Buday:  Ziegler's  Beitrage,  1910,  xlviii,  70. 

Hecht:  Ziegler's  Beitrage,  1910,  xlviii,  263. 

Karsner  and  Meyers:  Arch.  Inter.  Med.,  1913,  xi,  534. 

Ribbert:  Bruening  u.  Schwalbe,  Handb.  d.  Krankh.  d.  Kindesalters,  ii,  465. 

PUERPERAL  INFECTION 

Particularly  favorable  opportunity  for  the  development  of  a  serious  in- 
fectious process  is  offered  in  the  puerperal  uterus,  not,  as  is  so  often  stated, 
because  in  the  detachment  of  the  placenta  many  blood-channels  are  torn 
open,  but  because  tissue  which  is  no  longer  permeated  by  the  circulating 
blood  is  often  left  adhering  to  the  uterine  wall,  and  because  fluid  stagnates 
in  the  cavity.  It  is  the  same  danger  which  threatens  the  patient  after  an 
unskilful  operation  upon  some  internal  organ  in  which  a  portion  of  tissue 
is  left  constricted  so  as  to  be  deprived  of  its  blood  supply.  It  is  practically 
the  same  danger  of  infection  that  exists  in  a  strangulated  hernia. 

An  example  will  make  this  clear:  A  man  whose  leg  was  crushed  and  torn  below  the 
knee  was  treated  by  a  surgeon  who  washed  out  the  dirt  from  among  the  exposed  muscles, 
stopped  the  bleeding,  and  sewed  up  all  the  tears  in  the  skin.  Within  a  few  hours  the 
sutured  skin  became  tense  almost  to  bursting,  and  when  the  stitches  were  removed,  a 
bloody,  turbid  fluid  poured  out.  Next  day  the  muscles  and  shreds  of  tissue  were  bathed 
in  thin  pus,  the  man's  temperature  was  high,  and  there  were  evidences  of  a  rather  pro- 
found poisoning.  In  spite  of  every  proper  surgical  intervention  he  finally  died,  and  many 
abscesses  were  found  in  lungs  and  elsewhere.  Undoubtedly  the  accumulation  of  fluid 
within  the  sutured  skin  gave  a  medium  for  the  growth  of  bacteria  from  the  dirt  left 
behind,  and  at  the  same  time  rendered  the  tissues  anaemic  through  pressure. 


260 


TEXT-BOOK    OF    PATHOLOGY 


Differences  of  opinion  still  exist  as  to  the  source  and  nature  of  the  bac- 
teria which  are  responsible  for  puerperal  infection,  and  doubt  prevails 
still  as  to  whether  they  may  be  the  bacteria  already  present  in  the  genital 
tract,  or  only  those  introduced  by  the  hand  or  instrument  of  the  operator. 
Kronig  adheres  strongly  to  the  latter  view.  The  Streptococcus  pyogenes 
in  one  or  other  of  its  modifications  (q.  v.)  is  almost  always  found,  although 
the  pneumococcus  or  staphylococcus  may  be  the  organism  concerned,  and 
various  bacilli,  including  the  Bacillus  aerogenes  capsulatus,  may  play  a  part. 


Fig.  109. — Puerperal  endometritis.     In  this  case  there  was  no  thrombophlebitis. 


In  cases  of  criminal  abortion  at  any  stage  in  the  course  of  pregnancy 
infection  is  likely  to  take  place  on  account  of  the  haste  and  secrecy  with 
which  instruments  are  forced  into  the  uterus  at  the  hands  of  persons 
ignorant  of  the  conditions  of  bacterial  growth.  Fortunately,  with  the  ad- 
vance in  the  knowledge  of  bacteriology  puerperal  infection  is  no  longer  the 
dreaded  scourge  of  obstetrical  practice  that  it  once  was  before  the  time  of 
Semmelweiss.  Even  yet,  however,  the  cases  in  which,  after  a  complicated 
delivery,  infection  occurs  are  not  all  too  rare.  It  may  result  only  in  a 
temporary  fever,  or,  on  the  other  hand,  it  may  advance  to  general  septi- 


PUERPERAL   INFECTION  261 

csemia  and  death.  The  uterus  is  found  to  be  large,  relaxed,  and  soft,  with 
the  enormously  enlarged  blood-vessels  characteristic  of  the  later  stages  of 
pregnancy.  The  external  os  projects  into  the  vagina  as  a  swollen,  greenish- 
black,  rough,  friable  mass.  The  whole  cavity  of  the  uterus  is  lined  with 
the  same  greenish-black,  ragged,  necrotic  tissue,  the  walls  on  section  gray- 
ish red  and  cedematous,  the  veins  open  and  full  of  blood.  The  Fallopian 
tubes  contain  a  turbid  fluid,  No  changes  are  found  in  the  organs  except 
the  acute  splenic  tumor  and  the  cloudy  swelling  of  the  liver  and  kidneys 
which  are  so  regularly  seen  in  acute  infections.  But  everywhere  the  tissues 
are  blood  stained,  the  lining  of  the  heart  and  aorta  are  quite  red,  and  over 
thorax,  arms,  and  legs  there  is  a  network  of  broad,  brownish  purple  lines 
which  show  where  the  laked  blood  in  the  cutaneous  veins  has  stained 
through  into  the  skin.  Such  is  the  result  of  the  rapid  spread  of  the  hsemo- 
lyzing  streptococci  into  the  blood. 

In  other  cases,  when  the  resistance  is  not  so  readily  overcome,  the  process 
is  more  localized.  The  dead  tissue  lining  the  uterus  may  remain  odorless, 
or,  when  there  is  a  mixed  infection  with  putrefactive  organisms,  it  softens 
into  an  extremely  foul,  putrid  mass.  In  other  cases  a  fibrinous  exudate 
rich  in  leucocytes  forms  over  the  superficial  necrotic  tissue,  and  blends  with 
it  so  as  to  form  a  sort  of  false  membrane  (diphtheritic  or  pseudomembranous 
endometritis)  (Fig.  109) .  Beneath  this  the  wall  is  densely  infiltrated  with 
leucocytes,  red  corpuscles,  and  fluid,  and  abscesses  with  local  liquefaction 
of  the  muscular  tissue  develop  and  may  extend  even  to  the  outer  surface. 
Extension  in  this  way  or  along  the  Fallopian  tubes  to  their  fimbriated  ends 
is  likely  to  produce  a  peritoneal  infection  which  hastens  the  fatal  outcome. 
Otherwise  the  broad  ligament  and  adjacent  pelvic  tissues  become  infected 
and  enormously  thickened  and  infiltrated  with  the  spreading  inflammatory 
exudate.  Great  abscesses  may  develop  in  these  tissues,  and  at  an  even 
later  date  extend  and  rupture  into  the  peritoneum. 

The  infection  may  be  communicated  to  the  rest  of  the  body  in  two  other 
ways — one  by  the  lymphatics,  the  other  by  the  formation  of  infected 
thrombi  in  the  veins.  In  the  first  case  the  lymph-channels  become  swollen 
and  distended  with  pus,  adjacent  lymph-nodes  are  enlarged  and  softened, 
and  bacteria  finally  pass  into  the  thoracic  duct  and  blood.  The  second 
process  is  far  more  striking  in  its  appearance.  Section  through  the  wall 
of  such  a  uterus  shows  numerous  great  canals,  which  were  the  veins,  now 
filled  with  greenish-yellow  pus,  their  walls  converted  into  opaque  yellow 
material  or  destroyed  entirely  so  that  the  uterine  musculature  itself,  edged 
with  yellow,  necrotic  tissue,  forms  the  wall  of  the  canal.  For  a  long  dis- 
tance nothing  remains  of  the  more  solid  thrombus,  and  one  may  trace  such 
channels  far  out  into  the  broad  ligament  and  to  the  walls  of  the  pelvis. 
Aschoff  raises  the  question  as  to  whether  this  thrombosis  is  the  direct  result, 
of  the  infection,  but  I  cannot  doubt  it.  The  fluid  may  partake  of  the  foul 
character  of  the  uterine  lining  in  the  putrefactive  cases.  Fragments  of, 
such  infected  thrombi,  or  even  the  liquefied  material,  may  be  swept  into 


262  TEXT-BOOK   OF   PATHOLOGY 

the  blood-stream,  and  emboli  are  lodged  in  different  organs,  while  the 
blood  is  flooded  with  bacteria.  Hence  the  development  of  abscesses  in 
lungs,  kidney,  brain,  etc.,  or  even  in  the  joints  (pyaemia).  These  may  be 
foul  and  gangrenous  when  the  uterine  inflammation  has  that  character. 
Hence,  too,  the  production  of  endocardial  vegetations,  which  assume  an 
ulcerative  and  destructive  character  and  form  the  source  of  more  infected 
emboli. 

ABSCESS  FORMATION,  PY^MIA,  ETC. 

Certain  bacteria,  notably  the  staphylococci,  show  a  marked  tendency  to 
grow  in  the  tissues  in  closely  packed  colonies  about  which  the  cells  are 
rendered  necrotic  for  varying  distances.  A  violent  inflammatory  reaction 
ensues,  and  the  immediate  neighborhood  becomes  tumefied,  red,  and  pain- 
ful. Coagulable  fluid  exuded  from  the  vessels  into  the  necrotic  tissue  clots 
there,  and  converts  it  into  a  firm  mass,  rather  larger  than  it  originally  was. 
Leucocytes  in  great  numbers  accumulate  outside  these  neighboring  vessels, 
and  wander  into  the  necrotic  mass,  dying  and  becoming  disintegrated  as 
they  pass  beyond  the  zone  of  safety  into  the  poisoned  area.  Such  quanti- 
ties of  them  appear,  however,  that  the  proteolytic  ferments  which  they 
produce  become  sufficiently  concentrated  to  digest  the  outer  portions  of  the 
coagulum,  so  that  it  comes  to  lie  loose  in  a  cavity  surrounded  by  a  thick 
yellowish  fluid  filled  with  intima  and  partly  disintegrated  leucocytes  (pus) . 
At  this  stage  the  remainder  of  the  coagulum,  loaded  as  it  is  with  bacteria, 
constitutes  the  core  or  central  plug  (Fig.  110),  often  recognizable  when  an 
abscess  is  incised  or  when  it  bursts  through  the  skin.  Later  the  ferment 
process  may  succeed  in  dissolving  the  whole  of  it,  and  the  abscess  is  then 
merely  a  cavity  filled  with  pus  and  surrounded  by  an  intensely  inflamed 
wall.  Further  necrosis  of  this  wall  may  occur,  and  the  abscess  increases 
in  size,  often  in  the  direction  of  least  resistance,  so  that  the  pus  seems  to 
burrow  its  way  along  natural  lines  of  division  of  the  tissues.  It  is  reab- 
sorbed  only  with  difficulty,  and  unless  it  is  evacuated  by  the  surgeon  or 
bursts  its  way  to  a  free  surface  or  into  the  lumen  of  some  hollow  organ,  it 
remains  in  situ  for  a  long  time  and  is  gradually  inspissated  and  thickened. 
In  this  case,  and  indeed  in  all  abscesses  which  persist  for  a  long  time,  even 
when  they  have  been  opened,  a  thick  layer  of  granulation  tissue  springs 
up  to  line  the  cavity  and  to  encapsulate  the  remainder  of  the  pus,  or  more 
frequently  to  obliterate  the  cavity.  This  granulation  tissue  is  exceptionally 
thickly  infiltrated  with  leucocytes,  and  shows  the  presence  of  many  large, 
mononuclear  wandering  cells,  which  become  larger  as  they  approach  the 
surface  of  the  granulations.  Here  they  exhibit  their  voracious  phagocytic 
characters,  loading  themselves  with  the  debris  of  injured  and  dead  cells, 
and  usually  containing  many  large  fat-droplets  (Fig.  85). 

When  bacteria  and  dead  tissue  are  quite  removed,  as  when  an  abscess  is 
opened  and  thoroughly  cleansed,  healing  proceeds  rapidly  and  the  granu- 
lation tissue  later  forms  a  dense  scar. 


ABSCESS    FORMATION,    PYAEMIA,    ETC. 


263 


Abscesses  arise  at  the  point  where  direct  introduction  of  the  bacteria 
from  without  takes  place,  or  else  they  appear,  often  in  numbers,  through  the 
transportation  of  infected  emboli  from  some  focus  of  infection  in  another 
part  of  the  body.  These  emboli  may  consist  practically  of  masses  of  bac- 
teria, and  while  the  flooding  of  the  circulating  blood  with  organisms  of  this 
sort  is  known  as  septicaemia,  the  condition  which  we  are  discussing  is  often 
called  pysemia. 


Fig.  110.— Abscess  of  kidney  showing  necrosis  of  tubules,  some  of  which  are  filled  with 

bacteria. 

Abscesses  from  direct  introduction  of  bacteria  are  often  seen  in  the  skin, 
where  they  are  called  boils  or  furuncles,  or,  when  very  large,  with  several 
communicating  centres  of  infection,  carbuncles.  Most  often  the  organisms 
are  rubbed  into  a  hair-follicle  by  a  chafing  collar,  or  in  some  similar  way, 
hence  their  great  frequency  on  the  back  of  the  neck  or  on  the  buttocks 
Frequently,  too,  they  are  seen  about  the  nose  or  lips.  The  course  of 
such  abscesses  is  modified  by  the  thickness  of  the  skin  and  the  obstruc- 


264 


TEXT-BOOK   OF   PATHOLOGY 


tion  to  their  breaking  through.    Thus  an  abscess  within  the  red  line  of 
the  lip  readily  ruptures  and  is  cured,  while  one  which  arises  a  few  milli 
metres  away,  in  the  thick  skin,  may  be  much  more  extensive  and  last  much 


persons  whose  resistance  is  lowered  by  any  one  of  the  many 
things  which  seem  to  have  that  effect,  such  as  overwork,  unsanitary  sur- 
roundings, or  wasting  diseases  (among  which  are  other  infections,  such  as 


Fig.  111. — Abscess  in  the  liver.     The  drawing  shows  the  compression  and  destruction  of 
the  liver-cells  and  a  broad  layer  of  leucocytes  surrounding  the  central  mass  of  bacteria. 

typhoid  fever),  a  whole  series  of  boils  may  make  their  appearance — one 
is  no  sooner  healed  than  another  appears.  In  these  cases  it  seems  that  the 
skin  becomes  smeared  with  the  bacteria,  which  readily  find  the  oppor- 
tunity to  lodge  in  hair-follicles  or  sebaceous  glands  and  to  form  abscesses. 
From  the  fact  that  bacteria  of  a  pyogenic  character  are  normally  present 
in  the  superficial  layers  of  the  skin  it  appears  that  the  matter  of  resistance 
is  of  the  greatest  importance.  When  a  number  of  hair-follicles  become 


ABSCESS   FORMATION,    PY^MIA,    ETC.  265 

infected  side  by  side  with  the  staphylococcus,  a  most  extensive  necrosis  of 
the  skin  and  underlying  tissue  may  occur  (carbuncle),  and  with  the  lique- 
faction of  each  focus  of  dead  material  a  perfect  honeycomb  of  communicat- 
ing passages  filled  with  pus  may  be  formed. 

Such,  in  brief,  are  the  circumscribed  abscesses.  As  the  result  of  pysemic 
distribution  of  emboli  or  cocci  they  appear  in  the  lungs,  heart,  kidneys,  or 
any  other  organ  (Fig.  111).  In  the  lung  such  a  focus,  at  first  very  hsem- 
orrhagic,  is  soon  found  to  have  a  gray,  solid,  or  rapidly  liquefying  centre, 
surrounded  on  all  sides  by  a  barrier  zone  of  hsemorrhagic  pneumonic  con- 
solidation, outside  of  which  the  lung  is  oedematous.  Such  abscesses  seem 
to  reach  a  considerable  size  before  coming  into  communication  with  a 
bronchus.  Frequently  confluent  with  one  another,  their  origin  may 
generally  be  traced  by  finding  a  whole  colony  of  cocci  lodged  like  an  in- 
jection mass  in  the  lumen  of  a  central  blood-vessel.  So,  too,  the  embolus 
may  be  found  in  the  blood-vessel  in  the  centre  of  those  deeply  hsemorrhagic 
abscesses  sometimes  found  in  the  submucosa  of  the  small  intestine.  Rup- 
ture of  such  abscesses  through  the  mucosa  leaves  a  ragged  ulcer  which  heals 
by  granulation. 

While  there  is  thus  a  great  similarity  in  the  mode  of  formation  of  ab- 
scesses wherever  they  occur,  it  must  be  recognized  that  the  feature  which 
they  have  in  common  is  the  concentration  of  the  whole  effect,  which  not 
only  allows  the  bacteria  to  kill  tissue  which  might  resist  a  less  concerted 
attack,  but  also  allows  the  inflammatory  exudate  (perhaps  aided  slightly 
by  the  ferments  of  the  bacteria  themselves)  to  digest  and  liquefy  that 
necrotic  tissue. 

Phlegmons. — When  the  bacteria  are  spread  quickly  throughout  a  con- 
siderable area  of  tissue,  as  often  happens  in  the  loose  tissues  of  the  neck 
after  invasion  from  suppurative  processes  in  teeth,  salivary  glands,  or 
mouth  cavity,  there  is  nowhere  sufficient  concentration  to  produce  the 
effects  seen  in  an  abscess.  The  tissue  is  not  all  dead,  and  the  exudate  is  so 
spread  out  that  no  liquefaction  takes  place.  Such  an  intense  diffuse  in- 
flammation may  be  called  a  phlegmon,  and  so  dense  and  hard  may  the 
affected  tissue  become  that  the  phlegmons  of  the  neck  are  often  called 
ligneous  or  woody  inflammations. 

DIPHTHERITIC  INFLAMMATION 

On  any  mucosa  the  invasion  of  bacteria  or  the  destruction  produced  by  a 
chemical  irritant  may  cause  a  peculiarly  intense  inflammatory  reaction, 
usually  hannorrhagic,  and  different  from  the  milder  forms  in  that  the  ne- 
crotic surface  layer  is  welded  together  with  the  fibrinous  exudate  into  a 
membrane-like  film.  This  is  well  seen  in  the  mucosa  of  the  intestine  when 
bacteria  of  the  dysentery  group  invade  it,  or  when,  at  the  end  of  a  long 
illness,  streptococci  or  other  organisms  from  the  intestinal  lumen  attack  it. 
Perhaps  the  most  striking  changes  of  this  sort  are  produced  in  cases  of 
poisoning  with  bichloride  of  mercury,  possibly  because  the  corrosive  salt 
is  excreted  again  into  the  colon. 


256  TEXT-BOOK   OF   PATHOLOGY 

In  the  early  stage  of  any  of  these  cases  it  is  found,  on  stretching  out  the 
wall  of  the  intestine,  that  certain  parts  of  the  mucosa  are  covered  with  a 
grayish  or  bile-stained,  opaque,  rough  substance  which  may  be  scraped  off, 
showing  beneath  it  a  raw  surface  (Fig.  112).  Such  patches  are  bordered  or 
separated  by  mucosa,  which  is  soft  and  velvety,  but  swollen  and  deeply 
hiemorrhagic.  The  distribution  of  the  chaff-like  exudate  in  the  small 
intestine  is  primarily  along  the  crests  of  the  transverse  folds  or  valvulse— 


Fig.  112. — Diphtheritic  enteritis.     The  inflamed  and  partly  necrotic  mucosa  is  covered 
with  a  tenacious  layer  of  exudate. 

in  the  colon,  where  it  is  far  more  commonly  found,  it  is  in  patches,  inasmuch 
as  the  intestine,  in  its  contracted  state,  exposes  only  a  part  of  its  mucosa  to 
the  lumen.  The  rest  is  hidden  in  the  depths  of  the  folds,  and  less  constantly 
exposed  to  the  intestinal  contents.  Perhaps  this  is  inconsistent  with  ac- 
cepted ideas  of  the  normal  relation  between  the  intestinal  mucosa  and 
intestinal  contents,  but  the  appearance  of  the  inflamed  intestine  imposes 
such  an  explanation  upon  one,  and  it  is  easily  conceivable  that  the  presence 
of  a  sharply  irritating  substance  might  keep  the  walls  at  their  maximum 
contraction.  Thus,  in  addition  to  transverse  or  circular  bands  of  exudate, 
there  are  three  longitudinal  streaks  which  correspond  with  the  part  of  the 
mucosa  thrown  into  relief  by  the  longitudinal  muscle-bands. 

Microscopically,  it  is  found  that  the  superficial  part  of  the  affected  mu- 
cosa is  completely  necrotic  and  sharply  marked  off  from  the  underlying 
tissue,  which  is  intensely  inflamed  (Fig.  113).  Continuous  with  it,  and 
overlying  it,  is  a  layer  of  matted  fibrin  filaments  which  can  be  traced 
continuously  through  the  dead  tissue.  Through  both  parts  of  this  dead 


DIPHTHERITIC    INFLAMMATION  267 

layer  of  tissue,  which  constitutes  the  false  membrane,  remnants  of  leu- 
cocytes are  to  be  found,  with  many  signs  of  haemorrhage,  and  in  the  tissue 
beneath  and  about  the  site  of  the  pseudomembrane  there  is  an  exudate 
extremely  rich  in  red  corpuscles,  leucocytes,  and  fibrin.  All  this  is  often 
particularly  well  seen  in  the  stomach  after  intense  corrosive  poisons  have 
been  swallowed. 

Later  the  oedematous  and  hypersemic  parts  of  the  mucosa  between  the 
lines  and  patches  of  intensest  injury  become  involved  in  the  same  process 


Fig.  113.-Diphtheritic  enteritis.     The  crest  of  the  fold  of  mucosa  is  necrotic,  hiemor- 

i •          .«,-!    ^-^^-^T^ooliT  TnTiQimpH- 


rhagic,  and  intensely  inflamed. 


if  the  condition  progresses  and  does  not  heal.  The  older  sites  of  injury 
may  then  discharge  the  dead  tissue  into  the  intestine,  and  present  them- 
selves as  ulcerations  which  may  go  deep  into  the  intestinal  wa U 
ulcers  are  found  especially  in  the  colon,  and  are  characteristic  of  the  more 
chronic  forms  of  dysentery.  They  may  arise,  too,  when  ^ '%a°  ^ 
struction  of  the  intestine,  so  that  its  contents  accumulate  above  and 
remain  a  long  time  in  the  dilated  upper  part  of  the  loop.  Probably  this 


268  TEXT-BOOK    OF    PATHOLOGY 

dilation,  with  its  stretching  of  the  wall  and  narrowing  of  the  blood  sup- 
ply, may  be  a  contributory  cause  of  the  ulceration. 

LITERATURE 

Bumm:   "Puerperal  Infection,"  Arch.  f.  Gynak.,  1891,  xl,  398. 
Korte:  Handb.  d.  prakt.  Chir.  (Bruns,  Garre,  Kuttner),  1913,  iii,  37. 
Lenhartz:   Septische  Infecktionen,  NothnagePs  Handb.,  1903,  iii4,  Abth.  1. 
Nothnagel:    "Erkrankungen  des  Darms  imd   des  Peritoneum,"  Handb.  d.  spec.  Path. 

u.  Therap.,  1898,  xvii. 
Thorel:    Endocarditis;    extensive  literature  in  Lubarsch  and  Ostertag,  1907,  xi2,  319; 

1910,  xiv2,  331;   1915,  xvii2,  499. 


CHAPTER  XV 

INJURY  WITH  INFLAMMATORY  REACTION   AND   ATTEMPTED 

REPAIR.— NEPHRITIS 

Nephritis:  General  nature  of  the  process.  Its  diffuse  character;  acute  and  chronic  glomerulo- 
nephritis,  tubular  nephritis,  and  interstitial  nephritis.  Arteriosderotic  disease  of  the 
kidney.  Combined  inflammatory  and  arteriosderotic  disease.  Amyloid  deposit.  Sum- 
mary. Functional  alterations.  Renal  insufficiency. 

NEPHRITIS 

DISEASE  of  the  kidneys  which  affects  diffusely  both  organs,  and  which 
leads  to  structural  alterations  and  disturbances  in  the  function,  recogniz- 
able by  abnormalities  in  the  urine  and  by  various  other  symptoms,  such  as 
oedema,  high  blood-pressure,  etc.,  has  long  been  known  as  Bright 's  disease, 
or  nephritis.  Weigert,  in  his  classical  paper,  pointed  out  the  diffuse  char- 
acter of  these  diseases,  which  distinguishes  them  from  other  more  localized 
affections,  such  as  might  be  caused  by  an  abscess  or  an  infarct  in  one  kidney 
or  by  a  stone  in  its  pelvis  or  an  obstruction  in  its  ureter.  Still  it  must  be 
kept  in  mind  that  although  both  kidneys  are  affected  in  the  same  way, 
one  element  of  the  kidney  structure  may  suffer  more  than  others.  Thus 
the  glomeruli  may  be  especially  injured,  while  the  tubular  epithelium 
escapes  almost  entirely,  or  the  reverse  may  happen.  So  dependent  are 
these  elements  upon  one  another,  however,  that  in  the  long  run  the 
tubules  are  injured  by  the  destruction  of  the  glomeruli  and  vice  versa. 

Except  in  a  few  forms,  we  are  ignorant  of  the  causes  of  the  different  types 
of  diffuse  renal  disease,  so  that  it  becomes  difficult  to  repeat  their  produc- 
tion experimentally,  or  to  classify  them  satisfactorily.  It  is  hard  to  trace 
the  progress  of  their  anatomical  development,  since  in  human  beings  we 
can  study  in  each  case  only  one  stage,  and  it  is  even  yet  uncertain  what 
may  be  the  final  outcome  of  some  of  the  alterations  which  are  familiar 
enough  in  their  acute  stage.  It  is  true  that  experimental  nephritis  will 
probably  throw  a  great  deal  of  light  upon  this  problem,  even  though  up  to 
the  present  the  most  improbable  substances  have  been  used  to  produce 
nephritis  in  animals.  Such  substances  as  uranium  nitrate,  cantharidin, 
and  rattlesnake  venom  are  not  likely  to  be  the  cause  of  nephritis  in  many 
human  cases.  Yet  they  produce  changes  which  are,  in  principle  at  least, 
identical  with  those  in  human  kidneys,  and  therefore  give  useful  informa- 
tion. 

As  in  the  case  of  cirrhosis  of  the  liver,  we  must  believe  that  in  the 
kidney  the  extreme  distortions  which  are  so  frequently  met  with  are  prob- 
ably the  result  of  oft-repeated  or  constantly  acting  injuries  rather  than  of 

269 


270  TEXT-BOOK  OF  PATHOLOGY 

a  single  one.  It  is  the  destruction  and  disappearance  of  some  portion  of  the 
kidney  substance,  with  the  scar  which  forms  in  its  place,  that  cause  this 
distortion.  The  great  variety  in  the  appearance  of  the  kidneys  found  at 
autopsy  in  persons  who  have  shown  the  symptoms  of  diffuse  renal  disease 
becomes  more  intelligible  when  we  consider  that  these  appearances  must 
vary  not  only  according  to  the  character  and  severity  of  the  injury,  but 
also  according  to  the  duration  of  the  disease,  since  in  the  course  of  time  the 
injured  tissue  which  is  still  conspicuous  in  the  acute  stage,  is  removed,  and 
its  place  taken  by  a  scar.  This  decreases  the  size  of  the  organ  and  allows 
the  blood-vessels  to  show  through  more  plainly,  but  the  result  is  still  further 
modified  by  the  fact  that  whatever  secretory  tissue  remains  intact  becomes 
hypertrophied,  in  order  to  compensate  for  that  which  was  lost.  It  is  easy 
to  see  then  that,  whereas  in  the  acute  stages  of  severe  renal  disease  the 
kidneys  may  appear  swollen,  smooth,  and  translucent,  with  flecks  of  opaque 
yellow  and  of  bright  red  in  the  cortex,  they  would  look  quite  different  if  the 
person  survived  this  attack  for  months  or  years.  Then  there  would  appear, 
in  all  probability,  a  very  small,  rough,  granular  organ,  in  which  grayish, 
opaque  nodules  of  the  remaining  secretory  tissue  project  above  sunken  areas 
of  reddish  gray,  translucent,  scarred  tissue,  in  which  the  red  color  is  due 
to  the  visible  capillaries.  Further,  the  injury  which,  like  a  conflagra- 
tion, suddenly  destroys  a  great  part  of  the  secretory  substance  of  the  kid- 
ney, may  finally,  if  the  person  survives,  end  in  the  production  of  a  kidney 
which  looks  almost  exactly  like  another  which  has  gradually  reached  that 
stage  through  long  years  in  which  its  nutrition  has  suffered  through  nar- 
rowing of  its  blood-vessels,  and  which  never,  at  any  time,  had  shown  the 
picture  produced  by  extensive  acute  injury.  In  other  words,  it  is  dangerous 
to  conclude  anything  as  to  the  real  nature  of  the  disease  of  the  kidney  from 
the  mere  outward  appearance  of  the  organs  at  autopsy.  Even  micro- 
scopical study  often  leaves  us  uncertain,  although  there  are  generally 
traces  left  which  show  the  path  by  which  the  highly  elaborate  structures 
have  reached  this  stage  of  commonplace  wreck. 

To  have  a  clear  idea  of  the  nature  of  such  disease  we  must  follow  the 
symptoms  throughout  its  course,  and,  above  all  things,  make  clear-sighted 
tests  of  the  functional  capacity  of  glomeruli,  tubules,  etc.,  under  standard- 
ized burdens.  Up  to  the  present  we  have  not  learned  to  correlate  these 
things  precisely  with  changes  which  we  can  see  in  sections  of  the  kidneys, 
since  sometimes  blood-capillaries  or  tubules  which  seem  anatomically  intact 
are  quite  unable  to  carry  out  their  normal  function.  Beside  this,  each  of 
these  structures  has  a  variety  of  special  functions  which  may  separately 
become  defective,  without  our  being  able  to  suspect  this  from  any  change 
in  their  appearance. 

Only  the  very  grossest  correspondence  then  is  possible  at  present  between 
the  anatomical  changes  and  the  functional  disturbances.  This,  however, 
we  can  say — that  when  several  glomeruli  with  their  tubules  are  quite 
obliterated  and  converted  into  scar  tissue,  they  no  longer  play  any  part  in 


NEPHRITIS  271 

the  symptoms  of  the  disease,  except  in  so  far  as  the  kidney  substance  is 
reduced  by  their  loss.  It  is  aside  from  this,  in  the  better  preserved  tubules 
and  glomeruli,  that  we  must  look  for  changes  to  correspond  to  the  altered 
secretion.  It  is  perfectly  easy  to  understand,  therefore,  that  since  the 
remaining  tissue  may  retain  its  normal  state  and  hypertrophy  to  compen- 
sate for  the  areas  which  have  been  lost,  such  a  kidney,  sprinkled  with 
obsolete  scars,  might  carry  on  its  functions  perfectly  normally.  Doubtless 
that  is  exactly  what  happens  in  many  cases  in  which  a  single  injury — 
say  from  the  ingestion  of  a  poison  or  from  a  single  attack  of  some  acute 
infectious  disease— is  entirely  healed,  by  the  scarring  of  the  destroyed 
areas  and  the  compensatory  enlargement  of  the  tissue  that  is  left.  Per- 
haps the  majority  of  the  cases  in  which  the  pathologist  at  autopsy  writes 
down  " slight  chronic  nephritis"  are  only  instances  of  such  obsolete  scars 
in  the  kidney  whose  cause  it  is  now  impossible  to  tell. 

From  the  point  of  view  reached  by  anatomical  study,  it  seems  hardly 
justifiable  to  classify  these  cases  sharply  into  groups.  If  we  knew  the 
setiological  factors,  it  would  be  different.  Then  we  might  say  with  assur- 
ance, this  is  the  acute  stage  of  the  renal  change  produced  by  a  protein  in- 
toxication, that  the  terminal  result  of  a  long-past  infection  with  strepto- 
coccus. But  it  is  only  in  a  few  cases  that  we  can  do  this,  and  even  when  we 
can  definitely  assign  an  acute  infection  as  a  cause  of  the  renal  change,  we 
are  generally  ignorant  of  the  nature  of  that  infection.  So  it  is  in  the 
common  scarlatinal  nephritis.  But  we  do  know  that  streptococcus  in- 
fections cause  nephritis  and  are  possibly  responsible  for  the  scarlatinal 
form,  and  that  corrosive  sublimate  and  a  few  other  substances  which 
have  a  chance  of  being  introduced  into  the  body  can  do  so  too.  Other 
unusual  poisons  will  in  the  same  way  injure  the  kidney,  but  they  practi- 
cally do  not  come  into  consideration  except  in  experimental  studies. 
Indeed,  in  the  vast  majority  of  cases  we  do  not  know  what  the  injurious 
factor  is,  so  that  we  cannot  yet  make  our  classification  on  this  aBtiological 
basis. 

A  division  founded  upon  structural  alterations  is  the  one  in  common  use, 
and  yet  it  is  very  unsatisfactory,  since,  with  the  lapse  of  time,  the  responses 
to  injury  become  so  combined  that  we  can  never  outline  perfectly  sharply 
which  is  cause  and  which  is  effect.  Even  a  division  according  to  disturb- 
ances in  function  leaves  much  to  be  desired,  since  totally  different  condi- 
tions, both  renal  and  extrarenal  in  nature,  may  cause  the  same  changes 
in  the  excretory  power  of  the  kidney. 

With  this  in  mind  we  may  consider  first  the  anatomical  changes  and  then 
the  defects  in  function. 

Some  of  the  things  which  are  noxious  to  the  kidney  stir  up  an  acute  or 
inflammatory  reaction,  while  others  seem  to  destroy  tissue  and  leave  the 
gap  to  be  filled  up  by  regenerating  cells  or  by  scar  tissue  without  any  very 
striking  inflammatory  response.  Especially  is  this  thought  to  be  true  in 
those  cases  in  which  arteriosclerotic  thickening  and  narrowing  of  the  renal 


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arterioles  diminish  the  nutrition  of  small  patches  of  kidney  substance,  so 
that  their  place  is  taken  by  fibrous  tissue  in  which  the  remains  of  obliter- 
ated tubules  and  glomeruli  persist.  On  this  account  many  authors  set  this 
group  apart  as  quite  separate  from  the  other  diffuse  renal  affections,  but 
they  seem  to  me  so  closely  related  in  principle  and  marked  by  such  similar 
derangements  of  function  that  I  prefer  to  class  them  with  the  rest,  espe- 
cially since  we  are  not  in  all  cases  perfectly  sure  that  the  arteriosclerosis 
is  not  caused  by  the  renal  disease  rather  than  the  reverse. 


Fig.  114. — Glomerulus  with  capillaries  occluded  by  hyaline  thrombi  and  adherent  to 

capsule. 

In  studying  any  large  series  of  cases  one  meets  with  instances  (a)  in 
which  the  injury  primarily  affects  the  glomeruli;  others  (6)  in  which  the 
glomeruli  are  apparently  intact,  while  the  tubular  epithelium  has  suffered, 
and  still  others  (c)  in  which  neither  of  those  structures  seems  much  changed, 
although  there  is  an  intense  inflammatory  reaction  in  the  interstitial  tissues. 
The  results  of  these  things  are  found  in  many  cases  in  which  extensive  scars 
remain  to  show  where  the  injury  was  done,  and  in  which  there  are  generally 


NEPHRITIS 


273 


traces  of  some  sort  which  indicate  what  was  the  character  of  the  action 
Besides  these  there  are  (d)  kidneys  in  all  stages  advancing  toward  the  con- 
dition of  maximal  scarring,  in  which  there  are  not  to  be  found  the  distinctive 
traces  of  initial  destruction  of  the  glomeruli  or  tubules  proceeding  with 
inflammation.  In  these  the  arteries  are  almost  closed  by  sclerotic  changes, 
and  this  offers  the  easiest  explanation  of  their  state;  and  then  there  is  a 
group  (e)  in  which,  in  addition  to  other  injuries,  the  presence  of  amyloid 
causes  extensive  changes. 


Fig.  115. — Glomerulus  showing  formation  of  capillary  thrombus. 

Of  course,  the  healing  of  isolated  local  lesions  of  all  sorts  may  produce 
local  conditions  closely  resembling  these,  but  their  explanation  follows 
simply  from  what  may  be  said  about  the  diffuse  changes. 

It  is  obviously  unfortunate  that  such  terms  as  chronic  interstitial  nephritis,  chronic 
parenchymatous  nephritis,  etc.,  should  be  in  such  common  use,  since  they  do  not  ex- 
press exact  ideas.  It  is  possible  that  there  may  be  a  chronic  as  well  as  an  acute  inter- 
stitial nephritis,  but  this  is  by  no  means  what  is  meant  by  the  term  chronic  interstitial 
nephritis,  which  is  used  of  the  late  or  contracted  condition  of  a  kidney  in  which  the 
injury  actually  affected  chiefly  the  parenchyma.  Upon  the  complete  destruction  of 


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this,  of  course,  the  scar  tissue  which  remains  in  its  place  becomes  the  most  obvious  thing, 
audit  is  hard  to  escape  the  idea,  at  first  sight,  that  it  was  the  tissue  primarily  affected. 
So,  too,  the  wide-spread  use  of  the  terms  large  white  kidney,  small  red  kidney,  etc.,  is 
deplorable,  since,  though  graphic,  they  express  only  the  crudest  and  most  misleading 
opinion  of  the  nature  of  the  lesion.  As  Ponfick  complains,  we  might  as  well  speak  of  a 
small  blue  lung  or  a  large  red  liver. 

(a)  Acute  and  Chronic  Glomerulonephritis 

Scarlatina,  streptococcus  infections,  especially  the  protracted  subacute 
infections  with  the  Streptococcus  viridans,  certain  poisons  used  experi- 


Fig.  116. — Acute  glomerulonephritis.     Glomerular  capsule  filled  with  leucocytes. 


mentally,  such  as  cantharidin,  uranium  nitrate,  etc.,  and  probably  many 
other  violent  toxic  agencies  attack  especially  the  capillaries  of  the  glomeru- 
lar  tufts,  finally  producing  extraordinary  complex  alterations  in  the  whole 
glomerular  structure,  which  heal  with  distortion  or  obliteration.  Perhaps 
the  simplest  are  those  in  which  bacteria  actually  lodge  in  the  capillaries, 
sometimes  in  clumps  large  enough  to  occlude  the  lumen  or  when  bacteria 
or  toxic  substances  injure  the  wall  of  the  capillary  and  cause  the  formation 


NEPHRITIS 


275 


of  an  occluding  thrombus.  Generally  this  happens  in  only  a  part  of  the 
glomerular  tuft,  while  blood  circulates  still  through  the  rest  (Fig.  114). 
Such  occluded  loops  become  greatly  swollen  or  distended  by  a  mass  of 
hyaline,  pink-staining  material,  which  seems  to  be  formed  chiefly  by  the 
agglutination  and  fusion  of  red  corpuscles  (Fig.  115).  Ordinarily,  it  seems, 
we  must  believe  that  the  pulsation  of  the  arterial  stream  may  be  felt  in 
the  glomerular  capillaries,  which  move  a  little  backward  and  forward  in 
the  elastic  capsule  almost  as  the  lung  does  in  the  pleura.  But  now,  while 
the  rest  of  the  loops  still  slide  on  the  parietal  wall  with  their  expansion  and 


/  \  : 

-»/  ••••  » 

*-inafc 

Fig.  117. — Intracapillary  glomerulonephritis. 

relaxation,  the  occluded  ones  become  rigid,  and  because  of  their  distension 
press  continuously  against  one  place  in  the  wall  of  the  capsule.  This  place 
quickly  becomes  adherent  to  the  loop,  and  alterations  appear  in  it  like  those 
which  affect  the  loop  itself.  Later,  just  as  in  any  other  place  where  in- 
jured or  dead  tissue  is  left  surrounded  by  the  living,  connective  tissue  grows 
through  and  replaces  it,  making  the  adhesion  permanent. 

In  other  cases,  when  the  capillaries  are  not  quite  blocked,  leucocytes  may 
come  in  in  numbers  to  approach  the  injured  walls,  so  that  all  the  loops  seem 
stuffed  with  them,  and  even  the  capsule  and  the  tubule  are  found  to  con- 


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tain  those  which  have  penetrated  the  capillary  walls  (Fig.  116).  Even 
more  common  than  this  is  the  slightly  less  tempestuous  form  in  which  the 
glomerular  tufts  become  greatly  enlarged  through  the  appearance  of  quan- 
tities of  cells  in  the  lumina  of  the  capillaries,  which  are  not  polymorphonu- 
clear  leucocytes,  but  look  more  like  endothelial  cells.  At  least  they  are 
mononuclear  cells  with  indistinct  outline,  so  fused  together  that  their  ori- 
gin can  hardly  be  made  out.  With  them  there  is  always  an  indefinite 
foamy  or  spongy  mass  of  protoplasm  which  completes  the  occlusion  of  the 


Fig.  118. — Hyaline  clot  in  the  glomerular  capsule  overgrown  by  epithelium. 

capillary.  Such  glomeruli  must  be  entirely  impermeable,  for  practically 
all  the  capillaries  seem  to  be  thus  obstructed  by  the  mass  of  endothelial 
cells  (Fig.  117). 

The  lumen  of  the  capsule  generally  contains  albuminous  material  or 
blood,  with  leucocytes  and  fibrin.  That  the  lining  epithelial  cells  become 
desquamated  into  this  cavity  at  times  is  undoubtedly  true,  but  I  at  least 
have  never  seen  an  instance  in  which  they  were  abundant  nor  sufficient  to 
produce  the  appearance  known  as  the  epithelial  crescent.  That  is  rather 


NEPHRITIS  277 

the  outcome  of  a  well-ordered  proliferation  which  brings  with  it  a  supporting 
framework  of  connective  tissue.  When  blood  exudes  into  the  capsule  the 
corpuscles  often  fuse  into  a  hyaline  mass,  which  lies  in  contact  with  the 
epithelium  (Fig.  118).  This  may  be  one  of  the  stimuli  for  the  prolifera- 
tion of  the  epithelium,  because  just  as  in  the  case  of  the  endothelium  of  a 
vessel  which  grows  up  to  cover  a  mural  thrombus,  this  hyaline  clot  soon 
becomes  completely  encapsulated  by  epithelial  cells.  So,  too,  whenever 
adhesions  form  between  glomerulus  and  capsule,  the  epithelium  becomes 


Fig.  119— Glomerulus  with  blood-clot  adherent  to  capsular  wall. 

continuous  from  wall  to  tuft  (Fig.  119).  In  this  way  the  cavity  of  the 
capsule  may  be  divided  into  several  chambers  which  communicate  with  one 
another.  In  more  advanced  cases,  through  the  aid  of  still  other  mechan- 
isms, the  most  extraordinary  growths  of  the  epithelium  take  place,  always 
or  nearly  always  in  a  simple  layer,  but  in  folds  which  unite  with  one  another 
and  thus  form  a  sponge-like  tissue  all  the  cavities  of  which  ( Communicate 
with  one  another,  with  the  main  cavity  of  the  capsule,  and  thus  with  that 
of  the  tubule  (Fig.  120). 


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Flattened  down  in  the  narrow  space  of  the  capsule,  this  tissue  at  first 
sight  gives  the  impression  of  a  crescentic  mass  of  desquamated  cells,  whence 
the  term,  "epithelial  crescent"  (Fig.  121). 

All  these  changes  cause  the  glomerulus  to  become  greatly  enlarged,  so 
that  it  is  conspicuous  on  the  cut  surface  of  the  fresh  kidney— all  interfere 
greatly  with  the  permeability  of  the  glomerulus,  and  all  are  usually  associ- 
ated with  changes  of  an  inflammatory  character  in  the  membrana  propria 
and  surrounding  connective  tissue  of  the  capsule.  With  adhesions  and  the 
replacement  of  the  hyaline  and  necrotic  capillary  loops  by  connective  tissue 


Fig.  120. — Proliferation  of  capsular  epithelium  in  contiguous  folds. 

grown  in  from  outside,  the  glomerulus  may  be  in  large  part  obliterated  by 
being  converted  into  dense  fibrous  tissue.  Nearly  always,  however,  even 
in  the  latest  stages,  there  remain  traces  of  the  less  affected  capillary  loops, 
and  abundant  indications  of  the  method  by  which  obliteration  occurred. 

The  epithelium  of  the  tubules  is  undoubtedly  injured  also,  although  for  a 
time  it  shows  relatively  little  change.  Later  the  cells  show  every  sort  of 
degeneration,  and  globules,  both  of  neutral  fat  and  cholesterine  esters, 
accumulate  in  them.  With  their  desquamation  and  disappearance,  or 
even  with  their  shrinkage  and  atrophy,  the  tubule  belonging  to  that  glom- 
erulus tends  to  collapse  and  becomes  lost  to  view.  Often  for  a  time  the 


NEPHRITIS 


279 


epithelial  cells  are  greatly  swollen  through  the  presence  of  small  and  large 
globules  of  refractive  hyaline  material,  which  stains  like  fibrin  (Fig.  122). 
Often,  too,  the  lumen  is  filled  with  blood,  leucocytes,  epithelial  cells,  and 
granules,  or  with  hyaline  moulds  or  casts  to  which  these  various  things 
adhere,  being  swept  down  into  the  urine,  to  appear  there  as  different  sorts 
of  urinary  casts. 

About  the  glomeruli  and  about  the  injured  tubules  there  is  generally 


Fig.  121. Glomerulus  with  epithelial  crescent.     The  cavities  among  the  epithelial  cells 

communicate  with  one  another. 

some  inflammatory  reaction,  shown  by  the  presence  of  wandering  cells 
(Fig.  123),  and  in  the  course  of  time  in  these  somewhat  cedematous  areas 
new  connective  tissue  forms  in  ever-increasing  amounts  until  finally  the 
obliterated  glomeruli  and  atrophic  tubules  come  to  lie  in  a  very  dense 
framework  of  fibrous  tissue.  Aside  from  these  areas,  or  intercalated  some- 
where among  them,  there  are  intact  glomeruli  with  their  tubules,  which 
now  carry  on  the  work  of  the  kidney.  Such  glomeruli  actually  enlarge, 
and  the  tubules  increase  in  size  and  length  through  the  multiplication,  by 


280  TEXT-BOOK  OF  PATHOLOGY 

mitosis,  of  their  epithelial  cells.  It  is  a  compensatory  hypertrophy  on  the 
part  of  the  remaining  functional  tissue.  Such  groups  of  tubules,  until 
they  themselves  meet  with  destruction,  form  the  prominent  projecting 
granules  which  stand  up  on  the  rough  surface  of  the  contracted  kidney  in 
relief  above  the  shrunken,  scarred  areas  where  the  tubules  are  lost. 

No  attempt  is  made  to  subdivide  types  of  glomerular  lesions,  because  in 
every  instance  the  whole  of  the  glomerulus  is  somewhat  altered — where 
the  change  seems  to  be  intracapillary,  search  will  reveal  changes  in  the 
epithelium  of  the  capsule,  and,  when  the  striking  alteration  seems  to  be  in 


Fig.  122.— Colloid  or  hyaline  droplets  in  the  epithelium  of  renal  tubules. 

the  epithelium,  traces,  at  least,  of  occluding  thrombi  will  be  found  in  the 
capillaries. 

Such  lesions  of  the  kidney  are  recognizable  in  the  gross  organ  in  the  early 
stages  by  the  swelling  of  the  glomeruli,  which  project  as  pale,  translucent 
grams,  and  by  the  opacity  of  the  cortex,  with  its  sprinkling  of  ecchymoses 
Even  much  later  the  swollen  kidney  is  still  quite  smooth  when  the  capsule 
is  puled  off  and  generally  pale,  grayish,  and  translucent,  though  mottled 
thickly  with  flecks  of  yellow  opacity  and  to  a  less  extent  with  hemorrhages 
big.  124).  Occasionally  the  haemorrhages  are  very  abundant,— almost 


NEPHRITIS 


281 


confluent,  so  that  the  organ  is  deep  red  or  almost  black, — but  that  is  rare. 
With  the  gradual  removal  of  the  fat-containing,  opaque,  degenerated  epi- 
thelium, the  kidney  decreases  in  size,  the  translucent,  gray,  fibrous  stroma 
sinks  together,  the  hypertrophied  intact  tubules  stand  out  as  gray  nodules 
from  the  intervening  tissue,  where,  now  that  the  epithelium  is  gone,  the 
capillaries  begin  to  show  through  red — and  in  the  end  we  have  a  small, 


Fig.  123.— Acute  diffuse  nephritis  with  epithelial  degeneration,  oedema,  and  infiltration 
with  leucocytes  and  haemorrhage. 

hard,  reddish-gray  organ,  roughened  by  granules  of  gray  over  which  the 
capsule  is  quite  adherent— the  so-called  secondary  contracted  kidney 
(Figs.  125  and  126). 

Naturally,  the  disturbance  of  function  must  change  as  the  kidney  pro- 
gresses through  all  these  stages  of  the  disease.  Very  striking,  however,  in 
the  beginning  is  the  diminution  of  the  amount  of  urine,  its  high  concen- 
tration and  admixture  with  blood,  albumin,  and  casts,  and  the  coincident 


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oedema.     Later  the  whole  clinical  picture  may  change,  as  shall  be  described 
later. 

(b)  Acute  and  Chronic  Tubular  Nephritis 

Destructive  lesions,  affecting  especially  the  epithelium  of  the  tubules,  and 
followed  by  more  or  less  inflammatory  reaction,  result  from  various  poisons, 

among  which  bichloride  of  mercury,  ura- 
nium nitrate,  and  chromates  are  more 
familiar.  Baehr  has  recently  described 
an  exquisite  tubular  lesion  produced  by 
iodine.  But  there  are  many  others  of  less 
definite  nature,  since  general  peritonitis 
and  septicaemias  are  sometimes  accom- 
panied by  quite  analogous  changes,  and  the 
acute  nephritis  of  pregnancy  is  commonly 


„ 

S 


Fig.  124. — Acute  and  subacute 
nephritis,  showing  punctiform  haem- 
orrhages and  opaque  yellow  flecks 
which  are  produced  by  the  degen- 
erated epithelium. 


Fig.  125. — Secondary  contracted  kidney,  rep- 
resenting later  stage  in  the  development  of  the 
diffuse  glomerulonephritis. 


of  this  type.  In  eclampsia,  too,  one  sometimes  finds  the  tubular  epithelium 
necrotic.  In  any  series  of  cases  anatomically  studied  one  must  be  careful 
to  rule  out  possible  postmortem  autolytic  changes,  but  with  this  in  mind, 
there  are  still  found  many  instances  in  which  a  great  proportion  of  highly 


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283 


sensitive  epithelial  cells  of  the  convoluted  tubules  are  necrotic,  as  shown  by 
their  disintegration  and  the  loss  of  their  nuclei.  Nevertheless,  severe  altera- 
tions of  these  cells  may  occur  without  proceeding  to  actual  death,  and  in 
most  infectious  processes,  including  typhoid  fever  and  pneumonia,  and  in 
such  nutritional  disturbances  as  result  from  chronic  passive  congestion, 


Fig.  126.— Chronic  diffuse  nephritis  following  repeated  glomerular  injuries  (secondary 

contracted  kidney). 

striking  functional  derangements,  referable  at  least  in  part  to  the  tubular 
epithelium,  appear,  while  nothing  more  than  the  so-called  cloudy  swelling 
can  be  demonstrated  anatomically.  In  glomerulonephritis,  in  which  the 
tubules  often  seem  to  be  spared,  the  occurrence  of  mitoses  in  their  lining 
epithelial  cells,  which  is  an  indication  of  their  extraordinary  power  of  regen- 


284  TEXT-BOOK  OF  PATHOLOGY 

eration,  may  give  a  clue  to  their  participation  in  the  injury,  even  when 
actual  destruction  of  the  cells  is  not  evident.  So,  too,  the  ultimate  fate 
of  the  tubules  in  an  area  of  atrophy,  whether  brought  about  by  glomerular 
obstruction,  by  intoxication,  or  by  malnutrition,  gives  us  convincing  evi- 
dence of  the  fact  that  their  cells  suffer  very  regularly,  even  though  the 
glomerular  lesions  may  be  far  more  conspicuous. 

Pure  tubular  nephritis  is  probably  not  quite  so  uncommon  as  is  generally 
thought,  since  recovery  with  complete  compensatory  new  formation  of  the 


Fig.  127.— Destruction  of  tubular  epithelium    caused    by  poisoning    with    mercury 

bichloride. 

cells  seems  so  easily  possible,  and  even  when  the  affected  tubules  lose  all 
their  epithelium  and  collapse,  the  signs  of  their  downfall,  when  some  time 
later  the  person  dies,  are  inconspicuous.  Apparently  when  a  tubule  be- 
comes permanently  obliterated  its  glomerulus  soon  falls  together  in  a 
bloodless  state,  and  is,  some  time  later,  surrounded  by  a  progressively  thick- 
ening hyaline  and  connective-tissue  capsule,  which  accompanies  its  com- 
plete obliteration.  The  best  example  of  tubular  lesions  is  that  produced  by 


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285 


mercuric  bichloride,  a  condition  which  has  become  peculiarly  frequent  of 
late,  and  there  one  finds,  side  by  side  in  the  tubules,  living  and  necrotic 
cells  (Fig.  127).  Those  which  have  succumbed  soon  become  formless 
masses,  often  calcified,  which  may  be  surrounded  and  encapsulated  by  the 
new  epithelial  cells  which  quickly  grow  from  the  division  of  those  remaining 
intact  (Fig.  128). 

The  ultimate  result  of  destruction  of  the  epithelium  of  the  tubules  must 


Fig.  128.— Later  stage  of  nephritis  following  bichloride  poisoning.     The  necrotic  cells 
are  calcined  and  surrounded  by  new-formed  epithelium. 

depend  upon  its  extent,  since  if  it  be  partial,  the  tubule  may  be  perfectly 
relined  from  the  cells  which  remain,  while  if  it  be  complete,  the  collapse 
of  the  tubule  will  lead  shortly  to  destruction  of  the  glomerulus  and  the 
formation  of  a  scar  in  the  place  once  occupied  by  the  whole  structure. 
Doubtless  this  is  the  origin  of  some  of  the  scattered  scars  which  are  so 
frequently  seen  in  the  kidney,  but  in  its  completed  form  it  is  almost  im- 


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possible  to  say  whether  such  a  scar  was  brought  about  in  this  or  in  some 
other  way. 

Rarely  one  encounters  renal  changes  resembling  closely  those  produced  by  Baehr 
through  the  injection  of  iodine,  and  found  in  animals  which  have  survived  a  long  time.* 
In  a  case  studied  recently  the  kidneys  were  found  to  be  smooth,  pale,  and  hard,  and  on 
section  the  tubules  were  uniformly  atrophic  and  shrunken,  while  the  glomeruli  remained 
large  and  conspicuous  (Fig.  129).  It  is  true  that  in  this  case  the  capillaries  of  the 


Fig.  129. — Subacute  and  chronic  nephritis.     Glomeruli  fairly  well  preserved  in  spite  of 
universal  atrophy  and  shrinkage  of  the  tubules  which  are  embedded  in  scar  tissue. 

glomeruli  appear  to  be  blocked  by  masses  of  large  cells,  so  that  other  interpretations  of 
the  whole  condition  are  possible,  but  the  general  aspect  of  the  cortex  points  to  a  primary 
lesion  of  the  tubular  epithelium. 

(c)   Acute,  Subacute,  and  Chronic  Interstitial  Nephritis 

By  this  is  meant  strictly  the  injury  which  seems  to  affect  particularly 
the  framework  of  the  kidney,  causing  an  inflammatory  reaction  there, 

*  Ziegler's  Beit.,  1913,  Iv,  572,  Fig.  12. 


NEPHRITIS 


287 


while  glomeruli  and  tubules  are  left  more  or  less  intact,  with  the  resulting 
formation  of  scars  throughout  the  organ.  It  does  not  apply  to  the  several 
varieties  of  scarred,  contracted  kidneys,  which  are  clearly  the  outcome  of 
injuries  to  the  specialized  secretory  mechanism,  that  is,  to  the  great  ma- 
jority of  the  contracted  kidneys,  which  are  so  commonly  and  loosely  spoken 
of  as  chronic  interstitial  nephritis.  It  is  perfectly  recognized  that,  as 
Weigert  pointed  out,  all  forms  of  nephritis  are  diffuse  in  that  every  element 
of  the  tissue  is  somewhat  affected,  so  that,  in  an  instance  in  which  the 


Fig.  130. — Acute  interstitial  nephritis  from  a  child  dying  of  diphtheria. 

glomeruli  show  the  most  striking  changes,  the  connective-tissue  framework, 
as  well  as  the  epithelium  of  the  tubules,  also  feels  the  shock  and  reacts. 
But  it  is  entirely  wrong  to  conclude,  from  the  fact  that  in  the  late  stages  of 
such  a  condition,  when  much  of  the  kidney  substance  has  disappeared 
and  is  replaced  by  scar  tissue,  the  connective  tissue  was  the  first  thing  to 
be  affected,  and  that  it,  in  its  growth,  has  constricted  and  destroyed  the 
secreting  structures.  It  is  not  in  this  sense  that  we  use  the  term  interstitial 
nephritis,  but  rather  to  describe  a  quite  uncommon  condition,  seen  only 


TEXT-BOOK  OF  PATHOLOGY 

once  or  twice  among  the  last  500  autopsies  at  the  Presbyterian  Hospital, 
where  the  patients  are  chiefly  adults,  but  much  more  frequent  in  hospitals 
for  the  infectious  diseases  of  children.  Councilman  found  42  cases  in  such 
material  in  the  course  of  two  years. 

In  its  rather  focal  distribution,  the  acute  interstitial  nephritis  resembles 
somewhat  the  forms  of  acute  suppurative  nephritis,  caused  directly  by  the 
lodging  of  bacteria  in  the  kidney  substance,  but  the  whole  course,  the  type 
of  wandering  cells  involved,  and  the  absence  of  bacteria  serve  to  distinguish 
it  from  them.  It  appears  usually  in  the  course  of  scarlatina  or  diphtheria, 
or  other  similar  intense  infections,  perhaps  more  commonly  in  mixed  in- 
fections than  in  pure  scarlatina  or  diphtheria. 

The  swollen  kidney  shows  on  section  clouding  with  grayish  areas,  which 
are  found  microscopically  to  depend  upon  the  accumulation,  between  the 
tubules,  of  great  numbers  of  wandering  cells  of  several  sorts  (Fig.  130). 
Most  of  these  are  mononuclear,  and  vary  in  form  from  those  resembling 
the  lymphocyte  to  plasma  cells  and  even  much  larger  types.  Usually 
there  are  also  some  polymorphonuclear  leucocytes.  There  is  a  spreading 
apart  of  the  interstitial  connective  tissue,  and  commonly  a  new  formation 
of  fibroblasts.  The  glomeruli  seem  to  suffer  very  little  or  secondarily,  as 
shown  by  the  penetration  of  wandering  cells  through  the  capsule  into  the 
intracapsular  space.  The  epithelium  of  the  tubules  may  also  be  relatively 
intact,  although  wandering  cells  are  sometimes  found  in  the  lumen.  But 
the  same  changes  are,  as  found  in  adults,  by  no  means  independent  of  alter- 
ations of  glomeruli  and  tubules,  and  most  often  accompany  them. 

The  healing,  or  rather  the  passing  into  a  stationary,  obsolete  condition  of 
this  process,  is  difficult  to  follow  certainly,  but  it  seems  probable  that  a 
rather  diffuse  thickening  of  the  interstitial  tissue  in  many  areas  may  repre- 
sent its  last  stages.  No  definite  symptoms  need  accompany  the  acute 
stages,  and  the  urine  may  be  normal.  If  this  be  so,  there  seems  no  reason 
to  suppose  that  the  later  stages  should  be  productive  of  symptoms.  This 
will  naturally  depend  upon  the  extent  of  the  injury  to  glomeruli  and  tubules. 

(d)   Arteriosclerotic  Disease  of  the  Kidney 

It  seems  incorrect  to  discuss  a  disease  of  the  kidney  brought  about  by  the 
gradual  diminution  of  its  blood  supply  under  the  heading  nephritis,  but 
the  main  principle  is  that  here,  too,  an  injury  leads  to  the  distortion  of 
the  kidney  anatomically  and  functionally  in  a  way  like  that  produced  by 
other  injuries,  which  bring  in  their  train  inflammatory  reaction.  After 
all,  the  existence  of  an  inflammatory  reaction  is  by  no  means  the  most 
important  feature,  and  this  arrangement  is  for  convenience,  it  having 
been  said  that  if  there  must  be  a  classification,  it  can  be  satisfactory  and 
logical  only  when  on  an  aetiological  basis. 

Long  ago  it  was  pointed  out  by  Gull  and  Sutton  that  thickening  of  the 
walls  of  the  renal  vessels,  causing  their  narrowing  and  hence  depriving  the 
kidney  of  blood,  is  found  in  kidneys  which  have  lost  much  of  their  substance, 


NEPHRITIS 


289 


and  have  become  scarred  and  contracted.  After  long  dispute  it  seems 
probable  that  the  sclerosis  of  the  vessels  is  actually  the  cause  of  these 
changes  in  the  kidney,  and  not  the  incidental  result  of  other  injuries  which 
also  affect  that  organ.  The  arteriosclerotic  thickening  of  the  intima 
associated  with  an  excessive  reduplication  of  the  internal  elastic  membrane 
extends  into  the  smallest  vessels,  and  may  completely  occlude  them  and 
narrow  them  to  the  minutest  channel  (Fig.  131).  Usually  the  effect  of 
this,  inasmuch  as  most  of  the  branches  of  the  renal  artery  are  thus  nar- 


Fig.  131.— Arteriosclerotic  narrowing  of  the  renal  vessels,  with  thickening  of  the  arterial 
coat  and  reduplication  of  the  elastic  lamellae. 

rowed,  is  to  produce  many  minute  areas  of  malnutrition,  in  which  the 
sensitive  tissue  suffers  and  finally  atrophies  away,  to  be  replaced  by  a  scar. 
This  is  the  type  of  arteriosclerotic  contracted  kidney  or  primary  contracted 
kidney  which  is  most  important  and  which  we  wish  to  describe. 

There  are  some  cases,  however,  in  which,  while  most  of  the  cortex  is 
quite  normal  and  shows  itself  to  be  smooth  and  normally  lobulated  on  the 
removal  of  the  capsule,  there  are  numerous  quite  large  depressions  into 
which  the  capsule  dips  and  becomes  adherent  (Fig.  132).  These  corre- 


20 


290 


TEXT-BOOK  OF  PATHOLOGY 


spond  with  gross  scarred  areas  sunken  below  the  general  surface,  in  which 
obliterated  glomeruli  and  remains  of  shrunken  tubules  persist.  Since  the 
intervening  tubules  have  collapsed  or  been  reduced  to  narrow  cords  of 
cells,  the  persistent  glomeruli  concentrate  themselves  into  a  small  space, 
and  are  embedded  in  scar  tissue  infiltrated  with  mononuclear  wandering 
cells.  The  explanation  usually  given  is  that  the  sclerotic  narrowing  of  the 
vessels  is  not  uniform  in  all  the  branches  of  the  artery,  and  that  these  are 
areas  which  have  suffered  especially.  This  explanation  does  not  rest  on 

an  absolutely  firm  foundation,  and 
since  it  is  obvious  that  the  scarred 
areas  are  entirely  like  slowly  pro- 
duced infarcts  which  are  organized 
as  fast  as  the  cells  disappear,  it 
seems  possible  that,  after  all,  they 


Fig.  132. — Atrophic  scarred  areas  in 
renal  cortex  produced  by  arteriosclerotic 
narrowing  of  the  vessels. 


Fig.  133. — Arteriosclerotic  contracted 
kidney  (compare  Fig.  136,  which  repre- 
sents a  section  of  this  kidney). 


may  have  had  an  embolic  origin.  The  functional  disturbances  in  such 
cases  are  not  especially  marked,  since  there  is  much  normal  tissue  to  carry 
on  the  work. 

The  changes  caused  by  diffuse  sclerosis  of  the  small  branches  is  quite  a 

different  matter.     Such  kidneys  are  usually  small  and  hard,  and  are  often 

surrounded  by  a  thick  mass  of  fat.     The  capsule,  which  is  thickened,  is 

dherent  to  the  surface,  tearing  it  somewhat  as  it  strips  off,  or  in  other 

instances  it  peels  off  easily  enough.    In  any  case  it  leaves  a  pale,  mottled 


NEPHRITIS  291 

surface  which  is  roughened  by  fine  projecting  nodules  of  a  pale  yellowish 
gray  or  pinkish  gray  color  (Fig.  133).  The  scar-like  tissue  between  these 
is  translucent,  grayish  red,  often  allowing  small  vessels  to  be  seen  shining 
through  beneath  its  surface.  On  section  it  is  usually  found  that,  with  the 
decrease  in  size  of  the  kidney  in  all  directions,  the  space  in  which  the  pelvis 
lies  is  enlarged  and  filled  with  fat  (Fig.  134).  The  blood-vessels  are  stiff 
and  thick-walled,  and  even  the  minute  ones  on  the  cut  surface  stand  open 
like  rigid  tubes.  The  pale  cortex  is  greatly  thinned,  measuring  sometimes 
not  more  than  2  to  3  mm.,  and  in  it  one  can  no  longer  make  out  the  ordi- 
nary striations  in  their  usual  parallel  lines.  Where  they  can  be  seen,  they 
are  greatly  twisted  and  distorted  and  interrupted  by  the  presence  of  opaque 
nodules  of  tissue  which,  beside  projecting  on  the  surface,  are  found  deeper 


Fig.  134. — Old  arteriosclerotic  contracted  kidney  showing  the  filling  of  the  widened 
space  about  the  pelvis  with  fat. 

in  the  cortex.     Flecks  of  opaque  yellow  or  deep  red  haemorrhage  are  some- 
times seen. 

The  gross  appearance  of  such  a  kidney  differs  in  no  way,  therefore,  from 
the  end  result  in  a  protracted  glomerulonephritis  (the  so-called  secondary 
contracted  kidney),  and  in  all  probability  something  similar  may  result 
if  the  destruction  be  severe  enough  and  time  be  given  in  the  case  of  the 
tubular  and  interstitial  forms.  As  a  matter  of  fact,  except  perhaps  through 
the  presence  of  the  strikingly  thickened  blood-vessels,  it  is  difficult,  if  not 
impossible,  to  distinguish  macroscopically  the  types  of  ultimate  contracted 
kidney.  The  arteriosclerotic  (so-called  primary  contracted  kidney)  may 
be  very  pale  or  quite  dark  red  in  color,  but  this  depends  in  great  part  first 
on  the  exposure  of  the  blood-capillaries  in  the  translucent  tissue,  and  then 
upon  the  degree  of  congestion  of  these  vessels.  The  same  difference  in 
color  may  be  seen  in  other  contracted  kidneys. 


292 


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Small  cysts  filled  with  clear  or  dark-brown  fluid  are  often  seen  projecting 
from  the  cortex  (Fig.  135),  but  these  seem  not  to  depend  entirely  upon  the 
scarring  of  the  kidney,  for  they  are  quite  frequently  found  in  kidneys  which 
have  undergone  no  such  change. 

The  microscopic  alterations  in  the  diffuse  arteriosclerotic  kidney  are 
about  as  follows  (Fig.  136) :  The  arcuate  vessels,  the  vasa  recta,  and  the 
afferent  vessels  of  the  glomeruli  show  throughout  or  in  patches  such  a 
thickening  of  the  intima  as  greatly  to  encroach  upon  the  lumen,  but  this 
cannot  affect  all  the  branches  uniformly,  for  there  are  the  projecting  gran- 
ules in  which  one  finds  the  glomeruli  enlarged  and  actively  functional,  and 
the  tubules  not  only  well  preserved,  but  greatly  hypertrophied,  being  both 

wider  and,  as  shown  by  recon- 
struction, actually  longer  than 
the  normal,  and  lined  with  cells  of 
normal  appearance.  In  every  re- 
spect these  seem  to  be  magnified 
normal  glomeruli  and  tubules 
which  have  undergone  a  work 
hypertrophy  to  compensate  for 
many  which  have  been  lost.  It 
is  true  that,  with  the  progress  of 
the  malnutrition,  these  epithelial 
cells  often  show  degenerative 
changes  and  become  granular 
and  disintegrated,  or  enormously 
swollen  from  the  presence  of 
large  and  small  hyaline  droplets. 
In  most  instances,  as  in  almost 
all  destructive  renal  changes, 
fat  accumulates  in  drops  in  the 
epithelial  cells,  and,  as  in  the  in- 
flammatory forms,  these  fats  may 
be  both  glycerin  and  cholesterine 
esters,  showing  well  all  the  chem- 
ical and  staining  peculiarities  of 

those  two  types,  as  well  as  their  different  effect  upon  polarized  light.  It 
is  the  presence  of  the  fats,  hyaline  droplets,  etc.,  which  confers  the  opacity 
upon  the  degenerating  projecting  granules  of  the  kidney  surface.  In  the 
kidneys,  in  which  the  process  is  less  active,  these  granules  have  practically 
the  color  of  the  normal  organ. 

The  more  severe  changes  in  the  tubules  produce  a  variety  of  appearance. 
Many  of  those  which  have  already  become  enlarged  through  the  compensa- 
tory hypertrophy  become  greatly  dilated,  probably  through  obstruction  at 
some  point  lower  down.  These  are  found  to  be  filled  with  a  homogeneous, 
pink-staining  fluid,  which  is  retracted  from  the  wall  during  fixation,  and 


Fig.    135. — Arteriosclerotic    contracted 
ney  with  cortical  cysts. 


kid- 


NEPHRITIS 


293 


Fig.  136. — Cortex  from  arteriosclerotic  contracted  kidney  (Fig.  133).  Narrowed 
blood-vessels  and  obliterated  glomeruli  and  tubules  are  conspicuous.  Hypertrophied 
and  dilated  tubules  are  present  in  groups. 


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TEXT-BOOK  OF  PATHOLOGY 


lined  with  extremely  low,  flat  epithelium  (Fig.  137).  The  other  tubules  in 
the  more  frankly  scarred  areas  show  no  epithelium  like  that  which  normally 
lines  the  convoluted  tubules.  The  cells  which  remain  are  cubical,  slightly 
granular,  or  with  clear  protoplasm,  and  often  desquamated  or  distorted 
and  shrunken.  There  is  scarcely  a  lumen  left,  and  the  epithelial  cord  is 
generally  inclosed  in  a  membrana  propria,  which  has  become  greatly  thick- 


Jig.  137.     Projecting  nodule  of  active  cortical  tissue  in  arteriosclerotic  kidney:    a, 
Dilated  tubules;    6,  degenerated  tubular  epithelium. 

ened  by  the  apposition  of  a  vague,  irregular,  wrinkled  hyaline  substance 
which  stains  blue  with  Mallory's  connective-tissue  stain  (Fig.  139). 

The  glomeruli  may  be  quite  intact  and  enlarged,  or  they  show  some  stage 
in  the  complex  process  leading  to  their  complete  obliteration.  It  seems 
that  in  this  type  of  renal  disease  the  obliteration  of  the  glomeruli  is  brought 
about  by  quite  different  changes  from  those  seen  in  acute  and  chronic 
glomerulonephritis,  and  it  is  generally  possible,  even  at  a  late  stage,  to 


NEPHRITIS 


295 


recognize  which  sort  we  are  dealing  with.  But  it  would  be  hazardous  to 
state  that  the  changes  about  to  be  described  are  peculiar  to  the  effects  of 
arteriosclerosis.  They  probably  depend  on  a  great  variety  of  injuries  to 
blood-vessels  and  tubules,  and  doubtless  play  a  part  in  the  end  results  of 
tubular  and  of  acute  and  chronic  interstitial  nephritis  as  well.  Certainly 
they  are  common  in  all  those  very  abundant  cases  in  which  atrophic  and 
scarred  areas  occur  in  the  kidney,  without  marked  vascular  change  and  in 
which  we  are  left  with  no  definite  clue  as  to  the  real  nature  of  the  injury. 


Fig.  138.— Glomerulus  from  arteriosclerotic  kidney.     The  capillary  tuft  is  converted 
into  a  compact  mass,  smoothly  covered  with  epithelium. 

In  all  cases  the  capillary  loops  become,  sooner  or  later,  impermeable  to 
blood.  This  may  happen  through  narrowing  of  the  afferent  vessel,  or 
through  collapse  of  the  capillaries  themselves,  possibly  the  result  of  ob- 
struction of  the  tubules  and  a  short-lived  distension  of  the  capsule  with 
urine,  or  through  changes  in  the  glomerular  capsule.  Here  the  imper- 
meability is  not  the  result  of  thrombotic  occlusion  of  the  capillaries  as  in 
the  glomerulonephritis.  Nevertheless,  unless  they  collapse  completely, 


296  TEXT-BOOK  OF  PATHOLOGY 

these  capillaries  are  left  filled  with  a  formless  material  which  may  be  de- 
rived partly  from  the  remaining  blood-corpuscles  or  from  proliferation  of 
the  endothelium.  In  the  end  it  stains  yellow  with  van  Gieson's  stain  and 
has  no  recognizable  cellular  character.  Evidently  the  epithelial  cells 
between  the  loops  fuse  and  disappear,  and  finally  the  rather  solid  tuft  is 
smoothly  covered  with  epithelium  in  a  continuous  layer  (Fig.  138).  At 
any  rate,  the  collapsed  glomerulus  remains  visible  a  long  time  and  is  recog- 


Fig.  139.— Late  changes  in  the  glomerulus  in  an  arteriosclerotic  kidney.     Collapse  of 
tuft  with  great  thickening  of  Bowman's  capsule.     Atrophy  of  adjacent  tubules. 

nizable  as  such.     It  may  finally  adhere  to  the  capsule,  but  such  adhesions 
are  not  characteristic,  as  in  glomerulonephritis. 

Changes  in  the  capsule  are  practically  constant,  and  by  many  thought  to 
be  the  cause  of  the  collapse  of  the  glomerulus  either  through  constriction 
of  the  vessels  at  the  hilum  or  through  direct  compression  of  the  whole 
glomerulus.  They  consist  in  hyaline  swelling  of  the  membrana  propria, 
with  masses  of  hyaline  bulging  into  the  capsular  lumen,  or  in  new  connective- 
tissue  formation  around  the  outside,  or  in  a  combination  of  the  two. 


NEPHRITIS 


297 


These  things  lead  to  an  extraordinary  thickening  of  the  capsule  surrounding 
the  collapsed  glomerulus,  so  that  this  comes  finally  to  look  like  a  small, 
wrinkled  structure  in  the  centre  of  a  great  hyaline  and  fibrillar  mass.  By 
this  time  the  capsular  epithelium  has  disappeared,  and  the  space  of  the 
capsule  being  lost,  the  hyaline  and  fibrous  material  incloses  the  glomerulus 
tightly"  (Fig.  139) .  In  later  stages  the  whole  becomes  fused  and  reduced  to  a 
homogeneous,  hyaline,  scar-like  nodule.  In  other  cases  hyaline  material 
appears  in  the  outer  wall  of  the  capsule,  in  the  walls  of  the  afferent  vessels, 


Fig.  140. — Hyaline  changes  in  a  glomerulus. 

and  even  in  the  walls  of  the  capillaries  of  the  tuft  outside  the  endothelium, 
and  it  is  easy  to  see  that  its  increase  may  lead  to  the  collapse  of  these 
capillaries  and  the  final  obliteration  of  the  glomerulus  (Fig.  140). 

The  connective  tissue  outside  the  glomeruli,  as  well  as  that  between  the 
tubules,  becomes,  in  the  course  of  time,  remarkably  increased  in  amount 
and  very  tough  and  firm.  In  its  meshes  the  blood-vessels,  obliterated 
glomeruli,  and  traces  of  tubules  become  very  closely  ranged,  because  of  the 
disappearance  of  so  many  structures  which  were  there  before.  This  is  in 


298  TEXT-BOOK  OF  PATHOLOGY 

a  sense  a  condensation  of  the  kidney  substance,  and  if  the  connective 
tissue  were  stretched  out  to  the  original  size  of  the  kidney,  it  would  seem 
less  abundant.  Infiltration  with  wandering  cells  of  the  mononuclear  type 
is  almost  the  rule.  Doubtless  they  appear  as  scavengers  in  an  organ  where 
tissue  downfall  is  so  constant  (Figs.  136,  137). 

(e)  Combined  Inflammatory  and  Arteriosclerotic  Disease 

Although  the  effects  of  toxic  and  bacterial  injury  to  the  kidneys  with  the 
striking  alterations  of  glomeruli  have  been  described  separately  from  the 
effects  of  arteriosclerotic  changes  in  the  blood-vessels  of  the  kidney,  leading 
finally  to  the  destruction  of  glomeruli  and  tubules,  still  by  far  the  com- 
monest condition  is  that  in  which  these  types  are  combined  in  the  same  kid- 
ney. It  is  unnecessary  to  enter  into  detail  with  regard  to  the  structural 
changes  in  such  altered  kidneys,  and  it  will  perhaps  suffice  to  say  that  in 
any  series  of  cases  in  which  renal  changes  appear,  as  those  of  a  chronic 
diffuse  nephritis,  it  is  extremely  common  to  find  marked  intimal  thicken- 
ings in  the  blood-vessels,  as  well  as  evidence  of  thrombosis  and  inflamma- 
tory changes  in  the  glomeruli  and  destructive  alterations  in  the  tubules. 

It  is,  of  course,  conceivable  that  the  inflammatory  reactions  to  toxic  or 
other  injuries  may  supervene  in  kidneys  already  somewhat  injured  by  the 
narrowing  of  their  blood  supply.  On  the  other  hand,  it  is  just  as  easy  to 
understand  that  the  kidneys  of  persons  who  have  survived  for  a  long  time 
repeated  toxic  inflammatory  processes  may,  in  the  natural  course  of  events, 
show  some  defects  from  arteriosclerotic  changes  of  the  blood-vessels  which 
are  so  common  in  persons  of  mature  age.  It  must,  therefore,  be  under- 
stood that,  while  it  cannot  be  stated  directly  that  toxic  lesions  in  the  kidney 
bring  about  arteriosclerotic  changes,  or  vice  versa,  the  combination  of  the 
effects  of  these  things  must  be  recognized  in  a  very  great  number  of  cases. 

AMYLOID  DEPOSIT 

Amyloid  deposit  in  the  kidney  has  been  very  generally  regarded  as  consti- 
tuting a  special  type  of  nephritis,  but  it  seems  that  this  material  may  appear 
just  as  it  does  elsewhere,  in  an  organ  which  is  otherwise,  for  a  time  at  least, 
practically  normal,  so  far  as  one  can  see,  while  in  other  instances  its  ap- 
pearance is  associated  with  any  or  all  of  the  changes  described  in  progres- 
sive nephritis.  It  is  clear,  then,  that  in  the  most  extreme  degrees  of  scar- 
ring (Fig.  141),  distortion,  and  contraction  of  the  kidney,  we  may  find 
amyloid,  as  well  as  in  those  acute  and  subacute  stages  in  which  the  secre- 
tory elements  of  the  kidney  are  still  present,  though  often  much  injured. 

Most  commonly  amyloid  is  found  in  kidneys  which  are  greatly  swollen 
and  pale,  with  mottlings  of  opaque  yellowish-white,  and  sometimes  haem- 
orrhages. The  capsule  is  not  adherent  in  this  stage,  and  the  surface  of  the 
kidney  is  quite  smooth  or  slightly  granular.  The  tissue  is  often  gray  and 
translucent,  except  in  the  yellow,  opaque  areas,  where  fat-globules  and  dead 
cells  are  accumulated  and  the  glomeruli  are  visible  and  prominent  as 


AMYLOID    DEPOSIT 


299 


translucent  points.  On  the  application  of  iodine  they  flash  out  into  a 
bright  brown  color,  showing  very  distinctly  their  arrangement  along  the 
straight  vessels  of  the  cortex.  Often,  too,  there  are  brown  lines  in  cortex 
and  pyramid  which  indicate  the  presence  of  amyloid  in  tubule  or  vessel- 
walls.  Microscopically,  the  minuter  blood-vessels  are  surrounded  by  the 
pink-staining  amyloid  which  lies  directly  under  the  endot helium.  In  the 
glomeruli  (Fig.  142)  one  finds  it  especially  abundant,  occupying  the  same 


Fig.  141.- 


-Extreme  scarring  of  the  kidney,  with  amyloid.     The  glomeruli  approach  each 
other,  since  the  tubules  have  been  destroyed. 


position,  and  thus  separating,  in  the  capillaries,  the  endothelium  from  the 
epithelial  covering.  Sometimes  it  thus  forms  a  tube  lined  with  endothe- 
lium, through  which  blood  may  still  pass,  but  if  it  becomes  more  abundant, 
the  lumen  of  such  a  tube  is  narrowed,  and  although  one  or  two  endothelial 
cells  may  still  persist  there,  it  becomes  obstructed,  as  far  as  the  passage  of 
blood  goes.  In  late  stages  the  glomeruli  become  almost  solid  masses  of 
amyloid.  Thickening  of  the  capsule  may  occur,  but  there  are  not  usually 


300 


TEXT-BOOK  OF  PATHOLOGY 


adhesions  with  the  glomerular  tuft.  The  membrana  propria  of  the  tubules 
may,  in  the  same  way,  become  the  point  of  deposit  of  the  amyloid,  espe- 
cially in  the  pyramids. 

The  epithelial  cells  of  the  tubules  show  the  most  advanced  degenerative 
changes,  being  loaded  with  fat-globules  or  becoming  desquamated.  Hya- 
line droplets  with  great  swelling  of  the  cell  are  common,  too  (Fig.  143). 
It  is  characteristic  of  such  amyloid  kidneys  that  in  patches  the  tubules  be- 
come greatly  dilated  and  lined  by  very  flat,  low  epithelium.  In  other 


Fig.  142. — Amyloid  in  glomerulus.     The  amyloid  lies  between  the  endothelium  and  the 
capsular  epithelium  in  each  capillary. 

areas,  with  the  obstruction  of  the  glomeruli,  the  tubules  atrophy  and 
collapse,  and  the  region  is  involved  in  scar  tissue.  The  blood-vessels  may 
or  may  not  be  sclerotic.  The  further  changes  in  more  advanced  cases 
differ  in  no  essential  from  those  seen  in  other  contracted  kidneys,  and  it  is 
difficult  to  say  whether  the  presence  of  the  amyloid  caused  the  degeneration 
of  the  cells.  Possibly  the  destruction  of  the  cells  and  the  presence  of 
amyloid  were  the  parallel  results  of  the  same  long-standing  intoxication, 


AMYLOID   DEPOSIT 


301 


for,  as  has  been  stated  before,  the  source  of  the  amyloid  is  connected  with 
the  existence  of  some  protracted  intoxication  or  infection. 

It  is,  perhaps,  because  of  the  usual  existence  of  some  such  disease  as 
syphilis,  tuberculosis,  or  malignant  growth,  with  their  secondary  anaemia, 
that  the  heart  and  blood-vessels  fail  to  hypertrophy.  Indeed,  during  the 
life  of  these  patients  blood-pressure  seldom  runs  high,  though  exactly  why 
arterial  hypertension  should  fail  to  appear  in  amyloid  disease  is  not  clear. 


8       ":  /»J^^O^^-"V-4       >".'.'.' 

a&fc^     •\taKU' 


Fig.   143.— Subacute  and  chronic  nephritis  with  amyloid.     Tubules  show  epithelial 

degeneration  and  dilatation. 

Probably  the  amyloid  has  little  to  do  with  this,  for  in  the  later  stages,  when 
renal  tissue  is  largely  destroyed,  a  rise  in  blood-pressure  may  occur.  It 
has  been  suggested  that  the  amyloid  involvement  of  the  adrenals  may 
prevent  the  rise  of  pressure.  .  . 

The  urine  is  abundant,  with  low  specific  gravity,  and  pale,  but  rich  in 
albumen;  hyaline  casts  and  epithelial  and  other  cells  appear  there  It  has 
never  been  shown,  though,  that  the  specifically  staining  amyloid  plays  any 
part  in  forming  these  casts. 


302  TEXT-BOOK  OF  PATHOLOGY 

In  general,  then,  while  some  of  the  symptoms  of  nephritis  are  changed 
by  the  amyloid  in  the  kidney,  we  may  regard  its  presence  there  as  inci- 
dental, rather  than  as  the  cause  of  the  nephritis  or  as  constituting  a  new 
form  of  the  disease. 


Fig.  144. — Great  hypertrophy  of  the  heart  affecting  especially  the  left  ventricle,  in  chronic 
nephritis  without  valvular  lesion. 

SUMMARY 

If,  now,  we  consider  together  all  the  anatomical  changes  found  to  occur  in 
the  kidneys,  we  find  that  they  are  the  effects  of  various  injuries,  with  re- 
sponses arising  according  to  clearly  defined  principles,  and  ending,  if  time 
be  allowed,  in  the  production  of  altered  organs  in  which  one  may  recognize 
great  destructive  effects  side  by  side  with  strenuous  attempts  at  healing 
and  at  compensatory  hypertrophy.  The  injuries  are  of  many  different 
kinds:  they  affect  one  or  other  part  of  the  kidney  predominantly;  they 
frequently  occur  in  combination,  and  they  often  act  repeatedly  and  per- 
sistently over  a  long  time.  No  sooner,  then,  is  one  injury  complete,  the 
dead  tissue  removed,  and  the  place  healed,  with  perhaps  some  compensa- 
tory growth  of  functional  tissue  elsewhere,  than  a  new  injury  ensues,  and 
in  another  place,  or  even  in  the  compensatory  new  tissue,  the  whole  process 
begins  again.  Nor  is  this  all — the  destruction  or  distortion  of  one  element 


SUMMARY  303 

entails  the  downfall  of  another — the  tubule  is  dependent  on  the  glomerulus, 
and  the  glomerulus  on  the  tubule,  both  on  the  blood  supply,  so  that  an 
injury  anywhere  has  far-reaching  results  in  this  complex  organ. 

It  is  difficult  to  unravel,  then,  the  anatomical  effects  of  such  injuries  act- 
ing singly,  but  far  more  so  when  they  are  combined.  A  still  greater  dif- 
ficulty arises,  however,  when  we  attempt  to  estimate  the  importance  of 
these  anatomical  changes,  since  we  know  that  the  function  of  the  kidney  is 
affected  so  profoundly  by  alterations  of  the  cell  which  do  not  show  them- 
selves at  all  to  our  eyes,  even  with  the  best  of  microscopes,  aided  only  by 
our  present  technical  methods. 

We  recognize  certain  types  of  change  in  each  element  of  the  kidneys. 
The  tubular  epithelium  may  be  swollen  and  granular  in  various  infections 
and  intoxications:  the  cells  in  all  severer  injuries  usually  become  clogged 
with  droplets  of  fat,  glycerin,  and  cholesterine  esters,  or  with  peculiar 
hyaline  droplets,  or  they  finally  pass  through  even  more  profound  changes 
and  lose  their  structure,  becoming  necrotic.  These  things  in  one  form  or 
another  are  common  to  all  sorts  of  nephritis.  In  the  lumen  of  the  tubules 
we  find  fluid  holding  albumen,  and  therefore  coagulable,  granular  debris, 
epithelial  cells,  leucocytes,  red  blood-corpuscles,  and  finally  curious  moulds 
or  casts  which  are  hyaline,  compressed  products  of  the  fusion  of  all  these 
things,  characterized  often  by  the  adhesion  of  better  preserved  leucocytes 
or  epithelial  cells  or  granules.  Slipping  down  the  tubule,  they  appear  in 
the  urine.  The  glomeruli  may  have  their  capillaries  obstructed,  when 
bacteria  or  poisons  injure  them,  by  thrombi  formed  from  the  blood,  or  by 
masses  of  leucocytes  or  proliferated  cells.  Rigid  loops  adhere  to  the  capsule, 
the  capsular  epithelium  proliferates  to  cover  these  adhesions,  or  to  encap- 
sulate exudate  which  appears  in  its  lumen.  Or,  on  the  other  hand,  the 
blood  may  be  shut  off  from  these  capillaries  from  a  point  in  the  afferent 
vessel  at  some  distance,  or  by  the  obstruction  of  the  tubule  and  the  con- 
sequent accumulation  of  secretion  in  the  capsule,  or  even  by  the  thickening 
of  the  capsule  with  hyaline  changes.  The  end  result  in  every  case  is  the 
impermeability  and  final  obliteration  of  this  complex  mechanism. 

The  blood-vessels  may  be  sclerotic  and  thickened,  so  that  their  stream- 
bed  is  narrowed,  or,  as  we  have  just  said,  they  may  be  occluded  or  com- 
pressed, but  all  these  changes  lead  alike  to  an  obstruction  of  the  blood- 
flow.  The  framework  of  the  kidney  responds  to  the  loss  of  the  structures 
which  it  supports  by  an  attempt  to  replace  and  heal  the  loss,  or  it  itself 
is  injured  and  heals,  often  with  excess  of  tissue.  It  probably  plays  little 
part  in  embarrassing  and  trammeling  the  tissue  of  more  important  func- 
tion, although  this  idea  has  so  long  been  held  to  be  true. 

Injuries  may  occur,  and  renal  tissue  be  destroyed  and  removed  and  re- 
placed by  a  scar,  and  yet  the  remaining  tissue  will  grow  to  compensate  for 
this  loss  until  the  kidney  resumes  perfectly  the  normal  function.  If  too 
much  tissue  is  destroyed,  signs  of  renal  insufficiency  will  arise,  but  a  rela- 
tively small  amount  of  normal  renal  tissue  will  suffice  to  carry  on  the  nor- 


304  TEXT-BOOK  OF  PATHOLOGY 

mal  function.  Diseased  renal  tissue,  however,  is  at  once  inefficient  in  some 
respects,  and  symptoms  arise  to  show  it.  So  it  is  that  we  may  have  normal 
function  in  a  kidney  in  which  there  are  many  obsolete  scars  of  an  old  injury, 
because  the  remaining  tissue  is  normal  and  equal  to  its  task,  while  in  other 
cases,  what  seems  a  relatively  slight  change,  may  cause  great  disturbances 
in  function. 

FUNCTIONAL  ALTERATIONS— RENAL  INSUFFICIENCY 

From  the  changes  observed  anatomically  in  human  kidneys,  it  is  clear  that 
the  injury  may  affect  the  blood-vessels,  including  the  capillaries  of  the 
glomeruli,  the  epithelial  cells  of  the  glomeruli  and  tubules,  or  even  the 
connective-tissue  framework,  and  it  has  already  been  seen  that  the  func- 
tional disturbances  vary  with  these  different  lesions.  But  what  we  find 
in  the  injured  kidney  is  usually  a  combination  of  these  changes,  because 
one  entails  another  in  course  of  time,  and  it  is  only  rarely  that  we  are  able 
to  study  the  very  beginning  of  the  disease.  Besides,  what  we  see  is,  for 
the  greater  part,  not  the  direct  effect  of  the  injury,  but  evidence  of  a  reac- 
tion or  response  on  the  part  of  the  tissue.  It  is  true  that  we  can  see  de- 
structive changes  in  the  epithelium  after  necrobiotic  or  fermentative  proc- 
esses have  combined  with  the  accumulation  of  the  materials  of  metabolism 
to  make  them  evident,  but  it  is  important  to  bear  in  mind  that  extreme 
functional  disturbances  may  result  from  injuries  which  produce  in  the  cells 
no  changes  that  we  can  see.  The  functional  activities  of  the  cells  go  on  in  a 
mysterious,  invisible  way  that  we  may  appreciate  only  by  the  results,  and 
to  certain  cells  there  seem  to  be  assigned  special  duties,  even  in  the  course 
of  a  single  renal  tubule.  Thus  Aschoff  states  that  uric  acid  is  secreted  in 
the  first  and  second  division  of  the  convoluted  tubule,  while  sugar  passes 
out  through  its  fourth  division  or  is  stored  in  those  cells  in  the  form  of 
glycogen.  Carmine  is  secreted  in  solution,  but  may  be  stored  in  the  epi- 
thelial cells  in  granules.  Similarly  water  and  salt  are  specifically  secreted 
by  certain  cells,  which  may  cease  their  function  long  before  any  morpho- 
logical change  is  visible  in  them  or  resume  it  without  having  ever  shown 
such  a  change. 

Of  course,  when  cells  are  obviously  injured  or  killed  and  disintegrated, 
their  function  falls  away  with  them,  and  glomeruli  whose  capillaries  are 
plugged  with  clots  no  longer  filter  out  water,  but  these  are  very  gross 
changes  which  we  may  not  find  at  all  in  a  kidney  whose  disability  is,  never- 
theless, extreme.  And  yet  we  continue  to  insist  on  finding  them  and 
attempting  to  correlate  them  with  the  functional  changes  in  order  to  estab- 
lish a  classification  of  renal  disease.  We  must  know  far  more  about  the 
exact  site  of  functions,  and  we  must  be  able  to  disentangle  extrarenal 
influences  from  the  actual  renal  changes  before  we  succeed  in  this.  For 
at  most  such  scars  represent  areas  where  kidney  substance  has  been  com- 
pletely lost,  and  they  give  an  indication,  therefore,  of  a  possible  quantita- 
tive insufficiency  of  that  part  which  remains.  But  if,  as  so  often  happens, 


FUNCTIONAL   ALTERATIONS — RENAL   INSUFFICIENCY  305 

the  remaining  tissue  is  functioning,  but  in  a  perverted  way,  symptoms 
arise. 

Of  these  symptoms,  perhaps  the  most  common  is  the  excretion  of  al- 
bumen in  the  urine,  sometimes  merely  a  recognizable  trace,  sometimes  such 
a  large  quantity  that  a  thick  coagulum  is  formed  when  the  acidulated  urine 
is  boiled.  This  evidently  depends  upon  some  injury  to  the  endothelium 
of  the  glomerular  capillaries,  or  the  renal  epithelium,  and  the  wonder  is 
not  so  much  that  the  albumen  should  appear,  but  that  it  should  be  so 
completely  retained  by  the  normal  kidney.  It  is  most  abundantly  excreted 
in  the  acute  stages,  and  in  chronic  forms  of  nephritis  in  which  the  injury 
to  the  structures  of  the  kidney  is  actively  progressing  or  passing  through 
an  exacerbation.  In  the  more  completed  conditions,  such  as  are  found  in 
the  old  contracted  kidneys,  where,  although  there  are  great  distortion  and 
loss  of  substance,  the  active  injury  has  ceased,  there  is  little  or  no  albumin- 
uria,  although  evidences  of  renal  deficiency  may  persist,  and  at  any  moment 
with  a  new  poisoning  the  albumen  may  reappear  in  the  urine. 

Red  blood-corpuscles  and  leucocytes,  as  well  as  epithelial  cells,  come 
down  the  tubules  when  there  is  acute  inflammation,  and  hyaline  casts 
or  moulds  of  the  tubules  are  an  almost  constant  accompaniment  of  all  the 
more  active  processes.  Exactly  what  goes  to  form  the  casts  is  not  certain, 
but  it  seems  that  they  must  arise  from  the  fusion  of  many  things,  including 
the  debris  of  cells,  hyaline  droplets  which  are  found  in  the  epithelium,  al- 
buminous materials,  and  sometimes  fibrin.  Adhering  cells  which  are 
better  preserved  are  easily  recognized. 

Variations  in  the  amount  of  water  excreted  are  extreme,  and  do  not 
always  accord  perfectly  with  what  we  should  expect  from  the  anatomical 
state  of  the  kidney.  Schlayer  has  attempted  to  establish  the  idea  that 
this  depends  upon  variations  in  the  sensitiveness  of  the  capillary  walls— 
that  with  increasing  severity  of  the  injury  there  may  be  at  first  an  increase 
in  the  sensitiveness,  and  consequent  secretory  activity  or  permeability  of 
the  capillaries,  which  results  in  the  excretion  of  an  excess  of  water,  while 
later  the  more  injured  wall  becomes  less  sensitive,  and  oliguria  or  finally 
complete  cessation  of  urine  flow  (anuria)  results.  Aschoff  objects  to  this 
that  extrarenal  conditions  of  blood-pressure  and  blood  supply  are  more 
than  sufficient  to  account  for  these  variations;  but  it  may  be  that  these 
extrarenal  conditions  themselves  affect  the  sensitiveness  of  the  renal 
capillaries.  A  disturbance  of  water  and  salt  excretion,  or  a  deficiency  in 
the  whole  renal  activity,  as  shown  by  injections  of  phenolsulphonephthalein, 
may  be  greatly  accentuated  by  chronic  passive  congestion.  When  the 
renal  substance  is  greatly  reduced,  as  in  the  old  contracted  kidneys,  a  great 
amount  of  water  is  excreted,  with  relatively  little  solids,  while  actual  cessa- 
tion of  urine  or  the  excretion  of  only  a  little,  with  high  specific  gravity, 
accompanies  the  acute  destructive  stages.  The  reasons  for  these  differ- 
ences are  not  known,  but  it  is  suggested  that  the  high  blood-pressure  and 
rapid  stream  through  the  kidneys  so  characteristic  of  the  contracted  stage 
may  account  for  the  polyuria,  while  the  specific  inability  of  the  glomeruli 

21 


306  TEXT-BOOK  OF  PATHOLOGY 

to  excrete  water,  or  more  probably  its  specific  inability  to  excrete  sodium 
chloride  and  other  inorganic  substances,  may  explain  the  oliguria  or  anuria 
of  the  acuter  stages. 

Sodium  chloride  passes  into  the  urine  through  the  quite  specific  activity 
of  some  of  the  epithelial  cells,  and  when  these  fail,  it  is  retained  in  the 
tissues.  Since  the  tissue  fluids  must  remain  isotonic  for  the  cells,  water  is 
reserved  to  dilute  this  concentrated  salt  solution,  and  the  consequence  is 
cedema,  hydrothorax,  and  ascites.  Little  doubt  can  exist  as  to  the  nature 
of  this  nephritic  cedema,  for  if  such  waterlogged  patients  are  deprived  of 
salt  in  their  food  and  given  water  in  restricted  amounts,  the  cedema  quickly 
disappears,  to  reappear  at  once  if  a  considerable  ration  of  salt  be  allowed. 
Thus  in  the  case  of  a  man  who  entered  the  hospital  with  enormous  swelling 
of  arms  and  legs  and  great  accumulation  of  fluid  in  pleura  and  peritoneum, 
a  salt-free  diet  restored  the  normal  appearance  very  quickly.  In  two 
weeks  this  man  lost  35  pounds  in  weight,  and  this  experience  is  practically 
of  daily  occurrence. 

But  with  this  it  must  not  be  forgotten  that  there  are  often  mechanical 
reasons  also  for  the  lessened  excretion  of  water.  Thrombosis  of  the  glom- 
erular  capillaries,  or  their  plugging  with  leucocytes  and  endothelial  cells, 
as  well  as  their  compression  by  exudate  in  the  capsule,  or  by  proliferation  of 
the  capsular  epithelium,  makes  them  impermeable  for  the  blood  and 
directly  interferes  with  their  function.  Similarly  it  is  conceivable  that  the 
tubules  may  be  obstructed  by  desquamated  cells  and  casts,  but  although 
these  things  have  their  part,  they  are  probably  not  so  important  as  the 
disturbances  of  the  specific  function  of  the  secreting  cells  themselves. 

Nitrogenous  substances,  such  as  urea,  are  often  retained  in  the  blood  in 
the  same  way,  and  although  urea  itself  seems  to  be  a  relatively  harmless 
material,  it  has  always  been  thought  that  the  retention  of  some  such  sub- 
stances, as  yet  unrecognized,  is  responsible  for  certain  general  conditions 
which  are  frequently  associated  with  nephritis.  Of  these,  the  most  im- 
portant are  uraemia  and  vascular  hypertension. 

Uraemia  is  an  intoxication  of  unknown  cause  which  may  arise  in  connec- 
tion with  any  sort  of  nephritis,  but  is  commonest  in  those  in  which  very 
extensive  destruction  is  quickly  produced,  and  in  those  contracted  kidneys 
in  which  an  extreme  diminution  of  the  kidney  substance  is  finally  reached. 
It  may  result  in  all  sorts  of  nervous  and  mental  disturbances,  delirium  of 
the  most  violent  sort,  delusions,  etc.,  ending  in  coma  or  convulsions.  The 
name,  indicating  a  retention  of  urea,  does  not  give  a  true  explanation  of  its 
cause,  and  we  are  still  in  the  dark  concerning  it. 

Arterial  hypertension,  in  which  the  systolic  blood-pressure  may  reach 
250  mm.  of  mercury  or  more,  is  a  characteristic  accompaniment  of  some 
forms  of  nephritis.  It  is  found  beginning  in  the  acute  or  subacute  stages, 
but  reaches  its  maximum  in  the  more  advanced  conditions  of  longer  stand- 
ing. Jores  thinks  that  it  is  particularly  associated  with  the  so-called  pri- 
mary contracted  kidney,  with  arteriosclerosis,  but  this  does  not  seem  to  be 
strictly  true,  for  we  have  found  the  highest  pressures  in  cases  in  which  there 


FUNCTIONAL   ALTERATIONS — RENAL   INSUFFICIENCY  307 

had  evidently  been  inflammatory  disease  of  the  glomeruli,  and  in  combina- 
tions of  the  inflammatory  and  arteriosclerotic  processes.  The  cause  of 
this  high  blood-pressure  is  again  a  mystery.  It  has  been  thought  to  be  due 
to  the  narrowing  and  obliteration  of  the  blood-channels  in  the  kidney,  but 
it  is  clear  that  ligation  of  the  renal  arteries  does  not  elevate  the  general 
blood-pressure.  Nevertheless,  compression  of  the  kidneys  seems  to  have 
some  effect  in  this  direction,  and  the  gradual  reduction  of  the  kidneys  by 
their  piecemeal  removal  does  produce  a  permanent  rise  in  blood-pressure 
after  a  certain  proportion  of  the  kidney  substance  has  been  destroyed. 
These  experiments  leave  us  still  with  the  problem,  however,  as  to  whether 
obstruction  of  the  circulation  or  inefficiency  of  the  kidney  is  the  important 
factor.  Schur  and  Wiesel  have  thought  that  chronic  nephritis  is  accom- 
panied by  hypertrophy  and  excessive  activity  of  the  adrenals,  and  that 
constriction  of  the  arterioles  by  the  epinephrine  thus  produced  should 
account  for  the  high  tension,  but  evidence  for  this  is  very  weak.  No  one 
has  found  a  sufficient  quantity  of  epinephrine  in  the  blood  to  support  this 
idea.  Still,  the  general  opinion  is  that  some  sort  of  vasoconstrictor  material 
must  be  retained  in  the  blood  to  keep  up  such  a  high  pressure.  The  heart, 
especially  its  left  ventricle,  becomes  greatly  hypertrophied,  and  in  time 
even  the  walls  of  the  vessels  thicken  their  muscular  coats.  Arteriosclerotic 
changes  in  the  vessels  are  common,  and  may  play  some  part  in  producing 
the  high  pressure  if  it  can  be  shown  that  it  causes  the  narrowing  of  arterioles 
in  general.  This,  however,  is  so  variable  that  it  does  not  afford  a  satis- 
factory explanation.  Albuminuric  retinitis,  which  is  a  change  often 
accompanied  by  arteriosclerotic  modifications  of  the  retinal  vessels,  and 
marked  by  the  presence  of  hemorrhages  and  shining  deposits  of  choles- 
terine  in  the  retina,  is  very  frequent  in  the  course  of  nephritis.  Actual 
blindness  may  be  caused  in  this  way.  Acute  pericarditis  and  acute  diph- 
theritic enteritis  are  also  frequent  terminal  affections. 

LITERATURE 

Aschoff:   Archives  of  Internal  Medicine,  1913,  xii,  723. 

Baehr:  Jour.  Exp.  Med.,  1912,  xv,  330;  Ziegler's  Beitr.,  1913,  Iv,  545. 

Fahr:   Frankf.  Zeits.  f.  Path.,  1912,  ix,  15. 

Frey:   Dtsch.  Arch.  f.  klin.  Med.,  1912,  cvi.  347. 

Gull  and  Button:   Medico-Chir.  Trans.,  1872,  Iv,  273. 

Harvey:   Proc.  N.  Y.  Path.  Soc.,  1912,  xii,  154. 

Herxheimer:   Ziegler's  Beitrage,  1909,  xlv,  253. 

Janeway:  Amer.  Jour.  Med.  Sci,  1913,  cxlv,  625;  Trans.  Cong.  Amer.  Phys.  &  Surg., 

1913,  ix,  14. 

Jores:   Deut.  Arch.  f.  klin.  Med.,  1908,  xciv.  .     . 

Lohlein:  Ergebn.  d.  inn.  Med.  u.  Kinderh.,  1910,  v,  411;  Arb.  a.  d.  Path.  Inst.,  Leipzig, 

1907,  Heft  4. 

Muller,  Fr.:  Verh.  Dtsch.  Path.  Ges.,  1906,  ix,  64. 

Ponfick:  Verh.  Dtsch.  Path.  Ges.,  1906,  ix,  49.  . 

Schlayer:    Beihefte  zur  Med.  Klinik,  1912,  viii,  211;    also   several  papers  in  Dtsch. 

Arch.  f.  klin.  Med.,  xcviii,  ci,  cii,  civ,  etc. 
Volhard  and  Fahr:   Die  Brightsche  Nierenkrankheit,  1913. 
Weigert:   Volkmann's  Samml.  klin.  Vortr.,  162,  163. 
Ziegler:  D.  Arch.  f.  klin.  Med.,  1880,  xxv,  586. 


308  TEXT-BOOK    OF    PATHOLOGY 

After  reading  the  extremely  voluminous  literature  upon  renal  disease  of  the  last 
three  years  I  have  decided  to  leave  the  foregoing  chapter  as  it  is.  Most  of  the  publica- 
tions have  been  from  German  authors  and  have  concerned  the  classification  and  espe- 
cially the  nomenclature  of  the  different  types  of  renal  change.  The  term  "nephrosis,"  in- 
troduced by  Miiller  to  denote  degenerative  changes  of  the  epithelium  without  promi- 
nent inflammatory  reaction  in  the  glomeruli  and  elsewhere  (the  tubular  nephritis 
referred  to  above),  was  adopted  at  once  by  clinicians,  but  later  rejected  by  the  German 
pathologists,  with  few  exceptions.  Nephropathia,  with  various  adjectives,  has  been  sub- 
stituted. Little  has  been  added  to  our  knowledge  of  glomerulonephritis,  although  in  the 
war  nephritis  there  was  opportunity  to  study  early  stages  (Herxheimer) . 

The  discussion  has  been  chiefly  over  the  nature  of  the  arteriosclerotic  contracted 
kidney.  Various  names  have  been  coined  to  describe  it,  and  the  most  recent  separates 
it  as  nephrodrrhosis  arteriolosclerotica  initialis  and  progressa  into  early  and  late  stages 
of  a  condition  in  which  the  thickening  and  consequent  narrowing  of  the  afferent  arte- 
riolse  of  the  glomeruli  is  the  primary  cause  of  all  the  progressive  changes  (Lohlein). 
These  are  to  be  distinguished  from  those  forms  in  which  focal  areas  of  scarring  result 
from  arteriosclerosis  of  the  rather  larger  and  more  distant  vessels  (atrophia  arterio- 
sclerotica).  Lohlein's  is  by  far  the  clearest  paper;  all  appear  to  attack  Volhard  and  Fahr, 
who  recognized  clinically  the  existence  of  cases  in  which  the  prognosis  is  good,  and 
others  in  which  it  is  very  bad,  by  the  names  "benign"  and  "malign"  sclerosis,  which  were 
equivalent  to  bland  hypertonia  and  hypertonia  +  functional  defect.  In  attempting  to 
base  this  on  the  anatomical  state  of  the  kidney  they  decided  that  the  bland  hypertonia 
corresponds  with  a  pure  arteriosclerotic  disease,  while  the  malign  form  is  due  to  a  com- 
bination of  atherosclerosis  of  the  minute  arteries  of  the  organ  with  an  inflammatory  or 
degenerative  factor.  To  this  malign  form  they  gave  the  name  "combination  form,"  and  it 
is  to  this  that  all  the  other  pathologists  object.  Jores,  Lohlein,  and  others  conclude  that  the 
glomerular  changes  are  the  direct  effect  of  the  arteriolar  disease.  Lohlein  decides  that 
the  benign  forms  are  the  initial  stages  of  the  arteriolosclerotic  disease,  while  the  malign 
is  due  to  advanced  stages  of  the  same  process.  Still  later  Fahr,  assuming  a  position  in 
opposition  to  Volhard,  declares  the  arteriolar  changes  in  the  malign  sclerosis  to  be  of 
syphilitic  nature.  Herxheimer,  Lohlein,  and  others  agree  that  glomerulonephritis  is 
often  found  combined  with  the  changes  recognized  as  due  to  the  sclerosis  of  the  arterioles, 
and  accept  for  these  cases  the  term  suggested  by  Aschoff,  "complication  forms."  It 
seems  that  much  of  what  Volhard  and  Fahr  described  as  a  combination  form  might  fall 
under  this  heading. 

The  studies  of  renal  function  have  been  carried  on  chiefly  by  American  workers  with 
but  little  serious  consideration  of  the  pathological  anatomy  of  the  renal  changes  in  the 
cases  studied.  They  have  been  chiefly  efforts  to  determine  the  value  of  various  tests 
of  renal  function  in  the  diagnosis  and  prognosis  of  renal  disease,  and  most  of  the  authors 
agree  that  these  tests  are  of  relative  value  only.  They  include  the  study  of  non-protein 
nitrogen  and  urea  nitrogen  in  the  blood,  the  coefficient  of  Ambard  (the  ratio  between 
the  urea  of  the  blood  and  that  of  the  urine),  the  power  of  excretion  of  water,  salt,  and 
nitrogen  after  a  standard  test-meal,  the  power  of  excreting  phenolsulphonephthalein 
and  other  test  substances  when  injected  into  the  blood.  No  single  test  gives  a  clear 
idea  of  all  the  disturbances  of  renal  function,  and  although  they  are  useful  in  determin- 
ing the  degree  of  impairment  of  these  functions,  they  scarcely  permit  of  an  exact  diag- 
nosis of  the  anatomical  condition. 

During  the  war  there  were  many  cases  of  acute  nephritis  among 
the  soldiers,  and  the  name  "trench  nephritis"  tended  to  convey  the 
idea  that  a  new  disease  had  been  discovered.  It  appears,  however, 
that  there  is  scarcely  evidence  enough  for  this,  and,  indeed,  it  is  not 
certain  that  the  same  condition  is  present  in  all.  Bradford,  Tytler  and 


FUNCTIONAL   ALTERATIONS — RENAL   INSUFFICIENCY  309 

Ryle,  and  others  describe  it  as  characterized  by  the  rapid  appearance 
of  dropsy  and  by  the  associated  bronchitis  and  dyspnoea.  There  is 
severe  and  sudden  uraemia,  with  epileptiform  seizures,  but  the  mortality 
is  very  low. 

Dunn  and  McNee  and  Stokes  describe  acute  glomerular  changes  at 
autopsy  with  intracapillary  accumulation  of  cells,  which  resemble  endo- 
thelium  and  often  merge  into  a  sort  of  syncytium.  There  are  no  cap- 
illary thrombi,  and  no  changes  in  the  epithelium  of  the  glomeruli. 
The  degenerative  changes  in  the  epithelium  of  the  tubules  are  slight, 
but  casts  and  occasionally  blood  are  found  there.  The  lungs  show 
oedema,  bronchitis,  and  the  hyaline  layer  in  the  infundibula  and  ductuli 
alveolares  which  was  so  frequently  seen  in  the  lungs  of  those  who  died 
in  the  influenza  epidemic.  Petechial  haemorrhages  occur  also  in  the 
brain. 

LITERATURE 
Pathological  Anatomy: 
Fahr:  Virchow's  Arch.,  1919,  ccxvi,  119. 
GaskeU:  Jour,  of  Path,  and  Bact.,  1911-12,  xvi,  287. 
Herxheimer:  Ziegler's  Beitrage,  1918,  Ixiv,  297. 
Jores:  Virchow's  Arch.,  1916,  ccxxi. 
Lohlein:  Ziegler's  Beitr.,  1917,  Ixiii,  570. 
Ophtils:  Leland  Stanford  University  Publications,  1916. 
Oliver:  Jour.  Exp.  Med.,  1915,  xxi,  425;  1916,  xxiii,  301. 

Functional  Changes: 

Christian  and  others:  Amer.  Jour.  Med.  Sci.,  1915,  cl,  655.    Jour,  of  Urology,  1917,  i, 

319.     Cleveland  Med.  Jour.,  April,  1917.    Prog.  Med.,  1918,  iv,  135. 
Fitz:  Amer.  Jour.  Med.  Sci.,  1914,  cxlviii,  330. 
Frissell  and  Vogel:  Arch.  Int.  Med.,  1918,  xxh,  56. 
Frothmgham:  Amer.  Jour.  Med.  Sci.,  1915,  cxlix,  808;  1916,  cli,  72.    Arch.  Int.  Med., 

1918,  xxii,  74. 

Geyelin:  Arch.  Int.  Med.,  1914,  xiii,  96. 
Mosenthal  and  others:  Jour.  Amer.  Med.  Assoc.,  1916,  Ixvii,  933.    Arch.  Int.  Med., 

1917,  xix,  i,  329;  1915,  xvi,  733;  1914,  xiv,  844. 
O'Hare:  Arch.  Int.  Med.,  1916,  xvii,  711. 
Peabody  and  others:  Ibid.,  1916,  xvii,  980. 

Trench  Nephritis: 

Ameuille:  Jour.  Urology,  1918,  ii,  51. 

Bradford:  Quart.  Jour.  Med.,  1915-16,  ix,  125. 

Dunn  and  McNee:  Brit.  Med.  Jour.,  1917,  ii,  745. 

Tytler  and  Ryle  (with  Adrian  Stokes):  Quart.  Jour.  Med.,  1917-18,  xi,  112. 


CHAPTER  XVI 

.INJURY  WITH  INFLAMMATORY  REACTION  AND  ATTEMPTED 
REPAIR  (Continued).— INJURY  AND  REPAIR  OF  THE  LIVER 

Cirrhosis  of  the  liver.  Structure  of  the  liver  in  relation  to  disease.  Direct  injury  to  liver- 
cetts.  Acute  yellow  atrophy,  eclampsia,  and  infections.  Repair  and  compensatory  hyper- 
plasia.  Cirrhosis:  its  various  types.  The  alterations  in  architecture  involved.  Obstruc- 
tion of  portal  circulation.  Collateral  circulation.  Biliary  and  hypertrophic  cirrhosis. 

INJURY  AND  REPAIR  OF  THE  LIVER 

As  in  other  organs,  injury  is  possible  in  the  liver  in  all  sorts  of  ways,  but 
we  shall  discuss  here  more  especially  those  changes  which  are  caused  by  the 
introduction  of  the  destructive  agent  by  way  of  the  blood-stream  or  bile- 
ducts.  Poisons  or  infections  may  enter  in  these  ways,  and  produce  all 
degrees  of  injury  to  the  liver  tissue  with  many  types  of  reaction.  On  the 
other  hand,  the  lack  of  some  nutritive  substance  in  the  blood,  or  even  the 
mere  extreme  sluggishness  of  its  course,  may  be  sufficient  to  disable  or 
even  to  kill  some  of  the  liver-cells.  As  in  other  organs,  the  elements  which 
make  up  the  liver  tissue  are  not  all  equally  resistant,  and  it  is  constantly 
evident  that  the  highly  specialized  liver-cells  are  injured  or  killed  by  poison, 
which  leaves  the  less  delicate  gall-duct  epithelium  perfectly  intact  and 
capable  of  growth.  The  connective-tissue  framework  and  blood-vessels 
are  even  more  hardy,  and  show  little  effect  from  injuries  that  ravage  the 
liver-cells. 

Since  in  many  of  the  cases  which  we  are  about  to  consider,  the  noxa 
reaches  the  tissue  by  way  of  the  blood,  it  is  clear  that  if  there  are  any 
peculiarities  in  the  way  the  blood-stream  is  distributed  there  may  be  cor- 
responding variations  in  the  concentration  with  which  the  poison  reaches 
the  liver-cells. 

Structure  of  Liver. — The  surface  of  the  living  organ  is  uniformly  red,  but  on  the  death 
of  the  animal,  and  especially  if  the  blood  be  allowed  to  escape  from  the  large  veins,  a 
distinct  fine  lobulation  becomes  visible  because  the  blood  is  pushed  on  in  every  arterio- 
venous  communication  to  the  venous  end.  On  this  account  the  portion  about  the  effer- 
ent vein  normally  looks  red,  while  the  rest  is  paler,  showing  the  brownish  color  of  the 
liver-cells.  If  all  the  blood  be  washed  out,  the  liver  is  uniformly  light  brown. 

These  lobules  are  not  sharply  marked  off  from  one  another,  but  anastomose  in  such 
a  way  that,  from  the  arrangement  of  the  cells  alone,  it  is  not  easy  to  say  where  one 
begins  and  another  ends.  Naturally,  the  lobule  should  be,  as  suggested  by  Sabourin, 
the  unit  mass  of  tissue  which  pours  its  secretion  into  a  terminal  branch  of  the  bile-duct, 
but  even  there  it  is  difficult  to  determine  how  much  of  the  bile-duct  shall  be  adopted 
s  belonging  to  one  lobule,  and  the  lobule  tends  to  be  a  branched  mass,  forming  a  mantle 
around  the  end  ramifications  of  the  duct.  It  has  exactly  the  same  relation  to  the  portal 
vein  and  hepatic  artery.  This  relation  is  made  very  distinct  in  chronic  passive  conges- 

310 


INJURY   AND   REPAIR   OF   THE    LIVER 


311 


tion  when  the  parts  of  the  liver  tissue  most  distant  from  the  portal  vein,  that  is,  nearest 
to  the  efferent  vein,  are  destroyed  (c/.  Fig.  147).  Unfortunately,  the  efferent  veins 
which  receive  capillaries  from  adjacent  lobules  become  so  conspicuous  from  the  radial 
way  in  which  these  capillaries  enter  into  them  that  they  are  almost  irresistibly  attractive 
in  a  single  section,  as  the  centre  of  each  mass  which  they  drain.  A  purely  artificial 
lobule,  set  up  around  the  central  (efferent)  vein,  has  become  the  time-honored  lobule  of 
the  liver,  and  the  more  so  because  in  the  pig  that  mass  is  sharply  outlined  by  fibrous 
tissue.  Doubtless  we  should  break  away  from  this  conception  and  speak  always  in 
terms  of  the  true  lobule,  but  it  would  cause  great  confusion  and  add  little  of  great  value. 
Wherever  greater  clearness  can  be  reached  by  considering  the  liver  on  the  basis  of 
Sabourin's  lobule  it  will  be  done. 


Fig.  145. — Diagram  of  the  liver  lobule  (Mall). 


The  great  supply  of  blood  is  brought  in  by  the  portal  vein,  but  from  the  capillaries  of 
the  hepatic  artery  which  unite  with  those  of  the  portal  where  they  enter  among  the  liver- 
cells,  blood  under  higher  pressure  gives  impetus  to  the  venous  stream,  driving  it  forward 
toward  the  efferent  vein.  The  portal  vein  may  be  ligated  and  its  blood  diverted  into  the 
vena  cava  without  causing  the  death  of  the  liver  tissue,  and  so,  too,  the  hepatic  artery 
may  be  obstructed  without  effect,  but  if  the  smaller  branches  of  the  portal  vein  are 
occluded  where  the  hepatic  arterioles  join  them,  the  blood  supply  is  cut  off  from  the  liver- 
cells  and  they  die.  Capillaries  once  formed,  after  the  union  of  portal  and  hepatic  ter- 
minals, run  in  part  directly  to  the  efferent  veins,  but  some  take  a  more  roundabout  course, 
so  as  to  supply  liver-cells  not  lying  in  that  direct  line  (Fig.  145).  The  disadvantageous 
effect  of  this  longer  course  becomes  apparent  in  chronic  passive  congestion. 


312 


TEXT-BOOK  OF  PATHOLOGY 


The  bile-ducts  branch  minutely  so  as  to  connect  with  the  end  of  each  complex  cord  of 
liver-cells,  the  bile  capillary,  bounded  on  all  sides  by  liver-cells,  forming  the  continuation 
of  their  lumen.  The  bile-duct  epithelium,  although  of  the  same  origin  as  the  liver-cells 
and  presumably  endowed  with  the  same  potentialities  of  specialization,  has  not  become 
so  differentiated  and  remains  as  less  highly  organized,  but  more  hardy  cells,  with  the 
simpler  function  of  lining  the  ducts. 

Direct  Injury  to  the  Liver-cells. — With  such  a  distribution  of  the  circu- 
lation it  is  not  surprising  that  injuries  to  the  cells  are  often  zonal  in  their 


Fig.  146.-Necrosis  of  liver-cells  about  the  efferent  vein  in  each  lobule:   case  of  strepto- 
coccus peritonitis. 

arrangement.     It  is  true  that  in  many  infections  practically  all  the  cells 

nay  appear  turbid  and  cloudy,  and  in  extreme  accumulations  of  fat  in  the 

liver  all  the  cells  may  contain  globules,  but  usually  such  alterations  are  not 

so  uniform.     The  fat  may  be  lodged  especially  in  the  cells  nearer  the  portal 

vein,  or,  on  the  contrary,  especially  in  those  about  the  efferent  vein.     When 

here  is  actual  injury  sufficient  to  kill  the  cell,  it  may  affect  the  cells  of  the 


INJURY   AND    REPAIR    OF    THE    LIVER 


313 


zone  nearest  the  portal  vein,  as  in  eclampsia  gravidarum,  or  the  zone 
farthest  from  the  portal  vein,  and  therefore  encircling  the  efferent  vein,  as  in 
chronic  passive  congestion,  chloroform  poisoning,  many  acute  infections, 
especially  those  in  which  generalized  peritonitis  (Fig.  146)  or  other  exten- 
sive and  intense  inflammations  occur,  and  in  all  that  ill-defined  group  of 
cases  known  as  acute  yellow  atrophy  of  the  liver.  Sometimes,  as  Opie 
points  out,  in  intense  infections,  and  especially  where  a  toxic  injury  is 
combined  with  bacterial  infection,  a  zone  midway  between  portal  and 


•  • 


i 


Fig.  147. — Chronic  passive  congestion,  destruction  of  liver-cells  extending  from  one 
efferent  vein  to  another  and  isolating  the  periportal  tissue. 

efferent  vein  may  be  picked  out  for  necrosis.  One  cannot  doubt  the  deter- 
mining influence  of  the  blood-stream  in  producing  these  differences  of  dis- 
tribution, although  it  is  not  always  easy  to  understand  it.  Opie  has  shown 
that  colored  materials  injected  into  the  hepatic  artery  or  portal  vein  during 
the  normal  circulation  tend  to  lodge  in  the  middle  zone,  and  one  might 
imagine  that  a  peculiarly  acrid  poison  could  destroy  the  first  cells  it  im- 
pinged upon,  as  happens  in  eclampsia,  but  how  is  one  to  explain  the  exten- 
sive and  often  sharply  limited  necrosis  of  the  cells  farthest  from  the  entrance 


314 


TEXT-BOOK  OF  PATHOLOGY 


of  the  blood,  which  is  so  frequently  seen  in  the  conditions  mentioned  above? 
In  the  case  of  chronic  passive  congestion  it  is  probable  that  those  cells 
which  receive  the  blood  last  are  poorly  nourished  by  the  stagnating  stream, 
which  becomes  less  able  to  supply  oxygen  as  it  reaches  the  neighborhood 
of  the  efferent  vein.  It  is  interesting  that,  in  this  case,  as  in  many  infectious 
and  toxic  injuries,  the  cells  along  those  capillaries  which  take  a  long  course 
to  empty  into  the  efferent  vein  suffer  throughout  a  region  everywhere 
equidistant  from  the  portal  vein  and  artery,  but  not  everywhere  equi- 
distant from  the  efferent  vein.  Therefore  in  these  cases  the  necrotic 
tissue  does  not  merely  encircle  the  efferent  veins,  but  extends  from  one  to 


e 


Fig.  148.— Focal  necrosis  with  invasion  and  fragmentation  of  wandering  cells:   typhoid 

fever. 

another.  If  we  accept  Sabourin's  lobule,  the  whole  periphery  of  the  lobule 
is  necrotic;  if  we  regard  the  efferent  vein  as  the  centre  of  the  lobule,  the 
necrotic  area  occupies  the  centre  of  each  lobule,  and  stretches  across  to 
join  that  about  the  centre  of  each  adjacent  lobule  (cf.  Fig.  147). 

But  although  injury  and  destruction  of  liver-cells  may  often  be  distributed 
in  a  zone  of  each  lobule,  it  is  very  frequently  focal.  In  numbers  of  infectious 
diseases,  such  as  typhoid  fever,  diphtheria,  malaria,  smallpox,  and  in  pois- 
oning with  diphtheria  toxin,  ricin,  abrin,  and  similar  things,  one  discovers 
small  groups  of  cells  situated  anywhere  in  the  lobule  which  have  been 
killed  and  coagulated  (Fig.  148) .  Why  those  cells  should  have  been  picked 


INJURY   AND   REPAIR   OF   THE   LIVER  315 

out  for  destruction  it  is  not  easy  to  say.  Some  authors,  including  Mallory, 
believe  that  emboli  of  cells  or  agglutinated  red  corpuscles,  often  supple- 
mented by  fibrin  thrombi,  so  occlude  the  capillaries  about  a  tiny  group  of 
cells  as  to  deprive  them  of  their  blood  supply  and  thus  produce  an  anaemic 
necrosis.  In  spite  of  the  difficulty  of  finding  another  satisfactory  explana- 
tion, there  is  much  that  seems  hardly  plausible  about  this.  It  is  true  that 
such  cell  emboli  are  often  found,  but  it  is  hard  to  believe  that  they  could 
so  completely  surround  a  group  of  cells  in  the  liver  as  to  render  it  anaemic. 
Even  then  it  would  seem  that  such  a  small  mass  of  tissue  might  absorb 
enough  nutriment  by  diffusion  to  keep  it  alive.  On  the  other  hand,  if  a 
mass  of  liver-cells  did  die,  one  might  expect  its  capillaries  to  become  throm- 
bosed. 

It  would  seem  that  injection  of  granular  material  into  the  mesenteric  vein  ought  to 
decide  this  question  at  once.  In  my  hands  such  injection  (corn-starch)  does  rarely  pro- 
duce focal  changes  which  will  probably  lead  to  necrosis  of  the  liver-cells,  but  these  are 
in  the  beginning  areas  of  tearing  of  the  tissue  by  haemorrhage  evidently  as  the  result  of 
plugging  of  the  capillaries.  In  those  areas  stretched  and  dismembered  cords  of  liver- 
cells  are  found;  the  remainder  are  pressed  back  and  flattened,  but  none  are  necrotic. 
This  is  very  different  from  the  familiar  appearance  of  most  focal  necroses,  in  which  the 
tissue  is  not  in  the  least  disarranged,  but  each  cell  has  died  where  it  stood.  In  all  the 
rest  of  the  experiments  the  grains  lodged  singly  or  in  groups  in  the  capillaries,  without 
producing  the  least  change  in  the  liver-cells.  (See  further  discussion  under  Typhoid  Fever.) 

If  chloroform  be  administered  to  an  animal  for  an  hour  or  two  and  its 
liver  examined  after  a  time,  marked  changes  are  to  be  found  in  the  liver- 
cells  nearest  the  efferent  vein.  In  case  the  chloroform  has  acted  mildly, 
these  are  chiefly  evident  in  the  great  accumulation  of  fat,  but  in  other 
animals  where  it  has  acted  longer  or  more  intensely,  these  cells  are  quite 
dead,  their  nuclei  failing  to  stain,  while  the  cell-body  is  coagulated  and 
deeply  stained  with  eosin.  This  may  be  ascertained  by  excision  of  a  small 
piece  of  the  liver  tissue  shortly  after  the  poisoning,  the  animal  being  left  alive. 
After  three  weeks  the  liver  is  found  restored  to  practically  its  normal 
condition,  so  rapid  is  the  removal  of  the  dead  cells  and  the  regeneration 
of  new  ones  from  those  which  remain.  By  combining  bacterial  infection 
with  chloroform  poisoning  Opie  has  produced  much  more  profound 
injuries  which  are  not  so  readily  repaired.  In  the  zonal  necroses  which 
accompany  intense  septic  infections  a  similar  anatomical  condition  is 
produced.  All  the  liver-cells  most  distant  from  the  portal  vein,  that  is, 
encircling  the  efferent  vein  and  stretching  to  the  region  of  the  next,  are 
necrotic.  Nevertheless,  in  these  areas  of  cell  death  the  endothelial  cells 
and  connective  tissues  remain  alive.  Nearer  to  the  portal  vein  in  each 
lobule  is  a  zone  of  cells  distended  with  fat-globules,  and  still  nearer  the  liver- 
cells  seem  intact  (Fig.  146). 

Acute  Yellow  Atrophy.— This  name  is  loosely  given  to  those  cases  in  which  some  un- 
known agent  suddenly  produces  a  destruction  of  liver-cells  so  wide-spread  that  signs  of 
acute  insufficiency  of  the  hepatic  functions  appear.  It  occurs  most  commonly  m  young 


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women  or  men,  and  often  in  pregnant  women,  but  may  also  affect  children.  Sudden 
malaise,  symptoms  of  indigestion,  nausea,  rapidly  deepening  jaundice,  vomiting  of 
blood,  delirium,  mental  dulness,  and  coma  lead  to  death.  The  urine  is  deeply  jaundiced, 
but  contains  also  ammo-acids  in  crystal  form,  such  as  leucin  and  ty rosin.  At  autopsy 
the  liver  is  found  very  much  decreased  in  size,  and  very  soft  and  mushy,  of  an  opaque 
ochre  yellow  color,  often  with  areas  of  red.  In  each  lobule  all  the  liver-cells,  often  with 
the  exception  of  those  nearest  the  portal  veins,  are  reduced  to  a  necrotic  debris.  If, 
as  rarely  happens,  the  person  survives,  regeneration  takes  place  to  some  extent  in  a  way 
that  shall  be  described. 

It  is  in  such  extreme  injuries,  and  perhaps  only  there,  that  the  liver  actually  shows 
itself  insufficient.  This  is  a  point  which  is  far  too  frequently  overlooked  by  clinicians 
who  search  for  tests  of  hepatic  function  to  apply  to  cases  in  which  there  may  be  scattered 
focal  necroses,  or  in  which  regeneration  has  restored  the  normal  functional  strength  of 
the  organ.  As  we  shall  see,  in  even  the  most  extreme  cirrhosis  of  the  liver  there  need 
be  no  functional  insufficiency.  Icterus  is  present  in  the  most  intense  form,  doubtless 


Fig.  149. — Hsemorrhagic  necrosis  in  the  liver  in  puerperal  eclampsia. 

because  the  columns  of  liver-cells  which  form  the  walls  of  each  bile  capillary  are  inter- 
rupted, so  that  the  bile  which  is  still  formed  escapes  into  the  blood.  Hemorrhages  into 
the  mucosse  and  elsewhere  are  abundant,  partly  on  account  of  the  jaundice,  but  partly, 
perhaps,  because  the  liver,  which  is  so  important  in  the  formation  of  fibrinogen,  has 
ceased  that  function.  The  amino-acids  in  the  urine  and  tissues  probably  appear  in 
large  part  because  they  are  ordinarily  brought  to  the  liver  in  that  form  from  the  intesti- 
nal wall,  and  finding  the  deamidizing  power  of  the  liver  in  abeyance,  they  pass  on  into 
the  general  circulation. 

Eclampsia  gravidarum  is  a  condition  appearing  before,  during,  or  after  childbirth, 
and  accompanied  by  the  most  violent  convulsions  and  evidence  of  the  most  extreme 
disturbances  of  metabolism,  somewhat  similar  to  those  found  in  acute  yellow  atrophy. 
Nothing  certain  is  known  of  its  cause,  although  Schmorl  at  one  time  thought  that  syn- 
cytial  masses  from  the  placenta  swept  into  the  liver  produced  the  necroses  found  there, 
while  others  ascribe  them  to  the  action  of  poisons  derived  from  the  foetus  or  from  the 


INJURY   AND   REPAIR   OF   THE    LIVER 


317 


placenta.  At  autopsy  the  liver  is  found  sprinkled  with  haemorrhages,  which  may  become 
confluent  into  great  patches  (Fig.  149).  These  haemorrhages  correspond  with  areas  of 
necrosis  of  the  liver-cells  beginning  essentially  in  the  periportal  region  of  each  lobule, 
but  often  becoming  confluent  (Fig.  150).  In  and  about  them,  it  is  true,  one  may 
sometimes  find  syncytial  masses  in  the  capillaries,  but  it  no  longer  seems  probable 
that  this  explains  the  condition,  since  they  occur  as  well  in  normal  pregnancy. 

In  the  other  infectious  and  toxic  processes  mentioned,  in  which  scattered 
focal  necroses  occur  (typhoid  fever,  diphtheria,  etc.),  one  finds  anywhere 


^t^^iS^l^llfeJI^^^iiv^, 

'••'  «#  V-V^'-    ,-:.•;•    J-T.  '-°;\  *.  °v»°      .  s>  • 


^f^vMa^ 


.'.-?i'3fl£mSk-  xT-  !  '»•"«*••'!    -*.^/'      ....  •',  «-'.,"*}°  °°«  *<    .•  ,8°  ".  ="'   *!•''  '    •••»' 


,°°. 


Fig.  150.— Eclampsia  gravidarum.     Peripheral  focal  necrosis  with  haemorrhages. 

in  the  lobule  circumscribed  areas  in  which  the  liver-cells  are  dead.  Here, 
as  in  the  zonal  type,  delicate  hyaline  thrombi  are  common  in  the  capillaries, 
entangling  the  many  wandering  cells  which  hurry  there  and  which  are  active 
in  dissolving  and  removing  the  debris  of  dead  cells. 

Repair  and  Compensatory  Hyperplasia  in  the  Liver.-The  liver  possesses 
very  great  powers  of  repairing  losses  of  its  substance.  Whipple  has  shown 
that  destruction  of  the  liver-cells  throughout  two-fifths  of  each  lobule  m 
the  dog  can  be  repaired  in  a  few  weeks  by  the  removal  of  the  dead  cells, 
and  their  accurate  replacement  without  any  distortion  of  the  lobule. 


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Thus  the  necroses  so  constant  in  typhoid  fever  are  healed  without  an 
appreciable  scar.  This  power  belongs  not  only  to  the  highly  specialized 
liver-cells,  but  also  to  the  epithelium  of  the  bile-ducts,  which,  if  they  become 
disconnected  from  their  liver-cell  strands  by  the  destruction  of  some  of  the 
cells,  quickly  bridge  the  gap  and  reestablish  the  connection.  All  these 
cells'multiply  by  mitotic  division,  and  are  guided  in  the  direction  of  their 
growth  by  the  persisting  liver  framework.  Thus,  when  all  the  liver-cells 


^^^-•^^m^&r/ 


Fig.  151. — Beginning  repair  of  the  liver  by  sprouting  bile-ducts  after  destruction  of  all 

the  liver-cells  in  a  lobule. 

about  the  efferent  vein  of  the  lobule  have  been  destroyed,  numerous  karyo- 
kinetic  figures  can  be  found  in  the  cells  of  the  adjoining  zone,  where  they 
are  so  loaded  with  fat-globules,  but  are  rather  fewer  in  the  better  preserved 
cells  immediately  about  the  portal  veins  (Fig.  146) . 

Often  recognizable  as  young  cells  by  their  pale,  clear  protoplasm  and 
convex  outline,  these  fresh  liver-cells,  together  with  some  of  the  older  ones, 
push  their  way  along  the  spaces  formerly  occupied  by  those  which  were 
killed,  unless  those  spaces  are  collapsed  and  obstructed.  If  all  the  cells 


INJURY   AND   REPAIR   OF   THE    LIVER 


319 


of  the  lobule  are  annihilated,  the  framework  remains,  and  is  often  held 
open  by  the  rigidity  of  the  tissue  about  it  (Fig.  151).  Then  there  is  no 
source  for  new  liver-cells.  Broken  ends  of  bile-ducts  which  formerly  con- 
nected, one  with  each  of  these  strands  of  liver-cells,  remain  uninjured  in  the 
portal  spaces  and  now  grow  out  with  bulbous  ends  into  the  framework  of 
.the  lobule  toward  the  efferent  vein,  that  is,  in  the  Sabourin  lobule  they 
sprout  out  from  the  central  bile-duct.  In  the  lobule  in  which  the  efferent 
vein  forms  the  centre  these  bulbous  bile-ducts  appear  to  grow  centripetally. 
There  has  been  much  dispute  as  to  whether  they  can  actually  produce  new 
liver-cells.  I  believe  they  can  to  a  limited  extent,  as  shown  in  Fig.  152, 
where  the  club-shaped  masses  were  unquestionably  liver-cells  and  new, 
since  they  contained  none  of  the  pigment  which  was  so  abundant  in  all  the 


Fig.  152. — Formation  of  liver-cells  by  bile-ducts. 

older  liver-cells.  That  they  can  thus  become  differentiated  seems  certain, 
but  probably  they  do  so  but  seldom,  and  then  produce  very  few  liver-cells. 
Melchior  thinks  this  process  very  important,  but  it  seems  that  he  assigns 
to  it  cells  otherwise  produced. 

Thus  healing  or  readjustment  of  breaks  in  continuity  may  be  easily 
carried  out  by  the  liver-cells  and  the  bile-duct  epithelium.  It  must  not 
be  supposed,  however,  that  the  framework  of  the  liver  is  always  left  undis- 
turbed, so  that  repair  can  proceed  so  easily  and  accurately.  It  may  col- 
lapse when  the  liver-cells  are  gone,  and  become  consolidated  into  a  scar- 
like  band.  Then  bile-ducts  may  push  their  way  into  it  and  new  liver-cells 
may  be  formed  there,  but  their  arrangement  will  not  be  that  of  the  normal 
lobule. 


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Perhaps  the  simplest  available  example  of  repair  in  an  extensively  injured 
liver  is  furnished  by  a  case  studied  some  years  ago,  that  of  a  boy  who  had 
gone  through  a  severe  illness,  which  may  have  been  acute  yellow  atrophy 
of  the  liver,  six  months  before  his  death.  In  the  mean  while,  up  to  his 
death  from  an  infection,  he  had  been  fairly  well.  The  liver  was  greatly 
reduced  in  size,  but  contained  a  tumor-like  mass  in  the  right  lobe,  composed 

of  dark-green  lobules  like 
swollen     liver     lobules. 
Throughout  the  general 
liver     substance     every 
liver-cell    had   been   de- 
stroyed;   the  framework 
had  remained  intact  with 
the  bile-ducts  and  blood- 
vessels, and  from  every 
bile-duct     branching 
sprouts     were     growing 
into  the  old  framework, 
although    nowhere    pro- 
ducing definite  liver-cells. 
In  the  right  lobe  a  por- 
tion of  liver  tissue  had 
evidently  been    left   in- 
tact,  and   this  had  be- 
come    the     tumor -like 
mass  by  the  symmetrical 
enlargement  of  each  re- 
maining   lobule.       This 
mass,  which  was  finally 
about  the  size  of  a  small 
orange,  must  have  been 
very    much    smaller    at 
first,  and  yet  it  sustained 
life  and   prevented   any 
serious  symptoms  of  he- 


Fig.  153.— Coarse  cirrhosis  of  the  liver  with  large 
nodules  of  regenerating  liver-cells. 


patic  insufficiency.  This 
exactly  corresponds  with 
Ponfick's  experimental 

results,  in  which  he  found  that,  after  removal  of  a  large  part  of  the  liver 
the  remainder  enlarged  by  a  symmetrical  growth  of  each  lobule,  new  liver- 
cells  being  formed  everywhere  by  division  of  the  old  ones.  No  rearrange- 
ment of  liver-cells,  bile-ducts,  nor  blood-vessels  was  necessary  in  this  case 
and  we  have  the  effects  of  a  single  great  injury  before  us.  (Similar  cases,  in 
which  many  large  nodules  of  liver  tissue  are  found  embedded  in  a  scar-like 
organ,  are  probably  also  due  to  a  single  injury  (Fig.  153).  ) 


CIRRHOSIS    OF   THE    LIVER  321 

CIRRHOSIS  OF  THE  LIVER 

This  is  a  term  applied  to  an  extensive  diffuse  scarring  of  the  liver  which  has 
followed  the  destruction  of  much  of  the  liver  substance.  It  is  regularly 
accompanied  by  wide-spread  regeneration  of  the  functional  liver  tissue, 
usually  sufficient  to  prevent  the  appearance  of  any  signs  of  hepatic  in- 
sufficiency. 

There  are  great  difficulties  in  classifying  all  the  different  types  of  cir- 
rhosis, because,  except  in  about  three  or  four,  we  are  ignorant  of  their  causes. 
The  rest  we  have  to  classify,  then,  on  the  basis  of  the  anatomical  and  func- 
tional disturbances,  which  is  not  very  satisfactory.  We  know  that  syphi- 
litic and  tuberculous  infection  can  produce  scars  throughout  the  liver,  with 
profound  distortion  of  the  organ,  and  that  obstruction  of  the  bile-duct  will 
in  the  end  set  up  a  peculiar  type  of  scarring  about  the  bile-duct  branches, 
with  deep  jaundice — but  with  regard  to  all  the  other  cases  of  cirrhosis  in 
which  these  things  are  readily  excluded  we  are  still  rather  at  sea.  Of 
course,  in  the  lay  mind  the  abuse  of  alcohol  is  held  responsible  for  cirrhosis 
of  the  liver  in  a  quite  unprejudiced  way,  but  although  it  may  well  play 
some  part,  its  influence  is  undoubtedly  greatly  exaggerated.*  Long- 
cope's  recent  experiments,  which  show  that  lesions  resembling  those  found 
in  cirrhosis  may  be  produced  by  repeated  anaphylactic  shocks  caused  by 
injections  of  egg-white  or  other  protein,  are  most  suggestive  of  an  origin 
through  protein  sensitization  and  intoxication.  But  the  most  accurate 
approach  to  this  anatomical  condition  has  been  made  by  those  authors 
(Opie  and  others)  who  have  combined  bacterial  infection  with  various 
poisons,  such  as  chloroform,  which  destroy  liver-cells.  Probably  it  is  in 
some  such  protracted  and  complex  injuries  that  we  shall  find  the  actual 
cause  of  the  disease,  but  undoubtedly,  as  in  any  scar,  the  same  common- 
place result  may  have  a  great  variety  of  original  causes.  The  anatomical 
condition  of  the  liver,  and  the  occurrence  or  absence  of  certain  associated 
disturbances,  such  as  jaundice,  obstruction  of  the  portal  blood  flow  and 
ascites,  enlargement  of  the  spleen,  etc.,  form  the  further  basis  for  classi- 
fication of  the  cases,  and  we  find  that  the  following  types  may  be  separated: 

1.  The  Ordinary  Nodular  Cirrhosis  (Laennec's  Cirrhosis;    Atrophic  or 
Portal  Cirrhosis;  Hobnail  Liver;  Alcoholic  Cirrhosis,  etc.).— Liver  rough  and 
nodular,  tends  to  be  smaller  than  normal,  no  jaundice,  marked  portal 
obstruction,  with  ascites  and  enlargement  of  the  spleen.    ^Etiology  obscure. 

2.  Obstructive  Biliary  Cirrhosis.— Liver  enlarged,  smooth,  or  granular. 
Jaundice.     Clay-colored  stools.     Scars  following  bile-canals.     Usually  no 
portal  obstruction  nor  ascites,  but  spleen  may  be  enlarged.    ^Etiology: 
Obstruction  of  bile-ducts,  usually  accompanied  by  infection. 

*  It  is  misleading  to  try  to  determine  this  relation  by  estimating  the  percentage  of  the 
cases  of  cirrhosis  of  the  liver  in  which  there  has  been  abuse  of  alcohol.  If,  instead,  we 
study  a  great  number  of  chronic  alcoholics,  we  find  (Simmonds)  a  relatively  small  per- 
centage of  cases  of  cirrhosis  of  the  liver.  On  the  other  hand,  great  accumulation  ?f  fat 
in  the  liver  is  common  in  alcoholics.  Experimental  administration  of  alcohol  to  animals 
produces  no  cirrhosis,  even  when  enormous  doses  are  given  over  a  very  long  tn 


22 


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3.  Hanoi's  Cirrhosis,  or  Primary  Hypertrophic  Biliary  Cirrhosis. — Liver 
large,  smooth,  diffusely  and  finely  scarred.     Jaundice,  with  no  gross  ob- 
struction of  bile-ducts;  bile-stained  stools;  no  portal  obstruction;  splenic 
enlargement.    ^Etiology  obscure,  possibly  an  infectious  process. 

4.  Syphilitic  Cirrhosis,  Congenital  or  Acquired. — In  the  congenital  form 
the  liver  may  be  large,  smooth,  and  diffusely  scarred,  or  it  may  present 
gummata  which  later  become  scarred.     In  the  acquired  form  gummata 
heal  with  large  scars,  producing  deep  grooves  and  lobulations  in  the  liver. 
No  jaundice;  no  marked  portal  obstruction. 

5.  Tuberculous  Cirrhosis. — Especially  with  tuberculosis  of  peritoneum, 
producing  thickening  of  Glisson's  capsule,  with  constriction  and  distortion 


Fig.  154. — Diffuse  nodular  cirrhosis  of  the  liver. 

of  the  organ.  In  another  form  with  many  tubercles  in  the  liver  the  process 
is  somewhat  like  the  syphilitic. 

There  are  unquestionably  many  other  types,  for  any  injury  recovered 
from  and  healed  may  leave  its  trace  in  the  form  of  a  cirrhotic  process. 

1.  Diffuse  Nodular  Cirrhosis.— In  the  ordinary  cirrhosis  one  finds  the 
liver  hard  and  stiff— sometimes  larger  than  normal,  but  generally  shrunken 
and  deformed  and  roughened  all  over  by  projecting  nodules  of  a  yellowish- 
brown  or  chestnut-brown  color  (Fig.  154).  The  capsule  is  generally  thick- 
ened and  sometimes  finely  granular,  but  through  it  one  can  see  that  the 
shrunken  tissue  between  the  nodules  is  gray  and  translucent,  often  showing 
httle  veins  in  the  depths  of  the  depressed  areas.  It  is  hard  to  cut,  and  in 


CIRRHOSIS    OF    THE    LIVER 


323 


extreme  cases  creaks  or  cries  under  the  knife.  The  cut  surface  shows  just 
the  same  appearance — rounded  or  irregular  nodules  of  liver  tissue  'of 
variable  size  projecting  as  little  plateaus  from  the  gray,  translucent  ground- 
work. Every  kind  of  variation  in  the  appearance  of  these  nodules  may 
occur  (Fig.  155);  sometimes  they  are  all  quite  small  and  uniform,  more 
often  some  of  them  are  larger,  and  these  tend  to  be  pigmented  or  bile 
stained;  occasionally  they  are  all  very  large, — even  as  large  as  marbles, — 
and  widely  separated  by  a  rather  loose,  vascular  connective  tissue.  In 


Fig.  155.— Irregular  nodular  cirrhosis  with  ascites.     Half  of  liver. 

some  cases  the  liver  substance  forms  the  great  bulk  of  the  organ,  so  that 
scars  can  be  traced  through  it  with  difficulty;  in  others  the  whole  organ 
seems  to  be  composed  of  solid  elastic  fibrous  tissue,  with  only  scattered 
pockets  of  greenish  or  brown  granular  liver  substance  embedded  at  inter- 
vals through  it.  The  liver  tissue  itself  may  be  made  up  of  quite  normal- 
looking  cells,  or  the  cells  may  be  loaded  with  fat  or  pigment,  or  be  act 
on  the  way  to  necrosis  and  disintegration. 


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All  these  variations  are  of  subordinate  importance  though,  and  further 
study  shows  that  in  principle  these  cases  are  all  very  similar.  Large  iso- 
lated masses  of  liver  appear  when  only  widely  separated  groups  of  cells 
have  been  spared  and  have  been  allowed  ample  time  to  regenerate  as  much 
liver  tissue  as  possible.  Small,  closely  packed  nodules  result  when  destruc- 
tion has  occurred  in  smaller  foci,  and  some  portion  of  nearly  every  lobule 
has  survived.  Even  the  most  casual  examination  shows  that  these  nodules 
have  no  longer  anything  like  the  normal  arrangement  of  the  lobules.  They 
are  not,  as  a  rule,  isolated  nodules,  for  reconstruction  of  serial  sections 
shows  that  they  are  almost  all  connected  together  into  an  irregular  net- 
work, but  they  have  lost  their  regular  relation  to  the  original  portal  veins, 
bile-ducts,  and  hepatic  veins.  They  no  longer  even  approach  uniformity 
in  size,  nor  can  one  find  a  central  vein  in  each.  Instead,  they  generally 


Fig.  156.— Cut  surface  of  the  liver;    nodular  or  Laennec's  cirrhosis. 

appear  in  section  as  smooth,  finely  granular,  almost  velvety,  solid  masses  of 
liver-cells  and  nothing  more. 

Microscopical  study  confirms  all  this  (Figs.  157,  158).  Everywhere  in 
the  section  there  are  found  patches  of  liver-cells  arranged  in  a  most  dis- 
orderly fashion.  All  bear  evidence  of  having  been  enlarged  by  the  mul- 
tiplication of  their  cells,  so  that  the  arrangement  with  reference  to  portal 
and  efferent  veins  is  all  that  will  tell  us  whether  we  have  the  enlargement 
of  a  whole  lobule  or  of  an  isolated  group  of  cells.  In  the  latter  case  the 
patch  will  have  no  portal  and  no  efferent  vein  immediately  connected  with 
it,  but  is  merely  a  conglomeration  of  liver-cells  with  intervening  capillaries 
which  have  grown  into  a  perfect  labyrinth,  and  allow  the  passage  of  blood 
with  some  difficulty.  The  whole  lies  surrounded  by  vascular  connective 


CIRRHOSIS   OF   THE    LIVER  325 

tissue,  in  which  there  are  many  wandering  cells,  and  in  which  one  can  see 
numerous  tortuous  bile-ducts.  Very  often  one  can  make  out  in  this  tissue 
what  must  have  been  the  efferent  vein  which  originally  drained  the  lobule 
of  which  we  have  just  considered  the  hypertrophied  remnant,  and,  indeed, 
this  vein  doubtless  still  drains  that  overgrown  remnant  (Fig.  159).  Portal 
veins  are  also  visible,  but  they  are  commonly  in  no  clearly  recognizable 
relation  to  the  liver-cells,  but  lie  quite  far  away  in  the  intervening  tissue. 
So,  too,  the  original  bile-ducts  can  be  seen,  but  there  are  many  other  sinu- 


Fig  157  —Nodular  cirrhosis  of  the  liver.  The  low-power  drawing  shows  the  irregular 
arrangement  of  the  remaining  liver  tissue  and  the  distribution  of  the  newly  formed  bile- 
ducts. 

ous  channels  lined  with  epithelium  which  branch  abundantly  and  which 
one  may  trace  into  connection  at  one  end  with  the  bile-duct,  at  the  other 
with  a  strand  of  liver-cells  in  one  of  the  nodules  (Fig.  160). 

There  has  been  much  dispute  as  to  their  nature,  and  they  have  been 
thought  by  many  to  be  compressed  liver-cells,  but  everything  goes  to  show 
that  they  are  bile-ducts,  for  the  greater  part  newly  formed  from  the  stumps 
of  those  which  were  left,  and  now  growing  to  reestablish  connection  with 
the  liver-cells.  The  slight  part  they  play  in  the  new  formation  of  liver- 


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cells  has  been  mentioned.  'Of  course,  in  any  such  strand  of  tissue  as  we 
find  between  the  nodules  of  liver-cells  a  great  many  bile-ducts,  portal 
veins,  etc.,  are  concentrated  together  through  the  collapse  of  many  lobules 
whose  skeleton  framework  goes  to  form  a  large  part  of  the  strand,  but  the 
newly  formed  ducts  can  usually  be  recognized. 

One  might  trace  out  the  fate  of  any  isolated  portion  of  a  lobule  which 
remained  after  the  devastation  of  the  rest  in  this  process,  but  the  process  of 
reestablishment  of  relations  is  the  same  no  matter  how  much  or  how  little 
of  the  original  lobule  remains.  It  is  as  though  groups  of  liver-cells  were 
transplanted  into  a  vascular  tissue  rich  in  bile-ducts.  They  acquire  the 


Fig.  158. — Nodular  cirrhosis  showing  atypical  arrangement  of  liver-cells  in  each  nodule. 


best  vascular  connections  possible  for  their  situation,  and  the  ends  of  the 
strands  unite  with  the  sprouts  of  bile-ducts  which  approach  them,  after 
which  the  liver-cells  multiply  as  fast  as  possible  to  produce  a  larger  nodule, 
which  will  compensate  in  function  for  the  cells  which  were  destroyed. 
There  is  no  evidence  of  the  compression  of  the  liver-cells  by  the  fibrous 
tissue  in  which  they  are  growing— rather  one  might  say  the  fibrous  tissue 
is  pushed  aside  and  compressed  by  them.  Nor  is  there  any  justification 
for  the  term  lobular  cirrhosis,  since,  as  we  see,  it  is  by  no  means  a  question 
of  the  enveloping  of  lobules  in  fibrous  tissue.  Although  many  conflicting 


CIRRHOSIS   OF   THE    LIVER  327 

views  have  been  held,  it  seems  clear  enough  that  the  injurious  agent  effects 
the  destruction  of  the  liver-cells  in  the  first  instance,  and  that  the  scarring 
and  the  hyperplasia  of  the  epithelial  remnants  are  reparatory  processes. 
Very  commonly  the  liver-cells  are  quite  normal  in  appearance  and 
function,  and  doubtless  they  are  so  for  weeks  and  months  at  a  time.  If 
the  attacks  of  the  injurious  agent  could  be  stopped,  there  is  no  reason  why 
compensatory  hyperplasia  should  not  go  on  until  the  organ  had  once  more 
its  full  complement  of  cells  in  an  abnormal  arrangement.  But  they  are, 
of  course,  as  always,  susceptible  to  injury,  and  for  that  reason  they  are 


Tig   159  —Nodular  cirrhosis  with  very  great  hyperplasia  of  the  liver-cell  nodules.     Ob- 
serve the- distorted  relation  of  portal  and  efferent  veins  to  the  liver  ti 

often  found  at  the  death  of  the  individual,  loaded  with  fat  or  injured  in  some 
other  way.  Some  of  these  injuries  may  be  of  the  series  which  is  still  at 
work,  adding  to  the  changes  which  bring  about  the  cirrhosis,  but  others 
may  be  independent,  and  we  might  expect  to  find  focal  necroses  in  the 
liver-cells  of  a  man  who  has  long  had  a  cirrhotic  liver  and  who 

typhoid  fever.  ,, 

The  whole  condition  is  brought  about  in  exactly  the  same  way  as  the 
scarring  of  the  kidney  with  compensatory  hyperplasia     The  liver- 
are  killed  in  patches-whole  lobules  and  groups  of  lobules  at  a  tune,  o 


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only  parts  of  lobules.  There  remain  irregular  masses  of  liver  tissue  partly 
disconnected  from  their  bile-ducts.  The  framework  of  the  rest  of  the 
tissue  collapses  and  shrinks,  and  is  kept  in  that  position  by  the  growth  of 
new  fibrous  tissues,  but  through  that  tissue  blood  still  streams  readily. 
The  bile-ducts  which  were  interrupted  by  the  death  of  the  liver-cells 
send  out  sprouts  which  attempt  to  connect  again  with  liver-cell  strands. 
The  masses  of  liver-cells  quickly  increase  in  size  by  multiplication  of  their 
cells,  new  capillaries  are  formed  in  every  direction,  and  this  labyrinth  of 


Fig.  160.— Cirrhosis  of  the  liver  showing  the  reunion  of  bile-ducts  with  the  liver-cells. 


cells  expands,  pressing  the  stroma  away  on  all  sides.     For  a  time  the  liver- 
cells  are  normal,  but  then  comes  another  injury,  and  many  of  the  hyper- 
plastic  nodules  are  partly  destroyed.     The  whole  process  is  repeated,  and 
not  only  once,  but  many  times.     It  is  clear  that  this  must  lead  to  an  extra- 
rdmary  distortion  of  the  liver's  structure.     There  are  no  longer  lobules, 
t  only  nodules  produced  by  the  hyperplasia  of  smaller  groups  of  cells 
which  were  left  intact. 


CIRRHOSIS   OF   THE    LIVER  329 

Obstruction  of  the  Portal  Flow.— With  advancing  cirrhosis  of  the  liver  it  becomes 
difficult  for  the  portal  blood  to  pass  through,  and  all  the  branches  of  that  vein  come  to  be 
distended,  sometimes  even  to  the  point  of  bursting.  The  organs  which  are  drained  by 
them  are  swollen  and  blue  from  the  stagnation  of  venous  blood,  and  their  function  is 
disturbed.  Digestion  is  impaired,  and  the  spleen  becomes  greatly  enlarged.  Fluid 
niters  through  into  the  peritoneal  cavity,  and  the  ascites  accompanying  cirrhosis  may 
be  of  the  most  persistent. 

Why  so  much  obstruction  should  occur  is  not  as  simply  explained  as  might  appear  at 
first  sight.  With  the  great  reduction  in  the  size  of  the  liver  much  of  the  stream-bed  is 
doubtless  obliterated.  The  rigidity  of  the  scarred  organ  may  prevent  the  normal  dis- 
tensibility  of  the  blood-vessels,  but  the  capillaries  of  the  scarred  bands  are  still  more 
easily  injected  than  those  of  the  regenerated  nodules  of  liver  tissue.  In  the  liver  nodules, 
on  the  contrary,  the  tortuous  course  of  the  new  capillaries  offers  an  increased  resistance 
to  the  flow  of  blood. 

Herrick*  has  offered  the  explanation  that  the  communications  between  the  hepatic 
artery  and  the  branches  of  the  portal  vein  become  far  wider  than  normal  in  the  cirrhotic 
liver,  so  that  the  high  arterial  pressure  is  communicated  directly  and  obstructs  the  out- 
flow from  the  veins,  much  as  it  does  in  an  arteriovenous  aneurysm.  The  long-continued 
overdistension  of  the  portal  branches  is  sometimes  partly  relieved  by  the  widening  of 
certain  communications  between  the  portal  system  and  the  branches  of  the  vena  cava, 
which  always  exist  but  are  normally  too  small  to  be  of  any  use.  These  are  well  de- 
scribed by  Charcotf  and  are  diagrammatically  shown  in  Fig.  161.  They  are: 

1.  Anastomoses  between  the  left  coronary  vein  of  the  stomach  and  the  cesophageal 
veins  which  open  into  the  azygos  or  intercostals.     These  communicating  channels  often 
become  enormously  enlarged  (resophageal  varices),  and  may  burst  into  the  resophagus, 
with  fatal  results  (Fig.  162).     The  coronary  vein  may  also  anastomose  with  superior 
or  inferior  diaphragmatic  veins. 

2.  Anastomoses  exist  between  branches  of  the  inferior  mesenteric  vein,  the  superior 
haemorrhoidals,  and  branches  of  the  internal  iliac  veins,  the  inferior  hsemorrhoidals. 
These  are  apparently  not  especially  efficient,  and  haemorrhoids  are  said  not  to  be  common 
in  cirrhosis. 

3.  The  veins  of  Retzius,  which  originate  in  the  walls  of  the  intestines  and  through  a 
little  trunk  empty  into  the  vena  cava  or  one  of  its  branches. 

4.  The  veins  of  Sappey,  or  accessory  portal  veins,  which  originate  in  some  organ  other 
than  the  digestive  tract,  and,  after  forming  a  trunk,  reach  the  liver  and  ramify  in  its 
substance.     Some  of  them  are  quite  useless  in  establishing  a  collateral  circulation,  as, 
for  example,  those  which  connect  the  omentum  or  the  gall-bladder  with  the  liver,  or 
those  which  constitute  the  vasa  vasorum  of  the  portal  vein,  hepatic  artery,  and  bile- 
ducts.     But  the  veins  of  the  suspensory  ligament  which  unite  with  those  of  the  dia- 
phragm are  useful.     So,  too,  are  the  para-umbilical  veins  (Umb  C,  Fig.  161),  whose 
roots  communicate  with  the  epigastric,  the  internal  mammary,  and  the  subcutaneous 
abdominal  veins.     They  enter  the  liver  along  the  obliterated  umbilical  vein,  and  are  dis- 
tributed to  the  lobules  along  the  longitudinal  groove,  to  the  portal  vein  to  the  left  of 
the  umbilical  ligament,  or  to  the  still  permeable  part  of  that  ligament.     They  are  im- 
portant channels  of  communication,  and  sometimes  appear  in  their  swollen  state  under 
the  skin  of  the  abdomen  radiating  from  the  navel  (caput  medusae). 

Of  course,  other  collateral  channels  arise  through  the  formation  of  adhesions  between 
the  abdominal  organs  and  the  walls  of  the  abdomen,  and  they  are  often  intentionally 
produced  for  this  purpose  by  an  operative  procedure  (Talma's  operation). 

At  times  the  collateral  circulation  reaches  an  efficiency  which  allows  the  patient  to 
live  on  without  ascites  or  symptoms  of  chronic  passive  congestion,  but  usually  it  is  not 

*  F.  C.  Herrick:  Jour.  Exp.  Med.,  1907,  ix,  93. 
t  Charcot:    Maladies  du  Foie,  Paris,  1882. 


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so  complete.     Jaundice  in  the  type  of  cirrhosis  described  above  is  rare,  and  when  it  does 
occur,  is  probably  due  to  some  accessory  cause. 


-    Dicipn. 


HK. 


Fig.  161. — Diagrammatic  representation  of  the  collateral  circulation  established  in 
cirrhosis  of  the  liver  (from  Charcot):  1,  2,  3,  4,  5,  Accessory  portal  veins  of  Sappey; 
7,  7,  7,  veins  of  Retzius.  The  organs  are  viewed  from  behind. 


2.  Obstructive  Biliary  Cirrhosis. — It  has  been  shown  experimentally 
(Vaughan  Harley,  Ogata,  and  others)  that,  in  certain  animals  at  least,  the 


CIRRHOSIS   OF   THE    LIVER 


331 


occlusion  of  the  bile-ducts  results  in  the  destruction  of  some  of  the  liver- 
cells  and  in  the  formation  of  scar  tissue  in  their  place.  This  is  especially 
striking  in  zones  about  the  portal  veins  and  bile-ducts,  and  in  these  zones 
numerous  new  bile-ducts  sprout  out.  The  addition  of  infection  to  the 
mechanical  stasis  of  the  bile  intensifies  the  process.  The  same  thing  is 


Fig.  162.— Collateral  circulation  in  cirrhosis.     (Esophageal  varices  with  rupture  and 
fatal  haemorrhage  (liver  of  this  case  shown  in  Fig.  155). 

true  in  human  beings  when  the  hepatic  or  common  duct  becomes  obstructed 
by  a  gall-stone  or  by  a  tumor-growth.  Jaundice  results  promptly,  and 
the  liver  becomes  swollen  and  deep  green  in  color.  After  this  obstruction 
has  lasted  some  time  slight  irregularity  of  its  surface  arises,  and  on  sec- 
tion delicate  scars  can  be  seen.  There  is  rarely  time  for  the  development 


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of  any  such  extreme  changes  as  have  been  described  for  the  diffuse  nodular 
cirrhosis.  The  spleen  becomes  enlarged,  but  there  is,  except  in  advanced 
cases  of  long  standing,  no  obstruction  to  the  flow  of  portal  blood.  In  a 
man  aged  fifty-five  jaundice  appeared  and  quickly  deepened  to  a  dark, 
greenish  bronze  color.  At  the  autopsy  several  jack-stone-shaped  black 
gall-stones  were  found  in  the  gall-bladder,  at  the  fundus  of  which  a  small 
cancer  had  developed.  A  secondary  growth  from  this  lay  embedded  in 


Fig.   163. — Biliary  cirrhosis. 


the  liver  in  such  a  way  as  to  surround  and  compress  the  hepatic  ducts  as 
they  left  the  liver — below  this  the  ducts  were  normal;  within  the  liver 
they  were  distended  to  a  phenomenal  degree.  The  liver  was  deep  green, 
flabby,  and  coarsely  lobulated,  although  only  slightly  wrinkled  on  the 
surface.  Even  on  section  there  was  no  great  departure  from  the  regular 
lobulation.  Microscopical  study  showed  each  larger  bile-duct  twig  and 
portal  vein  surrounded  by  a  loose  scar  tissue  infiltrated  with  leucocytes, 


CIRRHOSIS   OF   THE    LIVER  333 

and  rich  in  young,  sprouting  bile-ducts,  evidently  growing  out  to  join  the 
remaining  liver-cells  after  the  destruction  of  many  of  those  nearest  the 
portal  space  (Fig.  163). 

Apparently  in  the  cases  of  longest  duration  a  great  deal  more  distortion 
of  the  liver  may  occur,  but  it  does  not  approach  that  seen  in  the  previous 
type. 

3.  Primary  Biliary  Hypertrophic  Cirrhosis  (Hanot's  Cirrhosis). — There 
exists  much  confusion  as  to  what  Hanot  actually  meant  to  include  in  his 
type  of  hypertrophic  cirrhosis  with  icterus  and  without  ascites,  but  Heineke 


Fig.  164. — Hanot's  cirrhosis. 

describes  it  as  a  change  resulting  from  the  inflammation  of  the  minuter 
bile-ducts,  and  producing  a  fine,  almost  intercellular,  scarring  throughout 
the  liver,  with  its  enlargement-enlargement  of  the  spleen,  fever,  but  no 
portal  obstruction.  There  are  other  cases  in  which  there  is  the  same  deep 
jaundice  but  no  evident  inflammation  of  the  bile-ducts  (Kretz),  and  st 
others  in  which  there  is  no  jaundice.  Nevertheless,  in  these  too  the  liver 
is  found  greatly  enlarged,  hard,  and  smooth,  and  on  section  no  definite 
lobulation  whatever  can  be  made  out.  Microscopically  there  is  found  a 


334  TEXT-BOOK  OF  PATHOLOGY 

finely  diffused  network  of  scar  tissue  all  through  the  tissue,  separating  the 
lobules  into  little  groups  of  cells  (Fig.  164). 

LITERATURE 

Ackermann:  Pathol.  Bindegewebsneubild.  in  der  Leber,  Berlin,  1894. 
Ford:  Amer.  Jour.  Med.  Sci.,  1901,  cxxi,  60. 
Heineke:   Ziegler's  Beitrage,  1897,  xxii,  259. 
Kretz:    Verb.   Dtsch.  Path.  Gesellsch.,  1904,  viii,  54;    1905,   ix,   260.     International 

Clinics,  1905,  iii,  fifteenth  series,  289. 
MacCallum:    Johns  Hopkins  Hosp.  Reports,  1902,  x,  375.     Jour.  Amer.  Med.  Assoc., 

1904,  xliii,  649. 

Meder  and  Marchand:  Ziegler's  Beitrage,  1895,  xvii,  143. 
Ogata:  Ziegler's  Beitrage,  1913,  Iv,  236. 
Opie:  Jour.  Exp.  Med.,  1910,  xii,  367. 
Ponfick:   Virch.  Arch.,  cxviii,  cxix,  cxxxviii. 
Ribbert:  Deutsche  med.  Woch.,  1908,  xxiv2,  1678. 
Vaughan  Harley:   Brit.  Med.  Jour.,  1898,  ii,  1743, 
Whipple:  Jour.  Exp.  Med.,  1911,  xiii,  136. 


CHAPTER  XVII 

FURTHER    ILLUSTRATIVE   EXAMPLES    OF   DESTRUCTIVE    AND 
REPARATIVE  PROCESSES 

Arteriosclerosis.  Structure  of  arteries.  Anatomical  changes  in  arteriosclerosis  in  aorta 
and  other  vessels.  Pathogenesis  and  (Etiology.  Syphilitic  arteritis  in  aorta  and  smaller 
vessels.  Obliterative  endarteritis.  Thromboangeitis  obliterans.  Aneurysms,  various  types; 
their  effects  and  their  relation  to  syphilis.  Apoplexy;  location  of  haemorrhage  in  brain. 

ARTERIOSCLEROSIS 

Structure  of  Arteries. — The  structure  of  the  arteries  changes  as  we  pass  from  the  aorta 
into  the  branches  and  finer  ramifications.  Everywhere,  however,  there  is,  as  in  the 
case  of  the  veins  and  lymphatics,  a  lining  membrane  composed  of  a  single  layer  of  flat- 
tened endothelial  cells  which  offers  a  smooth  surface  and  acts  as  a  protection  for  the 
blood  against  any  contact  with  other  tissues. 

In  the  aorta  the  outer  wall  or  adventitia  is  composed  of  a  loose  connective  tissue  carry- 
ing blood-vessels,  nerves,  etc.,  and  containing  a  loose  network  of  elastic  fibrils.  The 
middle  coat  or  media  is  composed  of  elastic  tissue,  smooth  muscle,  and  connective  tissue. 
The  elastic  tissue  which  forms  the  most  prominent  feature  is  arranged  in  a  complex  of 
laminae,  with  fibrils  which  run  obliquely  and  connect  the  lamina?.  In  a  cross-section 
one  sees  the  main  circular  strands  of  elastic  tissue  about  equidistant  from  one  another, 
running  with  a  somewhat  wavy  course  around  the  vessel,  and  connected  by  numerous 
oblique,  bridge-like  fibres;  but  since  in  a  longitudinal  section  one  sees  exactly  the  same 
thing,  it  seems  evident  that  were  the  elastic  tissue  isolated,  one  might  discern  something 
roughly  approaching  the  form  of  a  series  of  imperfect  concentric  tubes.  It  seems  to  be 
about  as  though  one  should  paste  on  a  sheet  of  paper,  one  after  another,  pieces  of  gauze 
irregular  in  size  and  outline,  gluing  only  their  edges  where  they  happen  to  fall,  until  a 
uniform  thick  layer  is  produced,  and  then  make  a  tube  of  the  whole,  except  that  each 
piece  of  gauze,  where  it  stands  away  from  the  underlying  and  overlying  pieces,  should  be 
connected  with  them  by  many  oblique  threads.  In  a  tangential  section  of  the  media 
the  muscle-fibres,  instead  of  being  perfectly  circular  in  their  course,  form  a  sort  of  her- 
ringbone pattern,  and  are  surrounded  everywhere  in  the  same  meshes  by  loose  white 
fibrous  tissue. 

There  is  a  vague  outer  condensation  of  the  elastic  fibres  which  might  be  called  the 
external  elastic  lamella,  but  at  the  inner  margin  of  the  media  there  is  a  continuous  mem- 
brane, uninterrupted  except  for  certain  fenestrations,  which  would  correspond  to  the 
sheet  of  paper  in  the  model— the  internal  elastic  lamella.  It  is  difficult  to  decide  whether 
this  should  be  taken  as  part  of  the  media  or  part  of  the  intima,  but  it  is  more  convenient 
to  consider  it  with  the  latter.  Blood-vessels,  the  vasa  vasorum,  springing  from  the 
roots  of  the  intercostal  arteries,  etc.,  penetrate  the  adventitia  and  extend  part  way 
through  the  media. 

The  intima  of  the  aorta,  which  in  very  early  life  seems  to  show  little  but  the  endothe- 
lial layer  resting  upon  the  internal  elastic  lamella,  develops  in  later  life  a  much  more 
complex  structure.  Just  inside  the  internal  elastic  lamella  there  is  a  layer  composed 
partly  of  smooth  muscle  running  longitudinally,  and  partly  of  fibres  and  lamellae  of 
elastic  tissue  which  are  abundantly  connected  with  the  fenestrated  membrane.  This 
is  the  musculo-elastic  layer  inside  which  a  second  layer  may  generally  be  distinguished, 

335 


336  TEXT-BOOK  OF  PATHOLOGY 

composed  of  similar  elastic  structures  intermingled  with  white  fibrous  connective  tissue. 
Within  this  is  a  third  layer  immediately  beneath  the  endothelium,  which  is  made  up  of 
connective  tissue  alone,  the  cells  of  which  show  beautiful  branching  processes.  Although 
with  the  advance  of  age  the  intima  thus  becomes  progressively  thicker  (Jores),  it  is 
normally  a  very  thin  layer  as  compared  with  the  media. 

The  branches  of  the  aorta  and  smaller  vessels  differ  from  this  in  their  structure, 
especially  in  that  the  elastic  tissue  of  the  media  is  far  less  abundant,  so  that  the  smooth 
muscle  becomes  the  predominant  element  of  that  layer.  The  elastic  tissue  is  for  the 
most  part  concentrated  in  a  layer  between  the  muscular  media  and  the  adventitia,  where 
it  forms  an  exaggerated  external  elastic  lamella.  The  radial  fibres  of  Dtirck,  which  run 
irregularly  from  the  internal  elastic  lamella  to  this  outer  layer,  are  more  clearly  seen  in 
the  arteries  of  medium  size  than  in  the  aorta.  They  can  be  stained  by  special  methods, 
and  probably  differ  somewhat  from  the  elastic  fibres  proper.  They  act  apparently  as 
dilators  of  the  vessel. 

In  the  smaller  arteries  the  intima  becomes  simplified  until  finally,  in  the  very  small 
vessels,  the  endothelium  lies  almost  directly  upon  the  internal  elastic  lamella.  Never- 
theless, in  many  small  arteries,  especially  in  such  organs  as  the  kidney,  stomach,  etc., 
the  internal  elastic  lamella  splits  in  the  third  decade  into  three  or  four  concentric  layers, 
between  which  are  connective-tissue  elements.  It  will  be  seen  that  much  attention  has 
been  devoted  to  this  reduplication  of  the  elastic  lamellae  in  the  discussion  of  arterio- 
sclerosis. In  accord  with  these  differences  in  structure  between  the  aorta  and  smaller 
vessels  we  may  expect  differences  in  their  pathological  alterations. 

Arteriosclerosis  is  the  term  in  most  general  use  for  that  disease  of  the 
arteries  which  leads  to  their  loss  of  elasticity,  and  changes  in  the  appear- 
ance and  structure  of  the  intima  and  other  coats  which  lead  to  dilatation 
and  deformity  of  the  artery.  The  condition  is  sometimes  spoken  of  as 
atheroma  of  the  arteries,  and  there  is  much  in  favor  of  the  name  athero- 
sclerosis, suggested  by  Marchand,  but  the  old  term,  endarteritis  deformans, 
of  Virchow,  is  now  but  little  used. 

We  may  consider  in  turn:  Arteriosclerosis  (properly  so  called),  syphilitic 
arteritis,  endarteritis  obliterans,  although  doubtless  this  list  is  far  from 
exhausting  the  list  of  related  vascular  changes. 


ARTERIOSCLEROSIS  PROPER 

The  earliest  changes  recognizable  in  the  aorta  as  the  beginning  of  arterio- 
sclerosis are  found  in  the  form  of  very  slightly  elevated,  flattened  yellow 
streaks,  which  usually  run  on  the  posterior  wall  of  the  vessel,  longitudinally, 
between  and  about  the  openings  of  the  intercostal  arteries,  although  they 
are  not  by  any  means  confined  to  this  position  (Fig.  165).  With  further 
advance  of  the  disease  these  yellow  patches  are  to  be  found  diffusely  dis- 
tributed among  the  older  lesions.  Sections  passing  through  them  show 
that,  while  the  artery  is  normal  elsewhere,  the  elevation  is  due  to  a  distinct 
thickening  of  the  intima  produced  by  a  new  formation  of  connective  tissue, 
with  small  and  large  wandering  cells  (Fig.  166) .  Both  the  original  branched 
connective-tissue  cells  and  the  wandering  cells  are  found  to  be  loaded  with 
fat.  Such  fat  is  by  no  means  lodged  only  in  the  deeper  layers  of  the  in- 
tima, but  extends  up  to  the  surface,  where  the  fat-laden  wandering  cells 


ARTERIOSCLEROSIS    PROPER 


337 


Fig.  165. — Fatty  streaks  and  patches  in  the  intima  of  the  aorta. 


Fig.  166.— Section  through  a  fatty  streak  in  the  aorta.     (The  fat  is  stained  red  with 

sudan.) 


338 


TEXT-BOOK  OF  PATHOLOGY 


lie  free  in  crevices.  If  the  upper  layer  of  the  intima  be  stripped  off  and 
laid  flat  under  the  microscope,  the  branched  connective-tissue  cells  with 
their  fine  fat-droplets  can  be  well  seen. 

In  a  later  stage  the  hillock  of  thickened  intima  becomes  more  extensive 
and  thicker,  and  the  tissue  becomes  hyaline  or  necrotic  about  the  most 
abundant  accumulation  of  fat.  The  superficial  or  innermost  layers  be- 
come very  much  thickened,  and  are  now  composed  of  a  dense,  homogeneous 
connective  tissue  (Fig.  167).  Rarely  do  the  vasa  vasorum  penetrate  from 


Fig.  167. — Margin  of  a  relatively  fresh  arteriosclerotic  plaque. 

the  media  to  take  part  in  this  new  formation  of  tissue,  and  generally  they 
can  be  found  only  in  the  later  stages,  although  it  is  stated  that  injections 
reveal  an  increased  richness  in  the  vascular  supply  about  the  patches  of 
disease.  Nor  is  there  any  invasion  of  wandering  cells  at  all  commensurate 
with  the  new  formation  of  tissue.  The  dense  connective  tissue  formed 
over  the  mass  of  fat  containing  tissue  is  bluish  white  and  translucent.  It 
covers  the  yellow,  opaque,  fatty  material,  so  that  it  now  appears  to  lie  in 
the  depths  of  the  intima,  encroaching  on  the  musculo-elastic  layer  and  the 


ARTERIOSCLEROSIS   PROPER 


339 


internal  elastic  lamella.  When  such  an  aorta  is  opened,  the  most  common 
and  characteristic  appearance  of  arteriosclerosis  is  revealed  (Fig.  168). 
Elevated  rounded  or  irregular  plaques  or  patches  stand  up  from  the  intimal 
surface  like  solidified  drops  of  paraffin.  They  are  often  about  the  orifices 
of  the  intercostal  arteries,  but  may  occur  anywhere.  They  seem  hard  and 
homogeneous,  but  on  cutting  through  them  there  is  always  to  be  found  the 
mass  of  opaque,  yellow,  fatty  material  hidden  in  their  depths.  From  the 
cut  edge  this  yellow  mass  can  be  expressed  or  dug  out,  and  its  soft,  mushy 
character  was  the  origin  of  the  name  atheroma.  Often  the  fat  extends 
so  as  to  form  a  yellow  halo  about  such  a 
plaque,  the  opaque  material  shining  through 
the  relatively  thin  surrounding  intima. 

At  this  stage  the  internal  elastic  lamella 
underlying  the  plaque  generally  shows  frag- 
mentation or  interruptions,  or  it  is  frayed 
out  into  several  thin  laminae  which  again 
unite  at  the  other  edge  of  the  plaque.  This 
is  best  seen  in  the  smaller  arteries  (Fig.  169), 
but  is  visible  also  in  the  aorta,  and  is  re- 
garded by  Jores  as  the  most  characteristic 
feature  of  true  arteriosclerosis.  Usually  the 
longitudinal  muscle-fibers  of  the  musculo- 
elastic  layer  are  involved  in  the  necrosis  in 
the  depths  of  the  plaque,  and  in  great  part 
destroyed.  Delicate  elastic  fibrils  appear 
in  the  new  tissue  which  forms  inside  the 
musculo-elastic  layer,  and  are  thought  by 
Jores  to  arise  independently  of  the  lamella? 
of  that  layer.  They  are,  he  thinks,  more 
characteristic  of  such  changes  as  occur  in 
the  obliteration  of  vessels  in  inflammatory 
processes  or  in  the  organization  of  thrombi 
than  of  the  true  arteriosclerotic  changes. 

The  media  under  the  plaque,  which,  for 
the  sake  of  the  various  theories  which  have 
been  put  forward,  has  been  studied  with 

especial  care,  generally  shows  surprisingly  slight  alterations.  Very  definite 
thick  plaques  may  form  in  the  intima,  while  the  underlying  media  seems 
practically  intact,  although  we  realize,  of  course,  that  ordinary  staining 
methods  may  well  fail  to  reveal  qualitative  changes  in  the  elasticity  of  the 
elastic  tissue  or  the  contractility  of  the  muscle.  Nevertheless,  there  are  often 
slight  accumulations  of  kfat  in  that  layer,  and  it  is  generally  thinner  under 
the  plaques  than  in  neighboring  regions.  Indeed,  such  thinning  out  may, 
especially  in  the  smaller  vessels,  proceed  almost  to  the  complete  disappear- 
ance of  the  coat,  leaving  us  to  determine  whether  this  is  the  primary  injury 


168. — Arteriosclerotic  plaques 
in  the  aorta  about  the  intercos- 
tal arteries. 


340 


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to  the  vessel-wall  which  is  compensated  for  by  the  formation  of  the  plaque, 
or  the  result  of  pressure  from  the  plaque  itself.  Again,  we  have  to  deter- 
mine whether  the  necrosis  which  occurs  in  the  substance  of  the  plaque  is 
due  to  malnutrition  of  the  central  part  of  that  mass  of  tissue  or  to  primary 
injurious  processes  affecting  the  newly  forming  tissue.  The  time-honored 
explanation  has  been  that  nutrition  from  the  vasa  vasorum  on  the  one 
side,  and  from  the  blood  in  the  main  vessel,  on  the  other,  kept  alive  the 
outermost  and  innermost  layers  of  the  plaque,  while  allowing  the  centre  to 


Fig.  169.— Sclerotic  plaque  in  the  mesenteric  artery,  showing  reduplication  of  elastic 
lamellae.     Lipoid  substances  are  stained  red  with  sudan. 

perish  (Fig.  170).  At  any  rate,  the  central  mass  often  becomes  very  soft, 
so  that  if  the  inner  wall  or  roof  of  this  sac  gives  way,  the  contents  are 
washed  out  into  the  blood-stream  and  the  ragged  edges  and  base  of  such 
an  "atheromatous  ulcer"  are  exposed  to  the  circulating  blood,  often  with 
the  result  that  a  thrombus  forms  in  that  situation. 

The  soft  material  is  found  to  be  rich  in  crystals  of  cholesterine  as  well  as 
globules  of  fat,  some  of  which  are  evidently  cholesterine  esters,  since  they 


ARTERIOSCLEROSIS    PROPER 


341 


fill 


Fig.  170. — Section  of  an  older  sclerotic 
plaque  in  the  aorta,  showing  cholesterine 
crystals  in  the  necrotic  atheromatous  sub- 
stance. 


Fig.  171. — Late  stage  in  arterioscle- 
rosis of  the  aorta:  ulceration  and  cal- 
cification. 


342  TEXT-BOOK  OF  PATHOLOGY 

are  doubly  refractive,  while  others  are  neutral  fats.  Granules  or  little 
spherules  or  larger,  irregular  masses  of  calcium  and  magnesium  phosphates 
also  appear,  and,  indeed,  the  deposit  of  calcium  salts  may  be  so  great  that 
the  whole  plaque  becomes  converted  into  a  solid  plate  of  stony  material 
which  will  crack  with  a  dry  snap,  like  a  scale  of  oyster-shell  (Fig.  171). 
Such  plates  correspond,  of  course,  fairly  well  with  the  contour  of  the  artery, 
although  they  project  awkwardly  when  the  vessel  is  laid  open.  Usually 
they  are  smoothly  covered  with  a  delicate  layer  of  intimal  tissue  and  en- 
dothelium;  otherwise  they  form  a  base  for  the  deposit  of  thrombi.  Actual 


Fig.  172. — Calcified  plaque  in  arterial  wall  with  bone  and  bone-marrow  formation, 

bone  formation  may  occur,  with  marrow  cavity  and  marrow  rich  in  cells,, 
either  in  calcined  plaques  in  the  vessel- wall  or  in  old  calcined  thrombi  which 
adhere  to  it  (Fig.  172). 

The  sequence  of  events  which  leads  to  the  presence  of  crystals  of  cholesterine,  granules 
and  masses  of  calcium,  etc.,  has  been  explained  by  Klotz  and  others  as  follows:  Glycerin 
and  cholesterine  esters  are  deposited  in  the  tissue  of  the  plaque,  but  readily  split  up  and 
become  saponified,  with  liberation  of  the  soluble  glycerin  and  crystalline  cholesterine. 
Of  the  soaps  formed,  with  the  resultant  fatty  acids,  calcium  soaps  are  insoluble,  and 
remain  where  they  are  formed  until  the  advent  of  phosphates  in  the  circulating  fluids, 
whereby  another  reaction  occurs  which  leaves  the  calcium  in  the  form  of  hard  calcium, 
phosphate. 


ARTERIOSCLEROSIS    PROPER 


343 


It  must  be  obvious,  from  this  description,  that  since  all  these  stages 
may  and  frequently  do  occur  at  one  time  in  the  same  aorta,  the  most 
variegated  appearance  is  produced.  Smooth,  rounded,  gray  eminences 
scattered  along  the  aorta,  and  especially  about  the  orifices  of  the  intercostal 
and  other  arteries,  are  interspersed  with  irregular  yellow  patches  of  stain- 
ing of  the  relatively  unthickened  intima,  while  atheromatous  ulcers  and 


.. 
KS^     ^ 


Fig.  173. — Arteriosclerosis  of  the  renal  artery  showing  fat-laden  wandering  cells  in  the 

thickened  intima. 

sunken,  calcified  remnants  of  former  atheromatous  plaques  occur  side  by 
side  with  them.  Sometimes  the  calcification  is  so  extensive  that  the  aorta 
is  converted  into  a  rigid  tube. 

In  all  cases  there  is  very  great  diminution  of  the  elasticity  of  the  artery 
wall,  although  its  rigidity  may  be  increased.  Usually  the  aorta  in  ad- 
vanced sclerosis  is  dilated  and  lengthened  so  that  it  curves  from  one  side 
of  the  vertebral  column  to  the  other,  and  bulges  irregularly  at  different 


344 


TEXT-BOOK  OF  PATHOLOGY 


points.     Distension  of  such  an  artery  reveals  the  rigidity  and  inelas- 
ticity of  the  affected  parts  of  the  wall,  while  other  places  may  still  be  quite 

elastic. 

Exactly  the  same  processes  in  the  same  sequence  are  found  in  the 
branches  of  the  aorta  (Figs.  173,  175).  In  these  branches,  in  comparison 
with  the  calibre  of  the  vessel,  the  intimal  plaques  may  be  far  thicker,  so  that 
they  go  far  toward  obstructing  the  channel.  It  is  by  no  means  rare  that 
the  lumen  of  such  an  artery  as  the  superior  mesenteric  or  the  splenic  is 
reduced  to  a  mere  slit  for  a  short  way  as  it  passes  the  projecting  mass. 


. 


Fig.  174. — Lower  layer  of  the  intima  from  Fig.  173,  showing  the  musculo-elastic  layer 
(a)  and  the  fat-holding  wandering  cells  in  crevices  (6). 


A  cross-section  at  such  a  point  reveals  the  misshapen  lumen  crowded  over 
to  one  side  of  the  artery,  and  bounded  on  one  side  by  the  normal  wall  of  the 
vessel,  with  its  wavy  internal  elastic  lamella,  on  the  other  by  a  great  mass 
of  tissue  over  the  outer  side  of  which  the  media  stretches  as  a  thinned-out 
layer  and  the  internal  elastic  lamella  as  a  tense  straight  line.  The  blood- 
pressure  in  the  distal  part  of  such  a  vessel  must  be  greatly  reduced,  and 
yet  one  may  find  a  series  of  plaques  of  this  kind  ranged  along  its  course. 
The  smaller  ramifications  of  the  arteries  in  the  organs  often  show  particu- 
larly well  such  relatively  huge  masses  of  new  tissue  bulging  out  one  wall, 
and  encroaching  greatly  upon  the  lumen.  The  endothelium  accommodates 


ARTERIOSCLEROSIS    PROPER 


345 


itself  to  the  decreased  surface  it  must  cover,  and  is  seen  to  be  intact  until, 
through  its  injury  or  otherwise,  a  thrombus  completes  the  occlusion  of  the 
vessel.  Calcification  of  the  necrotic  and  fatty  plaque  occurs,  exactly  as  in 
the  aorta. 

This  process  may  occur  in  the  arteries  of  the  extremities,  where  it  seems 
to  be  especially  common  in  cases  of  diabetes,  and  may,  by  causing  the 
narrowing  of  the  vessels  and  their  final  occlusion  by  secondary  thrombosis, 


Fig.  175.— Coronary  artery  encroached  upon  by  a  thick  arteriosclerotic  plaque. 

give  rise  to  the  senile  and  diabetic  forms  of  gangrene.  Other  changes  in 
the  peripheral  arteries  are,  however,  often  concerned  in  the  production  of 
gangrene,  and  we  shall  describe  them  later  in  discussing  obliterating  end- 
art  eritis. 

A  special  form  of  sclerosis  of  the  peripheral  arteries  which  gives  them  the 
appearance  of  being  ringed,  like  a  trachea,  with  stony  concretions,  was 
distinguished  by  Monckeberg,  although  known  long  before.  In  this  con- 


346 


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dition,  which  is  found  chiefly  in  the  arteries  of  the  lower  extremities,  the 
lesion  begins  in  the  media,  where  degenerative  and  destructive  changes  in 
the  muscle-cells,  associated  with  the  deposit  of  fat-droplets,  are  followed  by 
calcification,  which  appears  first  in  the  form  of  granules  of  lime  salts,  which 


Fig.  176. — Femoral  artery 
showing  transverse  rings  of 
medial  calcification  (Moncke- 
berg's  sclerosis). 


Fig.  177. — Medial  sclerosis  of  Monckeberg  in  a 
femoral  artery  in  longitudinal  section.  The  calcined 
rings  are  seen  in  cross-section. 


later  become  welded  together  into  irregular  rings  which  may  even  occupy 
the  whole  thickness  of  the  media.  Such  zones,  which  are  often  beaded  by 
further  concretions,  sink  below  the  level  of  the  adjacent  more  normal  intima 
when  the  vessel  is  opened  (Fig.  176).  The  internal  elastic  lamella  is 


ARTERIOSCLEROSIS    PROPER 


347 


stretched  straight  over  them,  as  though  they  had  solidified  while  the  vessel 
was  at  its  maximum  dilatation.  In  many  cases,  however,  they  are  by  no 
means  so  regular,  but  press  through  and  interrupt  and  distort  the  elastic 
lamella  (Figs.  177,  178).  Granulation  tissue  of  a  cellular  sort  arises  to  sur- 
round them,  and  extends  through  the  breaches  in  the  lamella  into  the  region 
of  the  intima.  Sometimes  actual  bone  with  marrow  cavities  and  red  marrow 
forms  in  these  places  by  a  metamorphosis  of  the  calcined  material  through 


Fig.  178.— Monckeberg's  medial  calcification  in  a  peripheral  artery. 

the  production  of  osteoblasts  from  the  granulation  tissue.  The  intima  is 
often,  but  not  always,  thickened  over  the  calcined  rings,  sometimes  with 
great  fraying  out  of  the  internal  elastic  lamella  and  loss  of  the  recognized 
relations,  but  there  is  rather  little  evidence  of  necrosis  or  the  accumulation 
of  fat  in  such  a  thickened  layer.  It  appears  on  section  rather  more  like  a 
granulation  tissue,  and  often  contains  blood-vessels  or  spaces.  This 
comparatively  common  condition  does  not  tend  specially  toward  the 


348  TEXT-BOOK  OF  PATHOLOGY 

obliteration  of  the  vessel,  which  is  rather  dilated  and  lengthened  so  as  to 
fall  into  sinuous  curves,  readily  seen  in  x-ray  photographs  even  through  the 
shadows  of  the  bones. 

Monckeberg  regards  it  as  independent  of  true  arteriosclerosis,  since  it 
differs  from  that  condition  in  the  slight  changes  in  the  intima  and  in  the 
extreme  alterations  of  the  media.  Its  existence  in  the  peripheral  arteries 
does  not  signify  that  there  are  arteriosclerotic  changes  in  the  internal 
arteries  and  aorta.  Nevertheless,  it  is  frequently  combined  with  arterio- 
sclerosis in  the  form  of  extensive  intimal  thickening,  and  it  is  then  difficult 
to  separate  the  two  processes  if,  indeed,  they  are  really  different.  Occa- 
sionally extraordinary  masses  of  new  tissue  may  be  formed  inside  the  in- 
ternal elastic  lamella  in  such  a  way  as  almost  completely  to  block  the 
lumen.  Such  obstructing  tissue,  which  converts  the  artery  into  an  ex- 
tremely" thick-walled  tube  with  pin-point  lumen,  generally  extends  only  a 
short  way,  so  that  the  vessel  opens  out  again  into  a  wide  tube.  Several 
such  strictures  may  be  found  in  a  single  artery,  suggesting  that  they  may 
have  been  due  to  the  organization  of  thrombi  with  secondary  canalization, 
although  they  can  be  equally  well  explained  as  arteriosclerotic  thickenings 
of  the  intima.  Such  changes  commonly  lead  to  great  reduction  of  the 
blood  supply  of  the  extremity  and  gangrene  of  the  toes  or  foot,  and  it 
is  probably  this  type  of  change  which  most  frequently  occurs  in  diabetic  and 
senile  gangrene. 

Pathogenesis  and  Etiology. — We  are  at  present,  in  spite  of  numerous 
theories,  practically  ignorant  of  the  cause  of  arteriosclerosis.  Rokitansky 
thought  the  plaques  deposited  from  the  blood;  Virchow  regarded  the  whole 
process  as  inflammatory,  whence  his  designation,  endarteritis  deformans; 
Koster  also  regarded  it  as  inflammatory,  but  rather  in  Cohnheim's  sense, 
as  an  exudative  process,  because  he  traced  the  formation  of  a  cellular  exu- 
date  in  the  vessel-walls  from  the  vasa  vasorum.  Thoma  elaborated  a 
theory  based  on  the  idea  that  the  cutting-off  of  the  placental  circulation  at 
birth  must  necessitate  an  adaptation  of  the  calibre  of  the  blood-vessels  to 
the  changed  amount  of  blood.  This,  he  thought,  was  effected  by  a  thick- 
ening of  the  intima  of  the  vessels,  especially  those  which  lay  in  the  course 
of  the  old  umbilical  blood-stream.  To  this  process  there,  might  be  com- 
pared the  thickening  of  the  intima  in  arteriosclerosis,  which  evidently 
occurs  at  those  points,  where,  owing  to  some  primary  weakening  of  the 
musculature  of  the  media,  there  arose  a  local  bulging  of  the  vessel-wall. 
In  such  a  bulging  area  the  passing  blood-stream  would  eddy  and  be  re- 
tarded, whence  the  intimal  growth,  which  should  be  just  sufficient  to 
compensate  for  the  bulging-out  of  the  media  and  thereby  reinstate  the 
original  level  of  the  intimal  lining  of  the  vessel.  Naturally,  such  a  patch 
would  be  thrown  into  relief  by  the  elasticity  of  the  arterial  wall  after  it  is 
laid  open.  It  is  evident  that  many  criticisms  of  this  theory  may  be  offered. 

In  general  there  has  prevailed  insistently  the  idea  that  the  changes  in 
the  vessel-wall  are  due  in  some  way  to  heightened  arterial  blood-pressure. 


ARTERIOSCLEROSIS    PROPER  349 

The  favorite  situation  of  the  lesions  in  the  arch  and  about  the  orifices  of 
the  branches  has  been  explained  on  the  ground  that  pressure  relations  at 
those  points  constitute  a  more  severe  test  of  the  strength  of  the  wall  than 
at  other  points  in  the  aorta.  Marchand,  Aschoff,  and  others  look  upon 
arteriosclerosis  as  a  degenerative  process,  brought  about  largely  by  the 
overworking  of  the  vessel-wall,  due  to  heightened  blood-pressure  (sudden 
strains,  Albrecht).  They  see  in  the  connective  tissue  a  substance  more 
rigid  and  less  distensible  than  the  elastic  tissue,  which  at  least  maintains 
the  strength  of  the  wall.  Aschoff  finds  the  weakening  due  to  degenera- 
tive changes  in  the  intima,  with  its  elastic  lamella,  and  not,  as  Thoma 
supposed,  to  primary  changes  in  the  media. 

Jores  described  the  progressive  thickening  of  the  intima  with  the  normal 
advance  of  age,  and  declared  that  such  a  thick  intimal  coat  is  especially 
prone  to  degenerative  changes  which  occur  at  the  level  of  the  musculo- 
elastic  layer.  The  reformation  of  the  elastic  tissue  by  repeated  splitting 
off  of  lamella  from  the  internal  elastic  lamella  is  characteristic  of  true 
arteriosclerosis,  as  contrasted  with  the  obliterative  changes  in  the  vessels 
where  the  elastica  is  formed  in  new,  delicate,  independent  fibrils  in  the 
new  tissue  of  the  intima. 

The  present  state  of  our  knowledge  is  unsatisfying,  but  it  seems  that 
we  are  far  from  having  proved  that  the  heightening  of  blood-pressure  as 
such  has  more  than  a  guiding  influence  upon  the  development  of  the  lesions, 
just  as  the  structure  of  cancellous  bone  and  other  tissues  is  adapted  in 
growth  to  the  strain  put  upon  it.  It  is  true  that  Klotz  claims  to  have  pro- 
duced arteriosclerosis  in  rabbits  by  hanging  them  head  downward  for  a 
long  period,  but  rabbits  are  notoriously  subject  to  spontaneous  arterial 
lesions,  and  Lubarsch  and  others  have  been  unable  to  confirm  his  results. 
Arteriosclerosis  sometimes  occurs  in  the  pulmonary  artery  in  cases  of 
mitral  stenosis,  or  in  the  arch  of  the  aorta  in  cases  of  stenosis  of  the  aorta 
at  the  isthmus,  but  it  is  often  absent  in  these  cases,  and  there  are  other 
explanations  than  the  high  pressure  to  offer  when  it  does  occur.  It  is 
common  in  cases  of  nephritis  when  the  pressure  is  high,  but  there  again  we 
are  unable  to  say  that  it  is  the  high  pressure  per  se  which  is  responsible 
for  the  disease  of  the  arterial  wall,  and  not  some  other  factor  which  may 
have  caused  the  nephritis.  There  are  many  cases  of  arteriosclerosis 
without  high  blood-pressure,  even  though  the  walls  of  the  arteries  may 
be  very  much  altered.  In  these  it  is  clear  that  the  cause  of  the  sclerosis 
must  be  sought  in  some  other  factor. 

It  seems  more  probable  that,  as  the  French  have  so  long  suggested,  ar- 
teriosclerosis is  the  effect  of  some  injurious  or  poisonous  agent  acting 
upon  the  intima  of  the  arteries,  as  it  might  upon  any  other  organ,  with 
destruction,  fat  accumulation,  and  repair.  What  this  agent  may  be  is 
as  yet  uncertain.  Every  sort  of  poisonous  substance  has  been  experi- 
mentally administered  to  animals  either  by  mouth  or  by  injection  into  the 
blood-stream  or  tissues,  but  without  any  very  constant  results.  The 


,350  TEXT-BOOK  OF  PATHOLOGY 

aetiological  factors  commonly  held  responsible,  alcohol,  lead,  nicotine,  etc., 
have  occasionally  given  rise  to  changes  comparable  to  those  of  arteriosclero- 
sis, but  not  constantly — indeed,  with  alcohol  and  lead  the  experiments 
have  generally  proved  negative.  Adrenalin  (Josue  and  others)  will  pro- 
duce medial  lesions  and  calcification,  with  corresponding  intimal  scars  in 
rabbits,  and  various  bacterial  toxins,  especially  those  extracted  from 
staphylococci  (Saltykow),  give  rise  to  changes  even  more  closely  resem- 
bling those  of  arteriosclerosis.  But  so  far  none  of  these  substances  can  be 
set  down  as  the  proved  cause  of  the  condition.  Recent  Russian  observers 
— Chalatow,  Anitschkoff,  etc. — have  found  that  cholesterine  and  its  esters, 
on  being  fed  to  rabbits,  lodge  in  the  intima  of  the  aorta  and  produce  tissue 
proliferation  there,  resembling  those  of  arteriosclerosis.  On  the  other 
hand,  the  idea  asserts  itself  that  since  repeated  anaphylactic  shocks  may 
produce  lesions  in  liver  and  kidneys  (Longcope),  they  may  also  cause 
injuries  to  the  arterial  walls.  All  these  things  are  yet  in  the  experimental 
stage,  but  it  seems  probable  that  long-continued  and  oft-repeated  injuries, 
such  as  might  arise  during  chronic  infections,  chronic  intoxications,  or  in 
sensitive  animals  from  repeated  absorption  of  the  sensitizing  protein, 
may  constitute  the  underlying  cause  of  injury,  which  is  responded  to  by 
reparatory  processes  and  by  an  accumulation  of  fats  and  fatty  acids  which 
may  be  protective. 

LITERATURE 

Anitschkoff:   Ziegler's  Beitrage,  1913,  Ivi,  379. 
Aschoff:   Beihette  z.  med.  Klinik,  1908,  4,  1. 
Faber:  Arteriosklerose,  Jena,  1912. 
Hiibschmann:  Ziegler's  Beitrage,  1906,  xxxix,  119. 
Jores:  Wesen  der  Arteriosklerose,  1908. 
Klotz:  Arteriosclerosis,  Publ.  Univ.  Pittsburgh,  1911. 
Longcope:  Jour.  Exp.  Med.,  1913,  xviii,  678. 
Marchand:  Verb.  d.  XXI.  Cong.  f.  inn.  Med.,  1904. 
Monckeberg:  Virchow's  Arch.,  1903,  clxxi,  141;  1914,  ccxix,  408. 
Saltykow:  Ziegler's  Beitrage,  1908,  xliii,  147. 
Thoma:  Virchow's  Arch.,  xciii,  xcv,  civ,  cv,  cvi,  cxii.  ccxvi. 
Thorel:  Ergebnisse  der  allg.  Path.,  ixx,  xi2,  xiv2. 

SYPHILITIC  ARTERIAL  DISEASE 

For  the  sake  of  convenience,  and  because  of  the  confusion  which  has  existed 
for  so  long  between  syphilitic  disease  of  the  artery  and  true  arteriosclerosis, 
that  condition  may  be  described  here.  Other  infectious  agents  cause 
disease  of  the  vessels  of  a  more  or  less  specific  character,  but  none  lead  to 
such  important  alterations  as  syphilis.  It  affects  the  aorta  as  well  as  the 
smaller  vessels,  and  is  then  apparently  the  commonest  original  cause  of 
insufficiency  of  the  aortic  valves,  as  well  as  aneurysm  formation.  In 
itself,  without  these  ultimate  effects,  it  may  often  be  recognized  during 
life  by  certain  clinical  phenomena,  such  as  the  reflex  respiratory  disturb- 
ances described  by  Longcope. 

Since  its  recognition  by  Doehle  and  Heller,  and  especially  since  the 


SYPHILITIC   ARTERIAL   DISEASE 


351 


papers  of  Chiari  and  Benda,  syphilitic  disease  of  the  aorta  has  come  to  be 
quite  clearly  understood,  because  the  ^tiological  factor,  the  Spirochseta 
pallida,  has  been  found  in  the  lesions,  and  even  made  to  produce  similar 
lesions  in  animals.  Then,  too,  the  anatomical  changes  are  quite  comparable 
with  those  produced  by  syphilis  elsewhere,  and  are  sometimes  distinctly 
gummatous  in  character.  They  are  found  in  all  three  coats  of  the  vessel, 
and  affect  the  vasa  vasorum  as  well.  In  the  adventitia,  and  extending 
into  the  media  or  even  into  the  intima,  there  are  found  around  these  vasa 
vasorum  collections  of  wandering  cells  of  the  character  of  lymphoid  and 
plasma  cells,  sometimes  with  multinucleated  giant-cells.  The  vasa  vaso- 
rum are  often  obliterated  in  this  process.  The  cellular  granulation  tissue 


Fig.  179.— Syphilitic  aortitis.     Gummatous  foci  about  vasa  vasorum  in  the  adventitia 
and  media.     Frequent  breaks  in  the  media. 

may  occupy  considerable  space,  and  may  even  be  evident  on  the  surface 
of  the  artery  as  a  nodular  mass.  Such  are,  clearly  enough,  gummata, 
for  they  tend  to  become  necrotic  in  their  centres  and  present,  in  general, 
the  architecture  of  gummatous  nodules  seen  elsewhere.  Nevertheless,  it 
is  more  common  to  find  mere  collections  of  cells  of  less  characteristic 
arrangement  in  the  adventitia  and  media.  They  often  surround  necrotic 
foci,  or  are  found  side  by  side  with  quite  extensive  necrosis  of  the  media. 
One  sees  sometimes  patches  of  necrotic  media  in  which  the  arrangement 
of  the  elastic  lamellae  and  muscle  is  still  visible,  as  in  an  anaemic  infarction, 
and  about  these  there  forms  the  cellular  granulation  tissue.  Later  such 
necrotic  patches  are  absorbed  and  scarred,  a  process  which  adds  to  the 
distortion  of  the  artery.  If  the  artery  be  examined  at  this  stage,  which  is 


352 


TEXT-BOOK  OF  PATHOLOGY 


the  one  most  commonly  seen  at  autopsy,  the  media  will  be  found  to  be 
interrupted  repeatedly  by  irregular  strands  of  scar  tissue  rich  in  wandering 
cells,  and  when  the  elastic  tissue  alone  is  stained,  one  receives  the  impression 
that  that  layer  is  composed  of  mere  fragments  or  clumps  of  elastic  fibres 
strewn  along  at  intervals.  Such  interruption  of  its  continuity  must  greatly 
weaken  the  aortic  wall,  and  goes  far  to  explain  the  ready  development  of 
aneurysms  on  a  syphilitic  basis.  Over  such  a  tattered  media  the  intima 
is  found  to  have  formed  a  thick,  irregular  layer  of  hyaline  fibrous  tis- 
sue, in  which  there  is  relatively 
little  fat  to  be  found  (Fig.  179). 
Cholesterine  crystals  and  calcium 
deposits  are  equally  rare,  unless, 
of  course,  as  frequently  happens, 
the  syphilitic  disease  is  developed 
in  an  aorta  already  the  seat  of  a 
true  arteriosclerosis.  In  the  syph- 
ilitic intimal  thickenings  the  in- 
ternal elastic  lamella  shows  no 
such  regular  fraying  up  into  ac- 
cessory lamellae  as  is  seen  in 
arteriosclerosis.  It  suffers  whole- 
sale interruptions  and  destruction 
with  the  rest  of  the  elastic  coats. 
The  gross  appearance  of  the 
aorta  is  most  clearly  to  be  under- 
stood on  the  basis  of  these  micro- 
scopical changes.  There  is  a  great 
roughening  of  the  lining,  which  is 
thrown  up  into  irregular  folds  and 
nodular  swellings,  some  translu- 
cent and  pearly,  others  yellowish 
and  opaque  where  there  is  fat  ac- 
cumulation. But  nowhere  is  there 
any  formation  of  calcified  plates 
nor  any  ulceration.  Beginning 
usually  at  the  aortic  orifice,  and 
generally  involving  the  aortic 

valves,  this  change  is  most  commonly  found  in  the  arch  and  extending 
downward  into  the  descending  aorta,  where  it  usually  stops  abruptly  at 
a  point  somewhere  above  the  orifices  of  the  abdominal  vessels.  Rather 
rarely  it  extends  below  these,  and  the  rest  of  the  vessel  is  smooth  and 
elastic,  or  there  is  a  sharply  outlined  patch  in  only  one  part  of  the 
vessel.  The  aortic  valves  are  thickened  and  shortened,  so  that  they 
become  insufficient,  and  the  aortic  ring  is  widened,  intensifying  the  in- 
competence of  the  valves.  A  further  characteristic  of  the  appearance  of  the 


Fig.   180. — Gross  appearance   of   syphilitic 
aortitis. 


OBLITERATIVE  ENDARTERITIS — THROMBOANGEITIS  OBLITERANS  353 

intima  is  its  peculiar  wrinkling.  It  is  thrown  into  longitudinal  rugae, 
quite  unlike  anything  seen  in  arteriosclerosis  (Fig.  180).  Thinned  out  and 
scarred  areas  are  frequently  seen  in  the  walls,  and  dilatations  of  all  sorts, 
from  small  saccules  to  aneurysms  of  the  hugest  size,  may  accompany  the 
later  stages  of  the  disease.  The  orifices  of  the  intercostal  vessels  may  be 
partly  occluded,  and  even  the  carotids  may  be  narrowed  at  their  mouths. 
This  encroachment  on  the  lumen  of  the  branches  of  the  aorta  is  most 
important  in  the  case  of  the  coronary  vessels,  which  may  be  constricted 
at  their  origin  to  a  very  small  calibre,  since  it  seems  probable  that  it  is 
in  some  cases  responsible  for  the  symptoms  of  angina  pectoris. 

In  the  smaller  arteries  and  veins,  such  as  those  of  the  meninges,  syphilis 
causes  changes  which  are  much  like  those  produced  by  tuberculosis,  in  that 
minute  gummata  are  formed  in  the  walls,  growing  in  the  adventitia  and 
intima,  and  destroying  the  intervening  media  in  such  a  way  as  to  produce 
an  excentrically  placed  nodule,  which  greatly  narrows  the  lumen  and  ap- 
pears as  a  little  pearly  lump  in  the  course  of  the  vessel  (Heubner,  Nonne, 
Verse,  Goldsborough) .  Such  lesions  of  the  meningeal  vessels  are  usually 
accompanied  by  a  definite  cellular  meningitis,  similar  to  that  caused  by 
tuberculosis,  and  in  which  the  wandering  cells  are  predominantly  of  the 
mononuclear  types.  The  most  varied  clinical  symptoms  result,  as  one 
may  read  in  the  monograph  of  Nonne. 

LITERATURE 

Benda:    Handb.  d.  Geschlechtskrankh.,  1913,  iii. 
Chiari,  Benda:   Verb.  Dtsch.  path.  Gesellsch.,  1904,  vi,  137,  164. 
Dohle:   Dtsch.  Arch.  f.  klin.  Med.,  1895,  Iv,  190. 
Goldsborough:  Johns  Hopkins  Hosp.  Bull.,  1902,  xiii,  105. 
Gruber:  Doehle-Heller'sche  Aortitis,  Jena,  1914. 
Longcope:  Arch.  Int.  Med.,  1913,  xi,  14. 

Nonne:  Syphilis  und  Nervensystem,  1902;   second  edition,  translated  by  Ball,  1913. 
Verse:  Ziegler's  Beitrage,  1913,  Ivi,  580. 
Wright  and  Richardson:  Publ.  Massachusetts  Gen.  Hosp.,  1909,  ii,  395. 

OBLITERATIVE  ENDARTERITIS— THROMBOANGEITIS  OBLITERANS 

It  has  been  pointed  out  that  typical  arteriosclerotic  thickening  of  the  intima 
may  narrow  or  almost  obliterate  small  arteries  in  some  cases,  and  that 
calcification  of  the  media,  often  associated  with  such  internal  changes,  may 
also  do  this.  There  are  still  other  physiological  and  pathological  methods 
of  occlusion  which  are  especially  important  in  the  small  vessels  when  the 
mechanics  of  the  circulation  or  the  protection  of  the  body  requires  their 
obliteration.  In  the  embryo  one  channel  survives  in  a  plexus  of  vessels 
because  the  others  are  closed  by  the  mere  adhesion  of  their  walls  when  blood 
is  no  longer  forced  through.  When  the  course  of  the  circulation  changes,  as 
it  does  after  birth  with  the  enlargement  bf  the  pulmonary  stream-bed,  the 
old  channel  through  the  ductus  arteriosus  is  gradually  closed  by  a  growth 
of  the  intimal  tissue  which  narrows  the  lumen.  This  method  is  probably 
the  one  used  in  the  slow  obliteration  of  the  blood-vessels  in  the  atrophy  of 
24 


354 


TEXT-BOOK  OF  PATHOLOGY 


such  organs  as  the  breast,  uterus,  and  ovaries  in  which,  after  sexual  activity 
is  over  the  blood  supply  is  diminished.  Nevertheless  in  these  vessels  calci- 
fication of  the  media  is  frequently  seen  (Fig.  181).  In  other  situations 
chronic  inflammatory  processes  throughout  the  tissue  are  accompanied  by 
a  gradual  occlusion  of  the  small  blood-vessels  by  a  slow  thickening  of  their 
intima  by  the  new  formation  of  connective-tissue  cells  beneath  the  endo- 
thelium.  It  is  difficult  to  draw  a  sharp  line  between  the  narrowing  of 
vessels  because  of  the  lack  of  an  adequate  blood-stream,  and  this  effect  of 


Fig.  181. — Wall  of  senile  uterus:    obliterative  endarteritis  with  calcification. 

surrounding  injury  and  inflammation.  Such  " obliterating  endarteritis" 
is  common  in  the  shrunken  kidney  of  chronic  nephritis,  in  indurative  affec- 
tions of  the  lungs  and  other  organs  caused  by  tuberculosis  and  syphilis, 
in  some  tumors,  and  in  a  host  of  other  sites  of  protracted  injury  and  irrita- 
tion. Sometimes,  as  in  the  advance  of  a  tuberculous  cavity  or  in  the  wall 
of  a  gastric  ulcer,  the  closure  of  an  artery  which  is  being  encroached  upon 
may  be  a  life-saving  event.  It  £  only  when  the  excavation  proceeds  too 
rapidly  and  surprises  the  vessel  that  great  haemorrhages  occur  in  chronic 
phthisis. 


OBLITERATIVE  ENDARTERITIS — THROMBOANGEITIS  OBLITERANS  355 

The  plugging  of  a  vessel  by  a  clot  or  thrombus  often  has  a  protective  significance  in 
that  it  abruptly  obstructs  the  flow  of  blood.  It  is  the  natural  method  of  stanching 
haemorrhage,  and  although  it  may  be  ineffectual  when  a  large  vessel  is  cut,  it  successfully 
closes  the  torn  ends  of  the  small  ones.  When  a  vessel  is  ligated,  a  clot  forms  at  the  point 
of  the  ligation  and  extends  to  the  next  branch,  where  the  blood-stream  is  still  active. 
If  the  wall  of  the  vessel  is  injured,  the  stream  may  continue  until  the  lumen  is  filled  by 
the  clot  which  forms  on  the  walls.  Since  this  is  formed  in  the  moving  blood  it  will  have 
the  character  of  a  thrombus.  When  a  vessel  is  obstructed  at  a  point  by  a  thrombus  so 
that  the  lumen  is  open  on  each  side,  efforts  are  made  to  reestablish  the  circulation.  The 
thrombus  is  "  organized"  by  the  springing  up  of  capillaries  and  connective  tissue  from  the 
vessel-wall  which  replace  it  with  a  vascular  granulation  tissue.  Crevices  in  its  substance 
are  lined  with  endothelium  and  constitute  new  blood  spaces.  The  dilatation  and 
anastomosis  of  these  new  vessels  and  blood  spaces  may  produce  new  channels  which  will 
again  carry  blood  through  the  obstructed  area.  They  are  in  time  supplied  with  muscular 
and  elastic  coats  like  those  of  any  other  vessel  (Fig.  182) .  A  vessel  thus  reinstated  seems 
like  an  elastic*  cord,  but  from  its  cut  end  many  fine  streams  of  blood  spurt. 


Fig.  182. — Vein  with  old  thrombotic  occlusion  recanalized  by  new  blood-channels. 

Thrombotic  occlusion  with  organization  appears  to  play  a  prominent  part 
in  another  form  of  obliterating  endarteritis  which  occurs  in  the  arteries  of 
the  extremities.  Von  Winiwarter  described  the  obliteration  as  due  to  pro- 
liferation of  soft  tissue  from  the  intimal  coat,  while  Zoege  von  Manteuffel 
and  Weiss  thought  it  essentially  the  result  of  thrombosis  with  organization. 

Apparently  both  processes  can  occur,  and  in  the  end-result  it  is  difficult 
to  determine  exactly  how  the  obliteration  occurred,  although  it  is  easy  to 
distinguish  these  obliterated  vessels  from  those  which  have  been  obstructed 
by  arteriosclerotic  thickenings  of  their  walls.  This  can  be  made  clear  by 
describing  the  process  as  it  affects  the  peripheral  arteries. 

In  some  cases  in  relatively  young  people,  and  principally  in  Russian 
Hebrews,  serious  symptoms  arise  without  any  warning,  beginning  with 
coldness  and  pallor  of  the  extremities,  pain  and  peculiar  tickling  or  burning 
sensations,  inability  to  walk  more  than  a  short  way  without  rest,  and 


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finally  gangrene  of  the  toes  or  of  the  whole  foot  or  leg.  The  inability 
to  walk,  which  is  called  intermittent  claudication,  is  explained  by  the  fact 
that  the  arteries  of  the  extremities  are  practically  pulseless,  and  converted 
into  a  firm  cord,  so  that  not  enough  blood  reaches  the  muscles  to  allow 
them  to  contract  properly. 

In  these  cases  z-ray  pictures  show  no  shadow  of  the  vessels  whatever, 
and,  indeed,  they  are  usually  found  not  to  be  calcified.     On  section,  too 


sws 

V    VK,^ 

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Fig.  183. — Obliterating  endarteritis  (thrombo-arteritis  obliterans)  with  shrinkage  of  the 
walls  and  partial  recanalization. 

(Fig.  183),  they  present  an  extraordinary  contrast  to  those  found  in  senile 
and  diabetic  gangrene,  inasmuch  as  there  is  little  or  no  change  in  the  media, 
although  it  and  the  adventitia  and  surrounding  tissue  may  be  infiltrated 
with  wandering  cells  and  indurated  by  the  new-growth  of  fibrous  tissue. 
Nor  is  the  internal  elastic  lamella  stretched,  distorted,  and  frayed  out,  as  in 
that  more  truly  arteriosclerotic  process.  Instead,  it  maintains  its  normal 


ANEURYSMS  357 

wavy  contour  around  the  lumen  of  the  vessel.  But  the  lumen  is  filled  with 
vascular  granulation  tissue,  sometimes  with  endothelium-lined  spaces, 
through  which  a  little  blood  may  flow. 

In  this  case,  too,  there  is  a  question  as  to  whether  the  obliteration  is  due 
to  a  growth  of  tissue  from  the  intima  or  to  the  organization  of  a  thrombus, 
but  thrombi  are  so  generally  present  in  all  stages  that  Burger  concludes 
definitely  that  it  must  be  named  thromboangeitis  obliterans.  The  ob- 
struction is  generally  accompanied  by  the  formation  of  adhesions  between 
the  vessel  and  the  surrounding  tissue,  and  although  no  definite  ideas  as 
to  its  causation  are  to  be  found  in  the  literature,  it  seems  probable  that 
it  is  of  infectious  or  toxic  nature. 

LITERATURE 

Burger:   Amer.  Jour.  Med.  Sci.,  1908,  cxxxvi,  567. 
Von  Winiwarter:   Arch.  f.  klin.  Chir.,  1878,  xxiii,  202. 
Weiss:   Dtsch.  Zeitschr.  f.  Chir.,  1894,  xl,  1. 
Zoege  von  Manteuffel:   Arch.  f.  klin.  Chir.,  1898,  xlvii,  461. 

ANEURYSMS 

A  difficulty  has  always  existed  in  deciding  exactly  what  constitutes  an 
aneurysm,  since  there  are  so  many  different  forms  of  enlargement  of  the 
artery  and  cavities  in  connection  with  arteries  which  might  fall  under  this 
name.  There  has  long  been  a  distinction  between  true  aneurysms,  in 
which  the  cavity  was  supposed  to  be  formed  by  the  stretching  of  the  wall 
of  the  artery  itself,  and  spurious  aneurysms,  in  which  rupture  of  the  artery 
wall  opened  its  lumen  into  a  blood-filled  cavity  formed  in  the  tissue  outside. 
But  since  it  has  been  shown  that  in  all  cases  the  wall  of  the  sac  is  formed 
of  tissue  of  a  character  very  different  from  that  of  the  normal  arterial  wall, 
this  distinction  is  anatomically  no  longer  so  valid,  although  naturally  the 
conditions  set  up  in  these  ways  are  in  principle  very  different.  Benda  has 
tried  to  cut  this  knot  by  saying  that  an  aneurysm  is  any  pathological 
widening  of  the  arterial  lumen  caused  by  change  in  its  walls,  which  for  a 
time,  at  least,  stands  in  open  communication  with  its  blood-stream. 

The  most  common  aneurysms  are  saccular  widenings  of  the  artery, 
opening  out  from  its  regular  channel  by  a  wide  or  narrow  orifice,  but  the 
opening  may  be  so  wide,  and  the  distension  so  shallow,  that  the  saccular 
form  is  lost,  and  if,  as  sometimes  happens,  the  widening  occupies  the  whole 
circumference  of  the  artery,  we  have  a  fusiform  aneurysm  or  aneurysmal 
dilatation.  Aneurysms  of  these  types  occur  in  diseased  arteries  in  many 
situations.  They  are  most  common  in  the  aorta,  especially  in  the  region 
of  the  arch,  but  may  arise  in  any  part  of  its  course  or  in  any  of  the  smaller 
arteries— even  in  those  which  lie  embedded  in  the  substance  of  an  organ. 

Generally  classed  with  aneurysms  are  certain  peculiar  widenings  and 
enlargements  of  the  blood-vessels,  which  also  increase  their  length  so  that 
in  a  given  area  a  whole  mass  of  wide,  tortuous,  and  tangled,  pulsating 


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vessels  is  found  (cirsoid  or  racemose  aneurysm).     One  is  inclined  to  suspect 

that  this  rare  form  may  be  of  a 
nature  more  allied  to  that  of  angi- 
omatous  tumors,  and  distinct  from 
ordinary  aneurysms. 

Dissecting  aneurysms  are  produced 
by  the  rupture  or  tearing  of  the  inner 
coats  of  the  artery — usually  the  in- 
tima  and  half  of  the  media,  and  the 
extravasation  of  the  blood  into  a 
cavity  which  it  makes  for  itself  by 
burrowing  into  the  wall  of  the 
artery.  In  sclerotic  arteries  it  is 
easy  to  split  the  wall  in  this  way, 
and  the  blood  may  work  its  way 
down  the  whole  length  of  the  aorta 
and  along  many  branches,  convert- 
ing each  partly  or  completely  into 
two  tubes,  one  within  the  other, 
and  separated  by  the  extravasated 
blood  (Fig.  184).  After  this  the 
blood  may  break  through  the  outer 
tube  and  accumulate  somewhere  in 
the  tissues,  or  again  through  the 
inner  tube,  thus  reentering  the 
regular  circulation.  Except  in  the 
last  case  the  whole  process  is  really 
merely  the  formation  of  a  hemor- 
rhage or  hsematom'a  in  the  artery 

/IfV^S  wall,  but  it  sometimes  happens — 

\  and  I   have  seen  one  case* — that 

,  ^\  when  the   rupture    back   into  the 

lumen  of  the  vessel  takes  place,  the 
extravasated  blood  actually  circu- 
lates, and  the  space  in  the  wall  be- 
comes lined  by  endot helium,  so  that 
something  like  a  double  aorta  is 
produced  (Fig.  185). 

Arteriovenous  Aneurysm. — Occa- 
sionally when  a  stab  wound  or  the 
wound  produced  in  venesection 

Fig.  184. — Dissecting  aneurysm  of 
aorta  splitting  the  arterial  wall  far  into 
the  branches.  A  haematoma  near  the  bi- 
furcation of  the  aorta. 


*MacCallum:     Johns    Hopkins    Hosp. 
Bull.,  1909,  xx,  9. 


ANEURYSMS 


359 


side,  a  hsematoma  or  massive  extravasation  of  blood  into  the  tissue  appears, 
and  later  retains  its  communication  with  both  vessels,  so  that  the  blood 


Fig.   185.— Old  dissecting  aneurysm  which  has  ruptured  again  into  the  aorta  and 
established  a  double  aortic  channel. 


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circulates  through  it  from  the  artery  into  the  vein.    Such  a  cavity  forms  a 
dense,  fibrous  wall  for  itself,  and  the  communication  is  permanent.     In  a 


A,  f  emo  rali.5 
V.   femora  its 


Fig.  186 .— Arterio venous  aneurysm  caused  by  a  stab  wound  of  the  femoral   artery 

and  vein. 


case  seen  in  Baltimore  the  femoral  artery  and  vein  communicated  in  this 
way  through  a  great  sac.     There  was  a  loud,  humming  murmur,  and  a 


ANEURYSMS  361 

thrill  over  this  sac,  and  the  pressure  of  the  arterial  blood  into  the  vein 
prevented  the  return  of  the  venous  blood  from  the  leg.  On  the  shin  of  that 
leg  there  were  great  varicose  veins,  and  a  persistent  varicose  ulcer,  quite 
like  those  seen  in  old  people,  although  the  other  leg  of  this  boy  was  per- 
fectly normal. 

In  other  cases,  the  so-called  false  aneurysms,  the  artery  alone  is  ruptured, 
and  the  hsematoma  becoming  encapsulated,  remains  in  open  communica- 
tion with  the  blood-stream,  being  constantly  washed  out  by  an  eddy  of 
blood. 

Of  all  these,  it  is  evident  that  the  most  important  and  interesting  form 
is  that  which  develops  through  disease  of  the  arterial  wall  by  a  gradual 
bulging  out  of  some  portion  into  a  sac,  or  widening  of  other  form.  As  to 
the  aetiology,  we  are  even  yet  insufficiently  informed,  although  the  work  of 
Doehle,  Heller,  Benda,  Chiari,  and  others  on  syphilitic  aortitis  has  thrown 
much  light  on  it.  There  is  great  diversity  of  opinion  as  to  the  part  played 
by  syphilis,  for  although  Heller  found  85  per  cent,  of  aneurysms  to  be  due 
to  syphilis,  Braun,  in  a  very  large  collection,  found  only  17  per  cent. 
Marchand,  too,  finds  the  percentage  of  proved  syphilis  rather  low.  Never- 
theless, the  character  of  the  syphilitic  disease  of  the  arterial  wall,  which  is 
so  preeminently  calculated  to  weaken  it  in  the  presence  of  a  strong  blood- 
pressure,  makes  it  seem  probable  that  more  accurate  methods  of  investiga- 
tion will  show  the  participation  of  that  disease  in  a  very  large  proportion  of 
the  cases,  if  not  in  all.  But  at  present  many  of  them  seem  to  be  associated 
only  with  the  ordinary  type  of  arteriosclerosis. 

Of  course,  it  must  be  remembered,  however,  that  encroachment  of  destructive 
tuberculous  processes  may  weaken  the  outer  wall  of  an  artery  and  allow  the  production 
of  a  small  aneurysm,  just  as  the  advance  of  a  gastric  ulcer  toward  such  an  artery  as  the 
splenic  may  allow  it  to  bulge  and  finally  rupture  in  the  base  of  the  ulcer.  So,  too, 
emboli  of  bacteria  may  weaken  the  arterial  walls,  and  multiple  "mycotic"  aneurysms 
appear,  while  certain  parasitic  nematodes  living  inside  the  arteries  in  the  same  way  pro- 
duce aneurysmal  dilatations  (strongyle  infection  in  the  horse). 

The  general  character  of  an  aneurysm  may  be  made  clear  by  the  de- 
scription of  one  of  the  commoner  forms— the  saccular  aneurysm  of  the 
aorta.  In  such  a  case  (Fig.  187)  it  is  found  that  the  sac  most  commonly 
springs  from  the  convexity  of  the  arch,  and  that  intense  arteriosclerotic 
alterations  of  the  aorta  surround  its  mouth.  The  orifice  is  round  or 
irregular  in  outline,  and  the  edge  is  rolled  over  into  it  somewhat,  so  as  to 
almost  overhang  its  cavity.  The  cavity  itself  may  reach  a  very  great  size, 
the  sac  thus  formed  pushing  aside  the  surrounding  organs  or  embedding 
itself  in  them  in  the  most  remarkable  way  (Fig.  188).  Mechanical  effects 
produced  in  this  way  are  of  great  variety,  depending  largely  upon  the  point 
of  origin  and  size  of  the  sac.  Pressure  on  the  recurrent  laryngeal  nerve  pro- 
duces an  alteration  of  the  voice  from  spasm  or  paralysis  of  the  vocal  cord, 
coughing,  dyspnoea,  etc.  Pressure  on  the  trachea  flattens  it  and  causes 


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dyspnoea— later,  the  aneurysm  may  rupture  into  it,. after  eroding  its  wall. 
The  lungs  yield  and  collapse  before  the  aneurysm.  Pressure  on  a  bronchus 
narrows  it,  and  behind  the  obstruction  bronchiectasis  arises.  When  the 
sac  reaches  the  bony  structures  of  the  thorax,  which  do  not  yield,  it  ham- 
mers its  way  through  them,  appearing  under  the  skin  through  a  hole  in 


Fig.  187. — Aneurysm  of  aortic  arch.     Aortic  valvular  insufficiency,  probably  syphilitic. 
A  second  aneurysm  in  the  dorsal  aortic  wall. 

the  ribs  or  sternum.  If  it  extends  backward  to  the  spine,  it  destroys  the 
centra  of  the  vertebrae  even  down  to  the  spinal  canal  (cf.  Fig.  29) ,  leaving  the 
yielding  intervertebral  discs  standing  almost  unaltered — in  the  same  way  it 
may  break  through  the  ribs  in  the  back  and  appear  under  the  skin  there. 
Then  it  is  not  long  before  the  skin  becomes  thinned  out  and  bluish,  and 


ANEURYSMS 


363 


finally  the  sac  ruptures,  so  that  death  follows  at  once.  Often  it  ruptures 
long  before  reaching  the  skin — into  the  pleura  or  pericardium,  trachea,  or 
oesophagus,  or  even  into  the  superior  or  inferior  vena  cava. 

The  character  of  such  a  sac  which  can  produce  a  huge  and  destructive 
tumor,  which  destroys  itself  as  soon  as  it  completes  its  advance,  must  be 
interesting.  It  is  not  really  composed  of  the  stretched-out  walls  of  the 
vessel,  for  microscopic  examination  with  suitable  stains  shows  that  prac- 


Fig.  188.— Saccular  aneurysm  projecting  between  the  aorta  and  the  heart.     Its  orifice 

shows  in  the  aorta. 

tically  all  those  elements  stop  sharply  at  the  edge  of  the  orifice  (Fig.  189). 
The  elastic  tissue  and  the  muscle  are  suddenly  interrupted.  Endothelium 
may  persist  and  attempt  to  line  the  sac,  but  it  is  evident  that  it  soon  fails 
in  this  and  is  lost.  Indeed,  nothing  but  connective  tissue,  and  that  essen- 
tially new  formed,  goes  to  make  up  the  sac.  It  grows  largely  by  new 
breaks  in  the  wall  which  seem  to  be  made  good  by  further  formation  of 
fibrous  tissue.  The  current  of  blood  eddies  about  in  the  cavity,  and  its 


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pulsation  gives  the  sac  its  power  of  breaking  down  the  resistance  of  the 
tissues.  But  the  endothelial  lining  is  imperfect,  and  thrombosis  occurs,  and 
if  time  be  allowed,  as  it  so  often  is,  layer  after  layer  of  compact  thrombus 
material  may  be  hammered  down  on  the  wall  of  the  sac  until  it  is  in  large 
part  filled  up  (Fig.  190).  Occasionally  the  aneurysm  may  be  completely 
obliterated  in  this  way.  The  character  of  the  fibrous  wall  is  such  that  little 


Fig.  189. — Edge  of  a  small  aneurysm,  showing  the  abrupt  cessation  of  the  elastic 
tissue  at  the  margin  of  the  sac.  One  wall  of  an  adjacent  vein  is  seen  at  the  bottom  of 
the  drawing. 


upgrowth  of  organizing  granulation  tissue  into  the  thrombus  appears, 
and  the  lower  layers  become  even  more  compact,  until,  on  a  smoothly  cut 
section,  they  look  like  onyx.  The  wall  itself  becomes  hyaline,  and  it  is 
often  impossible  to  say,  in  a  microscopic  section,  where  the  wall  ends  and 
the  thrombus  begins.  In  the  smaller  and  fresher  aneurysmal  sacs  the 
wall,  wrinkled  and  irregular,  is  generally  shining,  thick,  and  rather  trans- 


ANEURYSMS 


365 


lucent,  and  quite  uncovered  with  thrombi  or  covered  with  only  the  merest 
film. 

Quite  the  same  characters  are  found  in  aneurysms  in  the  abdominal  aorta 
or  its  branches,  in  the  arteries  of  the  extremity  or  the  head.  Sometimes 
several  small  ones  occur  side  by  side,  even  in  the  aorta;  sometimes  when 
one  in  a  peripheral  artery  has  been  cured  by  operation,  a  new  one  will 
appear  in  another  vessel.  There  was  a  syphilitic  negro  cook  on  a  steam- 
boat who  returned  to  the  hospital  three  times,  each  time  with  a  new  aneu- 
rysm.  But  usually  one  is  enough  if  it  affects  the  aorta,  and  all  the  vaunted 


Fig.  190.— Aneurysm  of  the  abdominal  aorta,  with  laminated  clot  almost  completely 

filling  it. 

methods  of  cure  are  rather  unsatisfactory,  except  in  rare  cases.  In  the 
small  arteries  of  the  brain  Charcot  has  described  miliary  aneurysmal  sacs 
which  are  said  to  be  the  points  at  which  haemorrhage  occurs  in  apoplexy. 

LITERATURE 

Benda:   Ergebn.  d.  allg.  Path,  1902-1904,  viii,  196. 
Marchand:'  Verh.  Dtsch.  path.  Ges.,  1904,  vi,  197. 
Osier:   Practice  of  Medicine,  1905,  sixth  edition. 
Osier  and  MacCallum:  Johns  Hopkins  Hosp.  Bull,  1905,  xvi,  119. 


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CEREBRAL  APOPLEXY 

Haemorrhage  into  the  substance  of  the  brain  is  one  of  the  most  direct  conse- 
quences of  arteriosclerotic  changes  in  the  arteries,  and  may  be  briefly 
discussed  here.  While  haemorrhages  may,  of  course,  occur  in  the  memnges, 
and  even  in  the  brain,  as  a  result  of  injury  and  in  connection  with  infectious 
processes,  the  most  characteristic  and  common  forms  are  those  which  arise 
spontaneously  or  in  the  course  of  some  violent  exertion,  from  rupture  of 
one  of  the  arteries  which  penetrate  into  the  brain  substance.  Many 
branches  are  liable  to  such  rupture,  but  in  fact  it  most  frequently  occurs  in 


Fig.  191.— Apoplexy,  both  fresh  and  healed.  The  large,  fresh  hsemorrhage  has  burst 
into  the  ventricle.  The  old  one  is  represented  by  a  cavity  with  pigmented  walls  in  the 
substance  of  the  opposite  hemisphere.  There  is  a  small  clot  in  the  ventricle  of  that  side. 

an  artery  which  turns  off  at  right  angles  from  the  middle  cerebral  artery  to 
pass  to  the  lenticular  nucleus  and  internal  capsule  (Fig.  191  A).  This  is  the 
so-called  lenticulostriate  artery,  named  by  Charcot,  on  account  of  its  fre- 
quent involvement  in  apoplexy,  the  artery  of  cerebral  hsemorrhage.  It  is 
not  usual  for  hsemorrhage  to  occur  from  diffusely  sclerotic  arteries :  rather 
it  arises  from  definite  local  alterations  which  are  described  as  miliary  aneu- 
rysms.  These  are  minute  globular  enlargements  of  the  artery,  two  or  three 
millimetres  in  diameter,  which  are  not  very  conspicuous,  but  which  may  be 
found  by  carefully  washing  away  the  brain  substance  with  a  stream  of 
water.  Even  the  ruptured  one  may  be  demonstrated  in  this  way. 


CEREBRAL    APOPLEXY 


367 


The  haemorrhage  may  occur  in  the  cortex,  in  the  basal  ganglia  involving 
the  central  portion  of  the  brain,  in  the  crura  or  pons,  or  even  in  the  medulla 
or  spinal  cord.  In  these  latter  cases  other  causes  are  usually  at  work. 
Haemorrhage  into  the  cerebellum  is  not  very  uncommon.  In  by  far  the 
greater  number  of  cases  the  haemorrhage  is  found  to  involve  the  corpus 
striatum  and  the  internal  capsule;  sometimes,  as  shown  in  the  drawing 
(Fig.  191),  bursting  into  the  cerebral  ventricles.  Such  extravasation  tears 
through  the  soft  tissue,  interrupting  nerve-fibers  and  destroying  nerve- 


• 


Fig.  191A—  Diagram  showing  the  branches  of  the  middle  cerebral  arteries  which 
supply  the  basal  ganglia  The  innermost  are  the  lenticulo-optic,  the  outer  two  on 
each  side  the  lenticulo-striate  arteries.  The  outermost  of  these  which  pierces  the  in- 
ternal capsule  to  end  in  the  caudate  nucleus  is  known  as  the  "  artery  of  cerebral 
haemorrhage."  Modified  from  Charcot-Duret. 

cells.  It  is  irregular  in  extent  and  in  outline,  and  at  the  margins  there  are 
always  little  extensions  into  the  adjacent  tissue,  where  one  usually  finds 
the  lymphatic  sheath  of  each  vessel  distended  with  blood.  The  mere 
appearance  of  such  a  quantity  of  blood  inside  the  rigid  cranial  enclosure 
is  enough  to  raise  the  pressure  there,  and  by  compressing  the  brain  generally, 
to  cause  unconsciousness  and  a  general  flaccid  paralysis,  and  it  is  in  this 
condition  that  the  victim  falls  in  the  street.  Later,  when  some  of  the  blood 
has  been  absorbed  and  the  pressure  lowered,  the  direct  effect  of  the  tearing 


368  TEXT-BOOK   OF    PATHOLOGY 

of  the  nerve-tracts  becomes  evident,  and  a  clear-cut  hemiplegia  or  one- 
sided paralysis  stands  out  instead. 

If  the  haemorrhage  is  not  confined  to  the  brain  tissue,  but  bursts  through 
into  the  ventricles,  much  freer  bleeding  can  occur,  and  the  blood  filling  both 
ventricles  and  running  down  through  the  aqueduct  of  Sylvius  intensifies  the 
effects  of  increased  general  pressure. 

The  distribution  of  the  paralysis  depends,  of  course,  on  the  situation 
of  the  destruction  of  the  brain  substance.  The  hemiplegia  is  complete 
when  face,  arm,  and  leg  on  one  side  are  paralyzed,  and  this  arises  when  the 
haemorrhage  involves  the  internal  capsule  and  the  beginnings  of  the  pyr- 
amidal tract  high  enough  to  include  the  origin  of  the  facial  nerves.  If, 
however,  it  is  in  the  lower  part  of  the  pons,  the  nuclei  of  the  cranial  nerves 
may  be  injured,  and  then  the  facial  paralysis  will  be  on  the  side  opposite 
that  of  the  arm  and  leg.  (Cf.  Osier's  Medicine,  1905,  fourth  edition, 
972,  Fig.  9.) 

Healing  of  the  area  of  haemorrhage  takes  place  by  the  disintegration  of 
the  blood  and  its  gradual  removal  by  phagocytes.  Sometimes  a  cavity  is 
left,  lined  by  granulation  tissue,  which  is  deeply  pigmented  and  contains 
a  clear  yellow  fluid  (Fig.  191).  The  neuroglia  may  play  a  large  part  in 
forming  the  wall  of  this  cavity. 

LITERATURE 

Monakow:  "Gehirnpathologie,"  Nothnagel's  spec.  Path.  u.  Ther.,  1897,  ix,  pt.  1. 
Ellis:  Publications,  Jefferson  Medical  College,  Phila.,  1915,  v,  1. 
Duret:  Arch.  de.  Physiol.  norm.  et.  pathol.,  1874,  2me,  Ser.  1. 


CHAPTER  XVIII 
TYPES  OF  INJURY:    PHYSICAL  AND  MECHANICAL  INJURIES 

Mechanical  injuries:  Pressure,  direct  violence  affecting  bones,  central  nervous  system,  etc. 
Gunshot  and  other  wounds.  Secondary  effects:  Complication  with  infection.  Shock. 
Experimental  study  and  various  theories.  Effects  of  heat:  Burns,  heat-stroke,  insolation. 
Effects  of  cold:  Freezing.  Effects  of  light-rays  and  radiant  energy  on  skin,  blood-forming 
organs,  etc.  Electricity:  Effects  of  strong  currents. 

MECHANICAL  INJURIES 

THE  variety  of  mechanical  injuries  is  almost  infinite,  and  is  constantly 
increasing  and  changing  with  the  invention  of  new  machinery.  The  old 
swashing  blow  with  the  broadsword  has  given  place  to  the  penetrating 
wound  of  the  high-speed  bullet;  wounds  of  encounter  with  wild  beasts  are 
rarer  now  than  those  from  the  fall  of  an  aeroplane.  But  the  principles 
concerned  are  relatively  few,  and  with  a  knowledge  of  the  complexities  of 
organ  structure  and  function  the  effect  of  any  type  of  injury  can  be  pretty 
readily  constructed. 

In  general,  mechanical  force  may  be  applied  to  the  body  in  the  form  either 
of  pressure  or  of  stretching,  and  according  to  the  shape  or  character  of  the 
instrument,  and  the  rate  and  violence  with  which  it  is  applied,  different 
results  follow.  Thus  gradual  exposure  to  a  high  air-  or  water-pressure 
will  produce  one  sort  of  effect,  while  a  sudden  blow  with  a  blunt  weapon  or 
crushing  between  two  flat  surfaces  will  have  quite  a  different  outcome. 
If  the  instrument  be  sharp  or  impinge  upon  the  body  with  great  velocity, 
it  cuts  or  penetrates,  separating  tissues  which  might  be  only  bruised  or  dis- 
located by  a  blunter  or  more  slowly  moving  object. 

Distension  by  gases  or  fluids,  stretching  and  tearing  of  extremities 
caught  in  machinery,  and  the  dismemberment  of  the  body  by  the  force  of 
an  explosion  are  examples  of  the  application  of  a  stretching  force  which 
often  involves  the  exertion  of  pressure  also  on  some  other  part  of  the  tissue. 

The  effects  of  such  violence  are  not  only  upon  the  tissues  directly  attacked, 
but  since  the  whole  structure  of  the  body  is  in  a  state  of  elastic  tension,  the 
severing  or  destruction  of  any  tissue  allows  those  remaining  to  gape  apart. 
Especially  is  this  true  of  the  elastic  blood-vessels,  in  which  the  blood  is 
under  high  presssure.  Any  break  in  the  wall  of  one  of  these  vessels  opens 
more  widely  and  allows  the  escape  of  blood.  Nor  is  the  effect  of  any  such 
mechanical  injury  necessarily  limited  to  its  direct  result.  Here,  as  else- 
where, it  is  usually  one  link  in  a  chain  of  events  which  in  the  end  leads  to 
quite  unexpected  terminations.  Thus  a  man  whose  back  is  broken  will 
die  from  the  formation  of  abscesses  in  his  kidneys,  but  there  is  a  long  series 
25  369 


370  TEXT-BOOK    OF    PATHOLOGY 

of  causes  and  effects  which  finally  bring  this  about.  It  is  an  example  of  the 
far-reaching  effects  of  injuries  to  the  nervous  system. 

A  brief  account  of  some  of  the  common  types  of  mechanical  injury  will 
suffice  to  direct  the  reader  to  the  literature  of  the  subject. 

Pressure. — A  diver  seen  deep  in  clear  water  through  a  glass-bottomed  boat 
becomes  perfectly  white  from  the  compression  of  the  blood-vessels  of  the  skin. 
Doubtless  this  may  have  some  influence  upon  the  general  blood-pressure,  but 
when  air  is  supplied  through  a  helmet,  no  great  discomfort  is  felt  if  the  changes 
of  pressure  are  gradual  enough.  The  same  anaemia,  lasting  for  a  long  time, 
if  locally  produced  by  the  weight  of  the  body  on  the  bed,  or  by  a  tight 
bandage,  may  be  more  complete  in  the  area  affected,  and  if  the  circulation 
is  sluggish,  and  especially  if  the  nerve  supply  is  interrupted,  death  of  the 
anemic  areas  will  follow  (decubitus,  bed-sores).  Thus  a  person  paralyzed 
by  an  injury  to  the  spinal  cord  will  quickly  develop  deep  ulcers  over  the 
sacrum,  heels,  etc.,  if  left  lying  in  one  position,  and  the  same  is  true  of 
those  bedridden  by  some  disease  or  infection  which  greatly  lowers  their 
vitality.  Violent  mechanical  pressure  on  the  trunk,  as  in  cases  of  people 
buried  under  an  avalanche  of  coal  or  grain,  or  caught  under  an  elevator, 
may  cause  death  by  actual  crushing,  but  short  of  this  it  produces  an  ex- 
treme obstruction  of  the  circulation  by  preventing  the  movement  of  the 
venous  blood  toward  the  heart.  The  head  and  neck  become  blue  black, 
and  haemorrhages  occur  from  the  burst  vessels.  Slighter  pressure  applied 
continuously  to  any  tissue  over  a  long  time  interferes  with  the  complete- 
ness of  its  blood  supply,  and  prevents  or  stunts  its  growth.  Well-known 
examples  are  found  in  the  distorted  feet  of  Chinese  women,  the  flattened 
heads  of  certain  Indians,  etc.  Tumors,  pressing  in  their  growth  against 
other  tissues,  cause  the  cessation  of  growth  and  gradual  absorption.  This 
is  true  everywhere,  but  becomes  especially  striking  in  the  case  of  the  rigid 
bone,  which  can  be  hollowed  out  by  an  advancing  tumor  growth.  Prac- 
tically the  same  thing  is  seen  in  the  liver  as  the  result  of  constriction  by 
tight  clothing,  but  also  in  the  form  of  deep  grooves  over  the  upper  surface, 
which  correspond  with  rigid,  contracted  bands  of  the  diaphragm.  Aneu- 
rysms  which  push  aside  yielding  tissues  and  destroy  in  their  advance  bone 
and  anything  else  which  is  resistant,  afford  another  example  in  which  the 
effect  of  pressure  is  probably  aided  by  the  actual  beating  of  the  pulsating 
sac  against  the  bone,  for  such  .eroded  bones  show  not  only  wasting  or 
atrophy  of  the  tissue,  but  fragmentation  of  the  bony  lamellae. 

On  the  other  hand,  intermittent  pressure  which  allows  the  resumption  of 
the  circulation  and  of  the  proper  metabolism  of  the  cells  in  the  intervals 
often  causes  an  excessive  growth  of  tissue,  as  one  sees  in  the  case  of  corns 
and  other  callosities,  and  probably  also  in  the  ingrowing  toe-nail. 

Heightened  air-pressure,  to  which  workers  in  caissons  and  submarine 
engineering  operations  are  subjected,  is  injurious  chiefly  through  sudden 
changes  in  the  degree  of  pressure.  The  sudden  application  of  a  high  pres- 
sure may  cause  haemorrhages  in  the  ears.  Sudden  decompression  produces 


MECHANICAL   INJURIES  371 

a  whole  series  of  phenomena,  chiefly  dependent  upon  the  expansion  of  gases 
which  cannot  readily  escape;  the  air  in  the  middle  ear  and  the  gases 
in  the  intestine  produce  discomfort  or  injury  by  being  suddenly  released 
from  pressure.  Most  important,  however,  is  the  appearance,  in  the  form 
of  bubbles,  of  the  gases  which  under  higher  pressure  were  dissolved  in  the 
blood.  These  are  chiefly  nitrogen  and  carbon  dioxide,  and  if  a  workman 
is  too  quickly  "decompressed,"  that  is,  if  he  remains  too  short  a  time  in  the 
air-locks  in  which  the  air  is  at  an  intermediate  pressure,  these  bubbles 
appear  in  the  blood-stream  and  act  as  emboli,  plugging  the  arterioles  and 
obstructing  the  blood  supply  until  they  can  be  redissolved.  In  this  way 
the  sensitive  tissue  of  the  brain  and  cord  undergoes  anaemic  necrosis  in 
focal  areas,  and  if  death  does  not  follow,  extensive  paralysis  and  other 
nervous  disturbances  appear  (the  so-called  "bends"  of  caisson  workers) 
Tearing  of  the  tissues  by  such  bubbles  seems  less  important.  Exposure 
to  low  atmospheric  pressure,  as  in  balloon  ascensions,  mountain  climbing, 
etc.,  brings  with  it  symptoms  that  are  milder  because  the  change  of  pres- 
sure must  be  more  gradual.  Rapid  respiration,  rapid  pulse,  and  an  in- 
crease in  the  number  of  red  corpuscles  of  the  blood  are  evidences  of  adapta- 
tion to  the  lowered  oxygen  tension  of  the  atmosphere.  Weariness,  nausea, 
drowsiness,  fainting,  etc.,  make  up  the  condition  known  as  mountain- 
sickness. 

Trauma. — Violence  in  the  form  of  blows  may,  of  course,  have  many 
different  results.  The  commonest  is  perhaps  the  bruising  of  tissues,  with 
the  stretching  and  tearing  of  many  minute  blood-vessels,  from  which  blood 
escapes  and  filters  into  the  crevices  round  about.  If  the  tissue  is  soft  and 
loose,  as  it  is  below  the  eye,  a  blow  may  cause  a  very  extensive  infiltration 
of  blood,  while  in  a  denser  place  a  much  harder  knock  will  leave  no  such 
great  black-and-blue  spot.  At  first  it  is  red  or  purplish  red,  but  with  the 
stagnation  of  the  escaped  blood  a  venous  color  supervenes  which,  in  the 
course  of  the  next  days,  gives  place  to  a  series  of  changing  colors  as  the 
haemoglobin  of  the  laked  blood  passes  through  the  stages  of  the  formation 
of  hsemosiderin  and  its  gradual  removal.  Hues  of  green  and  brown  and 
yellow  finally  fade  away  completely  after  all  the  pigmentary  remains  of  the 
escaped  blood  have  been  carried  away. 

A  stronger  blow  or  a  twist  may  dislocate  a  joint;  that  is,  separate  the  two 
articular  surfaces  by  stretching  the  articular  ligaments  or  by  forcing  one 
bone  through  them.  Haemorrhage  occurs,  as  a  rule,  and  unless  the  bone  is 
replaced  properly,  new  tissue  may  be  formed  in  such  a  way  as  to  render  the 
abnormal  position  permanent.  Such  a  blow  may,  even  though  it  does  not 
break  the  skin,  cause  the  rupture  of  internal  organs  or  the  fracture  of  a 
bone.  In  the  first  case,  if  the  organ  is  a  solid  one,  rich  in  blood-vessels, 
like  the  kidney  or  liver  or  spleen,  a  great  or  even  fatal  haemorrhage  may 
occur.  This  does  not  necessarily  follow,  however,  for  occasionally  there 
are  found  evidences  of  recovery  from  rupture  of  the  liver  in  the  presence  of 
masses  of  liver  tissue  surrounded  by,  and  healed  into  the  omentum. 


372  TEXT-BOOK   OF   PATHOLOGY 

Fracture  of  bones  can  occur  in  a  thousand  ways  known  to  every  one. 
It  may  be  only  partial,  leaving  the  rest  of  the  bone  bent  (greenstick  frac- 
ture), or  it  may  be  complete,  so  that  the  fragments  override  and  are  held 
in  the  false  position  by  the  muscles.  When  the  bone  is  shattered  into 
many  fragments  (comminuted  fracture),  the  dislocation  may  be  even 
greater.  Occasionally  one  fragment  is  driven  into  the  substance  of  the 
other,  so  that  it  remains  embedded  there  (impacted  fracture).  When  the 
skin  is  broken  and  the  fractured  bone  exposed  to  contamination  from  the 
outside  (compound  fracture),  infection  is  very  likely  to  occur.  Fractures 
of  the  skull  the  bones  of  which  are  so  intimately  associated  with  infected 
cavities  are  also  exposed  to  this  danger  which,  in  preantiseptic  times,  made 
a  compound  fracture  almost  inevitably  fatal.  Healing  occurs  by  the  forma- 
tion of  an  abundant  new  tissue  (callus)  about  and  between  the  ends  of  the 
bone.  Excessive  at  first,  and  composed  of  vascular  fibrous  tissue,  carti- 
lage, and  spongy  bone,  it  later  becomes  compact,  diminished  in  amount, 
and  consolidated  into  dense  bone,  which  is  gradually  modified  and  adapted 
to  give  the  greatest  strength  to  the  welded  point  of  fracture  (Fig.  192) . 

Blows  on  the  head,  besides  causing  fracture  of  the  bones  of  the  skull, 
which  may  be  driven  into  the  brain,  are  capable  of  injuring  the  brain  either 
by  concussion  or  by  producing  a  haemorrhage  from  either  or  both  sides  of 
the  dura,  or  from  the  pial  vessels  before  or  after  their  entrance  into  the 
brain.  A  blow  on  the  skull  frequently  produces  its  greatest  injury  at  a 
point  opposite  that  upon  which  it  impinges  (contrecoup) . 

The  mechanism  of  contrecoup  has  been  variously  explained  in  a  vague  way  as  the 
effect  of  driving  the  soft  brain  substance  against  the  unyielding  opposite  side  of  the  skull, 
the  concentration  of  forces  passing  round  the  arc,  etc.,  but  to  me  it  seems  more  plausible 
to  assume  that  the  skull,  like  a  hoop  struck  sharply  at  one  point,  takes  an  elliptical  form, 
so  that  the  side  opposite  the  blow  actually  approaches  that  which  is  struck.  At  any 
rate  it  is  common  to  find  laceration  of  the  brain  and  menmges  with  haemorrhage,  at  a 
situation  most  distant  from  the  blow. 

Concussion  is  recognized  as  the  effect  of  a  shock  to  the  brain  substance, 
which,  although  it  produces  no  obvious  gross  lesion  of  any  sort,  does  cause 
unconsciousness  of  brief  or  longer  duration  and  many  temporary  disturb- 
ances of  the  intellect,  sensory,  or  even  motor  sphere.  It  is  thought  to  be 
due  to  dissociation  or  disarrangement  of  the  cells,  possibly  with  tearing  of 
many  dendrites,  axones,  and  association-fibers. 

Meningeal  hcemorrhage  is  important  above  other  haemorrhages,  not  only 
because  it  may  tear  into  and  destroy  the  soft  brain  substance,  but  because 
it  can,  even  when  it  is  outside  the  dura,  occupy  so  great  a  space  within  the 
rigid  cranial  cavity  as  to  compress  the  brain,  and  especially  to  prevent  the 
access  of  blood  (Fig.  194).  A  gradually  deepening  loss  of  consciousness 
with  flaccid  paralysis  of  the  whole  body  may  lead  to  death— the  blood- 
pressure  rises  very  high,  while  the  pulse  sinks.  Operative  removal  of  the 
clot  may  allow  all  the  functions  to  return  to  normal  almost  instantly. 
Much  greater  violence  is  necessary  to  wound  the  spinal  cord,  but  crushing 


MECHANICAL   INJURIES 


373 


Fig.  192.— Healed  fracture  of  middle  of  femur,  shown  also  in 
section. 


Fig.  193.— Well- 
healed  fracture 
showing  remaining 
overstren  g  t  h  en  i  n  g 
of  the  shaft. 


TEXT-BOOK    OF    PATHOLOGY 

and  twisting  force  may  fracture  the  vertebrae  or  dislocate  them  so  as  to 
sever  or  compress  the  cord.  Extravasation  of  blood  in  the  substance  of  the 
cord  (hamatomyelid)  extends  up  and  down  in  the  gray  matter,  destroy- 
ing much  of  the  tissue  as  it  burrows,  but,  as  a  rule,  not  entering  the 
white  matter.  The  so-called  compression  myelitis,  produced  by  crushing, 
occupies  part  or  all  of  the  diameter  of  the  cord,  and  interrupts  the  course 
of  the  fibres.  In  such  an  area,  debris  of  cells  and  fibres  remains,  together 
with  quantities  of  phagocytic  wandering  cells  loaded  with  globules  of 
lipoid  material  from  the  disintegrating  myeline  sheaths. 

The  effects  vary  with  the  extent,  and  especially  with  the  position,  of  the 
injury.     Low  down  in  the  spinal  cord  the  lower  motor  neurons  are  es- 


Fig.  194. — Subperiosteal  and  subdural  haemorrhage  in  new-born  child  with  compression 

of  the  brain. 

pecially  affected,  and  paralysis  is  flaccid,  leading  to  atrophy  of  muscles 
and  reaction  of  degeneration.  Higher  up  a  lesion  gives  rise  to  a  mixture 
of  upper  and  lower  neuron  types,  while  still  higher  the  effect  is  to  produce 
paralysis  predominantly  of  the  type  following  destruction  of  the  upper 
motor  neuron,  such  as  comes  from  a  lesion  of  the  brain :  the  muscles  retain 
their  tone,  do  not  atrophy,  and  stimulation  of  the  nerves  shows  no  change 
of  electrical  reaction.  The  paralyzed  area  may  be  entirely  anaesthetic,  or 
with  a  zone  of  hypersesthesia  at  the  upper  limit.  Other  disturbances  of 
sensation  also  occur.  Reflexes  are  variable,  and  after  a  time  may  be 
exaggerated,  especially  with  high  lesions.  The  sphincter  of  the  bladder  is 
not  paralyzed,  although  other  muscles  controlling  urination  are,  so  that  the 
bladder  becomes  greatly  distended. 


MECHANICAL   INJURIES  375 

Wounds  made  with  a  cutting  instrument  sever  tissues  and  allow  them  to 
gape  apart,  or  in  the  case  of  stab  wounds,  penetrate  various  organs.  They 
are  especially  important  in  that  blood-vessels  are  laid  open,  nerves  cut, 
and  hollow  organs  punctured,  so  that  their  infected  contents  are  allowed 
to  escape.  Aside  from  the  direct  destruction  of  the  tissues  traversed, 
such  wounds  are  also  dangerous  because  dirt  and  bacteria  are  carried  in  to 
the  tissue.  In  all  these  respects  they  are  similar  to  gunshot  wounds,  which 
have,  however,  a  special  character,  depending  on  the  type  of  missile  and 
the  force  and  velocity  with  which  it  passes  through  the  tissues. 

Gunshot  Wounds. — A  hard  bullet  of  very  high  velocity  passes  cleanly 
through  the  body.  A  soft  bullet  spreads  and  tears  the  tissue,  inflicting 
much  greater  damage:  either  will  shatter  bones  in  its  course.  A  bullet 
almost  spent  or  of  low  velocity  may  be  deflected  by  a  bone  and  pursue  a 
most  devious  course,  so  that  its  track  is  difficult  to  follow,  even  at  autopsy. 
The  path  of  a  bullet  widens  as  it  proceeds,  especially  in  the  case  of  the  soft 
ones,  so  that  the  wound  of  exit  is  larger  than  that  of  entrance.  Ordinarily 
such  a  bullet  brings  practically  no  infection  to  the  tissues  unless  it  carries 
in  with  it  bits  of  clothing.  It  was  for  this  reason  that  the  Japanese  in 
recent  actions  bathed  and  put  on  sterilized  clothes. 

Immediate  Effects. — In  all  cutting  and  penetrating  wounds  the  most 
important  immediate  effect,  unless  the  brain  or  spinal  cord  is  injured,  is 
likely  to  consist  in  the  laying  open  of  blood-vessels.  A  wound  of  the  heart 
is  fatal  not  especially  because  the  heart  is  injured,  but  because  blood  escapes 
into  the  pericardium  (hsemopericardium),  and  by  occupying  the  limited 
space,  prevents  the  entrance  of  the  venous  blood  into  the  heart  and  stops 
the  circulation.  In  the  case  of  the  aorta  or  other  large  vessel,  death  results 
rather  from  direct  escape  of  blood  into  the  pleura  or  pericardium  or  to  the 
outside.  A  vessel,  in  virtue  of  its  elasticity  and  muscular  contractility, 
gapes  open  and  allows  a  maximum  escape  of  blood  if  it  is  only  partly 
cut  through,  while  if  completely  cut  across,  an  artery  of  moderate  size 
may  retract  among  the  muscles,  and  partly  by  their  compressing  effect, 
partly  by  its  own  contraction,  the  flow  of  blood  may  be  stopped  before  a 
fatal  loss  has  been  suffered. 

Peripheral  nerves  may  be  cut  through,  or  crushed  and  later  surrounded 
by  dense  scar  tissue  formed  during  the  healing  process,  and  in  either  case 
the  injury  may  be  sufficient  to  prevent  the  transmission  of  impulses. 
Degeneration  of  the  peripheral  portion  of  the  nerve  quickly  follows,  and 
in  a  few  days  lipoid  globules  are  found  in  place  of  the  myeline  sheaths, 
the  axis-cylinders  are  disintegrated,  and  electrical  stimuli  produce  no 
effect  (Fig.  31).  There  may  be  recovery  of  the  power  to  transmit  im- 
pulses if  the  injury  is  not  too  severe,  and  in  the  meanwhile  the  muscle 
loses  its  power  to  contract  to  galvanic  stimuli,  but  soon  recovers  it  and 
becomes  more  excitable  than  normal.  During  this  period  of  high  excitabil- 
ity, which  later  passes  away,  the  contraction  is,  however,  not  instan- 
taneous, but  slow  and  lazy,  and  almost  without  effect  (reaction  of  de- 


376  TEXT-BOOK   OF   PATHOLOGY 

generation  of  Erb).  There  are  many  variations  in  these  relations,  depending 
upon  the  extent  of  injury  of  the  nerve  and  the  degree  to  which  the  muscle 
suffers,  which  must  be  read  of  elsewhere.  Trophic  disturbances,  thought 
by  many  to  be  due  to  the  destruction  of  special  trophic  nerves,  consist  in 
the  gradual  wasting  of  the  muscle.  It  is  shown  that  constant  fine  stimuli 
are  being  sent  to  muscles  in  health  maintaining  their  tone,  and  that  when 
the  nerve  is  cut  and  the  muscle  becomes  flaccid,  its  metabolic  gaseous  ex- 
change is  far  less  than  that  of  the  properly  innervated  muscle,  even  when 
completely  at  rest.  It  seems  possible  that  this  might  be  the  basis  upon 
which  atrophy  after  section  of  the  nerve  could  be  most  readily  explained. 

Secondary  Effects. — Many  secondary  results  follow  such  injuries  as 
have  been  mentioned,  some  of  which  can  be  avoided  by  proper  surgical 
care.  Hemorrhage,  as  already  stated,  may  cost  the  person's  life  through 
sheer  loss  of  blood  or  through  the  compression  of  the  brain  or  the  heart; 
the  perforation  of  an  aneurysm  into  the  trachea  may  fill  the  lungs  and 
practically  drown  the  individual.  But  in  another  way,  especially  in  the 
brain  and  spinal  cord,  the  burrowing  of  blood  in  the  soft  tissues  is  most 
destructive.  In  the  walls  of  the  aorta,  particularly  when  the  seat  of 
arteriosclerotic  changes,  a  blow  or  strain  may  break  the  inner  layers, 
usually  the  intima  and  half  of  the  media,  and  allow  blood  to  escape  into 
a  space  which  it  tears  open  in  the  middle  of  the  media,  the  so-called 
dissecting  aneurysm.  In  one  case  of  this  kind  the  formation  of  a  huge 
hsematoma  about  the  roots  of  the  splanchnic  nerves  was  apparently  the 
cause  of  paratysis  of  the  intestine,  with  such  extreme  distension  as  to 
tear  the  muscular  coat  in  many  places. 

The  occurrence  of  bacterial  infection  in  wounds  adds,  of  course,  greatly 
to  their  seriousness,  and  many  mere  pin-pricks  terminate  fatally  because 
bacteria  have  been  introduced.  This  is  common  in  the  case  of  strepto- 
coccus and  tetanus  infections,  but  it  is  equally  true  of  syphilis,  glan- 
ders, anthrax,  and  a  host  of  other  infections.  Indeed,  it  is  the  very 
insignificance  of  the  wound,  leading  to  its  being  neglected,  which  affords 
opportunity  to  the  bacteria  to  gain  a  foothold.  The  presence  of  any 
foreign  body  in  conjunction  with  the  bacteria  helps  them  greatly  in  gaining 
this  foothold,  and  it  has  been  shown  repeatedly,  in  the  case  of  experi- 
mental infection,  that  bacteria  which  fail  to  grow  when  inoculated  into  an 
animal  alone,  will  often  do  so  if  implanted  together  with  some  inert  foreign 
material.  Sometimes  this  acts  by  merely  protecting  the  bacteria,  but  at 
other  times  it  forms  a  medium  upon  which  they  can  grow  and  multiply. 
This  is  true  of  extravasation  of  urine  when  the  bladder  is  ruptured,  or  of 
accumulations  of  tissue  fluid  in  the  cavity  of  a  wound.  Most  important 
in  this  respect,  however,  is  the  presence  of  dead  tissue  in  a  wound  exposed 
to  infection.  This  has  been  mentioned  before,  but  from  a  surgical  point 
of  view  cannot  be  mentioned  too  often.  No  matter  how  rigid  the  aseptic 
technique,  the  leaving  behind  in  the  wound  of  any  considerable  quantity 
of  tissue  constricted  so  as  to  be  incapable  of  surviving,  is  almost  sure  to  be 


MECHANICAL   INJURIES  377 

followed  by  infection.  In  other  cases  the  foreign  body  itself  may  be 
irritating  and  destructive  of  tissue,  so  as  to  furnish  a  place  in  which  bacteria 
can  thrive.  Considerations  of  this  sort  became  extremely  important  dur- 
ing the  war,  when  surgeons  were  confronted  with  wounds  which  involved 
not  only  mangling  of  the  tissues  and  extensive  soiling  but  also  on  account 
of  delay  in  transportation,  actual  infection  of  the  injured  structures. 
Whenever  possible  it  became  the  practice  to  perform  a  so-called  "debride- 
ment,"  which  means  the  wide  excision  of  everything  about  the  wound 
until  healthy,  uninfected  tissue  was  reached,  after  which  the  whole  wound 
might  be  closed,  and  primary  healing  attained.  Of  course,  it  was  in  the 
estimation  of  the  extent  of  the  infection  and  the  general  state  of  resistance 
of  the  patient  that  the  judgment  of  the  surgeon  became  of  especial  impor- 
tance. 

With  regard  to  the  bacteria  concerned,  and  especially  the  anaerobic 
forms,  consult  Bulloch  and  Mclntosh,  Med.  Research  Committee,  Special 
Report,  Series  No.  12,  1917. 

Perforation  of  the  stomach  or  duodenum,  which  are  in  themselves 
nearly  sterile,  nevertheless  sets  up  peritoneal  infection  because  of  the 
escape  of  food  and  of  the  irritating  digestive  juices.  Perforations  of  lower 
portions  of  the  intestine  are  even  more  quickly  productive  of  infection 
because  of  the  colossal  numbers  of  bacteria  which  pour  out  with  the  in- 
testinal contents  into  the  peritoneum.  This  is  one  of  the  chief  sources  of 
danger  in  gunshot  wounds  of  the  abdomen,  in  which  several  loops  of  intes- 
tine may  be  pierced. 

The  crushing  or  shattering  of  tissues,  involving  rupture  of  blood-vessels, 
often  allows  the  entrance  of  groups  of  cells  or  single  cells  of  various  organs 
into  the  blood-stream  in  such  a  way  that  they  are  swept  along  and  lodge 
as  emboli  in  the  lungs  or  elsewhere.  This  is  most  commonly  true  of  the 
bone-marrow,  where,  instead  of  cells,  droplets  of  fat  may  enter  the  blood- 
current.  Practically  every  fracture  of  a  bone  and  even  severe  blows  upon 
bones  may  produce  such  fat  embolism  of  the  lungs.  Usually  it  does  no 
harm,  and  even  at  autopsy  can  be  discerned  only  by  the  aid  of  the  micro- 
scope, but  occasionally  the  amount  of  oil  is  so  great  as  to  cause  death  by 
obstructing  too  many  of  the  capillaries  of  the  lungs. 

Traumatism  is,  of  course,  a  more  serious  matter  for  persons  already 
weakened  by  disease  than  for  those  in  full  health,  and  it  may  be  the  occa- 
sion for  the  flaring  up  of  an  infection  hitherto  latent.  On  the  other  hand, 
the  injury  of  tissues  may  produce  a  point  of  lessened  resistance,  where  a 
subsequent  infection  can  be  established  in  a  way  scarcely  possible  in  an 
uninjured  person.  This  is  doubtless  the  explanation  of  the  common  history 
of  a  fall  or  blow  which  antedated,  by  some  time,  the  appearance  of  a  focus 
of  tuberculous  infection  in  a  bone  or  joint.  This,  too,  is  doubtless  the 
immediate  predisposing  cause  of  the  so-called  contusion  pneumonia  of 
Litten,  which  follows  crushing  blows  on  the  chest. 

It  must  be  remembered  that  certain  persons  suffer  directly  from  slight  m- 


378  TEXT-BOOK    OF    PATHOLOGY 

juries  far  more  than  others,  for  example,  a  scratch  which  would  scarcely  be 
noticed  by  a  normal  individual  may  allow  a  fatal  haemorrhage  in  a  member 
of  a  hsemophilic  or  bleeder  family,  while  a  blow  which  at  most  might  cause 
a  bruise  in  one  of  us,  will  break  the  femur  of  one  afflicted  with  osteopsathy- 
rosis  or  fragilitas  ossium.  And  in  the  same  way  the  sequelae  of  injury, 
such  as  wound  infections,  resisted  easily  by  a  normal  person,  will  bring 
about  the  death  of  one  whose  resistance  is  low,  with  fulminant  symptoms 
of  general  septicaemia.  This  was  exemplified  recently  in  the  case  of  a 
man,  apparently  in  good  health,  who  had  his  tonsils  removed  preparatory 
to  a  vacation — a  streptococcus  infection  ensued,  of  which  he  died  in  two 
days,  with  evidences  of  acute  endocarditis  and  multiple  embolism. 

LITERATURE 

Bailey:   Diseases  of  the  Nervous  System  from  Accident  and  Injury,  New  York,  1909. 
Henke:  Krehl  and  Marchand,  Handb.  d.  allg.  Pathologic,  1908,  i,  21. 
Hill,  L.:   "Influence  of  Atmospheric  Pressure,"  Lancet,  1905;  ii,  1865,  Proc.  Roy.  Soc., 

1905-6,  Ixxvii,  442. 

Lagarde:   Gunshot  Wounds,  New  York,  1914. 
Mobius:   Diagnostik  der  Nervenkrankheiten,  Leipzig,  1894. 
Stimson:  Fractures,  Phila.,  1912. 

SHOCK 

This  is  a  peculiar  disturbance  of  almost  all  the  functions  of  the  body, 
especially  characterized  by  apathy  or  torpor,  dulling  of  sensibility,  failure 
of  the  circulation  with  great  lowering  of  the  blood-pressure,  irregular  gasp- 
ing respirations,  which  may  be  the  first  thing  to  fail  completely,  and  sub- 
normal temperature.  Fischer's  description  of  such  a  case  may  be  quoted 
from  Dr.  Meltzer's  paper: 

"A  strong  and  perfectly  healthy  young  man  was  struck  in  the  abdomen 
by  the  pole  of  a  carriage  drawn  by  runaway  horses.  No  recognizable  injury 
was  done  to  any  of  the  internal  organs.  Nevertheless,  grave  symptoms 
made  their  appearance  immediately  after  the  accident.  The  injured  man 
was  lying  perfectly  quiet,  and  paid  no  attention  to  anything  going  on 
around  him.  His  face  was  drawn  and  peculiarly  elongated,  the  forehead 
wrinkled,  and  the  nostrils  dilated.  His  weary,  lustreless  eyes  were  deeply 
sunken  in  their  sockets,  half  covered  by  the  drooping  eyelids  and  surrounded 
by  broad  rings.  The  eyes  had  a  glassy  and  vacant  expression.  The  skin 
and  the  visible  mucous  membranes  had  a  marble-like  pallor.  Large  drops 
of  sweat  hung  on  forehead  and  eyebrows.  The  rectal  temperature  was 
subnormal.  The  sensibility  of  the  entire  body  was  greatly  reduced;  the 
patient  reacted  slightly,  and  only  to  very  painful  impressions.  No  spon- 
taneous movements  of  any  sort  were  made  by  the  patient.  On  repeated 
and  urgent  requests  he  showed  that  he  could  execute  limited,  brief  move- 
ments with  his  extremities.  When  the  limbs  were  lifted  passively  and 
then  let  go,  they  fell  down  like  lead.  The  sphincters  were  intact.  The 
urine  obtained  by  catheter  was  scanty  and  concentrated,  but  otherwise 
normal.  The  almost  imperceptible  pulse  was  rapid,  irregular,  and  un- 
equal. The  arteries  were  narrow  and  of  very  low  tension.  The  patient 
answered  slowly,  reluctantly,  and  only  after  repeated  urgent  questioning. 


SHOCK  379 

His  voice  was  hoarse  and  weak,  but  well  articulated.  On  being  repeatedly 
questioned,  the  patient  complained  of  cold,  faintness,  and  deadness  of  all 
parts  of  the  body.  When  he  shut  his  eyes  he  felt  nauseated  and  dizzy. 
The  respirations  appeared  irregular;  long,  abnormally  deep,  sighing  in- 
spirations interchanged  with  rapid  and  superficial  ones,  which  were  scarcely 
visible  or  audible." 

This  is  a  typical  example  of  shock  following  traumatism,  a  condition  well 
known  to  surgeons  to  come  on  immediately  or  a  short  time  after  some 
extremely  painful  injury,  such  as  the  crushing  of  a  testicle  or  mangling  or 
laceration  of  the  body  in  machinery.  It  is  especially  common  in  injuries 
which  involve  the  exposure  and  mishandling  of  the  abdominal  organs,  but 
practically  the  same  complex  appears  after  extensive  burns,  and  in  the  case 
of  intense  peritoneal  and  other  infections  and  some  intoxications.  Possibly 
the  infections  and  intoxications  may  be  distinct  in  their  mode  of  action, 
but  in  the  present  confusion  of  our  knowledge  the  results  seem  to  be  prac- 
tically identical. 

An  immense  amount  of  experimental  study  has  as  yet  failed  to  explain 
this  phenomenon,  or  even  to  determine  exactly  what  happens.  Keen, 
Mitchell,  and  Morehouse,  and  later  Crile,  thought  the  fall  in  blood-pressure 
to  be  the  essential  feature,  and  this  they  explained  as  due  to  exhaustion  of 
the  vasomotor  centre,  which  allowed  relaxation  of  the  peripheral  arterioles 
and  the  accumulation  of  the  blood  in  the  large  splanchnic  veins.  Crile 
advised  massage  or  compression  to  drive  the  blood  again  to  the  heart. 
He  observed,  however,  that  death  in  most  cases  resulted  from  stoppage  of 
respiration  while  the  heart  continued  to  beat. 

Porter,  Seely,  Mann,  and  others  have  shown,  however,  that  the  vaso- 
motor centre  is  by  no  means  exhausted,  but  still  active,  and  that  the 
peripheral  vessels  are  distinctly  contracted  and  quite  susceptible  to 
vasoconstrictor  impulses,  which  can  be  elicited  by  sensory  stimulation. 
Nor  is  it  a  fact,  as  Boise  claimed,  that  the  heart  is  exhausted,  for 
if  blood  be  supplied  to  it  and  pressure  maintained,  it  works  perfectly 
well.  The  nervous  control  of  the  heart  is  intact;  so,  too,  the  nervous 
mechanism  which  controls  respiration  is  able  to  respond  to  various 
stimuli,  although  (Mann)  it  is  probably  the  most  easily  injured  and  most 
seriously  damaged  of  the  medullary  centres.  Henderson  ascribes  the 
whole  phenomenon  to  an  affection  of  the  respiratory  centre  following  the 
violent  forced  respiration  which  is  set  up  by  painful  traumatism.  This, 
he  states,  sets  free  so  much  carbon  dioxide  from  the  tissues  that  the 
condition  of  "acapnia"  arises,  namely,  a  poverty  of  the  carbon  dioxide 
which  is  necessary  for  the  stimulation  of  the  respiratory  centre.  Mere 
lack  of  oxygen,  he  says,  has  no  influence  in  stimulating  respiration,  and 
in  the  absence  of  carbon  dioxide  the  centre  remains  inactive,  so  that  in  this 
period  of  apncea  the  individual  dies  from  lack  of  oxygen.  It  seems  hard 
to  believe  that  the  excessive  respiration,  which  is  often  so  slight,  could 
produce  so  extreme  a  change,  or  that  the  carbon  dioxide  produced  while 


380  TEXT-BOOK    OF    PATHOLOGY 

the  animal  was  dying  for  lack  of  oxygen  should  not  be  able  to  stimulate 
the  respiratory  centre,  since  throughout  this  time  the  heart  continues  to 
beat.  Meltzer  regards  the  whole  process  as  the  expression  of  a  preponder- 
ance of  inhibitory  action  of  the  nervous  system,  which  after  such  ex- 
treme stimulation  affects  even  the  organs  of  fundamental  importance, 
the  regulation  of  which  is  usually  so  well  protected. 

Mann  emphasizes  the  predominant  part  which  injuries  to  the  peritoneal 
contents  play  in  the  production  of  shock,  and,  finding  great  increase  in  the 
specific  gravity  of  the  splanchnic  blood  and  changes  in  the  relation  of  the 
blood-cells,  thinks  the  symptoms  due  to  the  great  loss  of  cells  and  fluid 
from  the  blood  of  the  splanchnic  vessels — a  sort  of  acute  inflammatory 
exudate.  The  production  of  shock  in  cases  where  such  things  are  easily 
excluded  seems  to  militate  against  this  idea.  Haemorrhage  does  aid  in  the 
production  of  shock,  and  the  effects  of  very  severe  haemorrhage  are  hardly 
to  be  distinguished  from  it.  So,  too,  the  effects  of  such  infections  and  in- 
toxications as  are  found  in  general  streptococcal  peritonitis  or  in  fatal 
diphtherial  intoxication  are,  as  has  been  pointed  out  by  Passler  and  Rom- 
berg,  in  every  respect  similar.  They  lay  stress  on  the  vascular  relaxation 
and  stagnation  of  blood  in  the  great  veins  which  involves  decreased  flow  in 
the  coronary  arteries  and  cardiac  failure,  and  I  could  confirm  this  by  show- 
ing that  if  the  blood-pressure  be  maintained  by  a  mechanical  device,  and 
the  blood  driven,  regardless  of  the  vasomotors,  through  the  arteries  and 
veins  into  the  heart,  the  imminent  collapse  is  warded  off.  Much  has  been 
written  by  Crile  and  his  assistants  about  disintegrative  changes  in  the 
ganglion-cells  of  the  brain  in  shock,  but  it  seems  that  these  may  be  rather 
the  effect  than  the  cause. 

H.  H.  Janeway  and  E.  M.  Ewing  conclude,  from  their  experiments,  that 
acapnia  is  not  important  in  producing  shock,  but  that  artificial  respira- 
tion can  do  so,  when  forcible  enough,  by  preventing  the  flow  of  blood  from 
the  veins  into  the  heart.  Shock  may  be  produced  while  the  carbon  dioxide 
content  of  the  blood  is  high.  Further,  although  the  early  stages  of  shock 
produced  by  the  handling  of  the  intestine  are  due  to  inhibitory  efferent 
impulses,  the  nerve  centres  are  not  exhausted,  but  there  is  a  complete  local 
peripheral  splanchnic  paralysis,  so  that  blood  accumulates  there,  producing 
in  the  end  a  fatal  fall  in  blood-pressure.  This  permanent  loss  of  vasomotor 
control  is  the  all-important  factor  in  the  development  of  shock. 

These  older  ideas,  while  leaving  no  clear  impression  of  the  nature  of 
shock,  are  not  inconsistent  with  those  which  have  resulted  from  the  very 
extensive  studies  made  during  the  war.  Various  suggestions,  such  as  those 
which  ascribed  shock  to  pulmonary  and  cerebral  fat  embolism  or  to  acid- 
osis,  have  been  proposed,  only  to  be  abandoned.  It  has  been  observed 
that  in  most  intances  several  causes  have  been  combined;  cold,  haemor- 
rhage, crushing  and  laceration  of  tissues,  and  anaesthesia  stand  out  most 
prominently,  and  it  is  found  that  in  many  instances  the  addition  of  one 
or  more  of  these  factors  is  decisive  in  precipitating  shock.  Ether  anaesthesia 


SHOCK  381 

is  far  more  harmful  in  this  respect  than  that  with  nitrous  oxide  and 
oxygen. 

Distinction  is  made  between  primary  shock,  which  appears  to  be  the 
immediate  reflex  effect  of  a  sudden  injury  due  to  the  inhibition  of  the 
heart  through  the  vagus  and  dilatation  of  the  arteries  in  the  splanchnic 
area  (Goltz's  experiment),  and  secondary  shock,  which  is  more  gradually 
produced  and  depends  upon  other  causes. 

In  secondary  shock  the  blood-pressure  drops  sharply,  then  with  a  tem- 
porary constriction  of  the  arterioles  rises  almost  to  the  original  level, 
after  which  it  gradually  sinks  to  a  very  low  one.  When  it  reaches  this 
level  the  heart  still  beats  well,  but  there  is  very  little  blood  in  the  arteries 
or  veins  and  the  pulse  is  not  to  be  felt.  By  the  vital  red  stain  method  it 
has  been  shown  that  there  is  a  great  diminution  in  the  blood  volume  (Keith), 
and  it  is  clear  that  the  arteries  and  veins  are  collapsed;  the  heart  appears 
to  be  propelling  only  a  very  small  amount  of  blood.  The  explanation  of- 
fered is  that  the  enormous  capillary  stream  bed,  which  under  normal  con- 
ditions is  only  partly  used,  is  now  widely  opened  to  the  blood  by  the  paral- 
ysis of  the  capillary  walls.  It  is  recognized  that  the  endothelial  walls  of  the 
capillaries  have  a  certain  contractility  of  their  own  and  that  they  are  capa- 
cious enough  when  this  tone  is  lost  to  receive  almost  the  whole  volume  of 
the  blood,  which  thus  occupies  largely  capillaries  which  are  ordinarily 
collapsed  and  not  traversed  by  blood.  With  this  comes  an  increased 
permeability  of  their  walls  so  that  fluid  passes  out  into  the  tissues  and  the 
blood  becomes  concentrated.  Of  course,  there  is  not  enough  fluid  available 
to  give  any  appearance  of  oedema.  Respiration  may  cease  and  the  patient 
die  with  all  his  nerve  centres  and  his  heart  inactive  from  lack  of  nutrition. 
It  has  been  found  that  the  introduction  of  large  quantities  of  blood  or  of 
a  6  per  cent,  solution  of  gum  acacia  with  salt  often  relieves  the  situation 
by  furnishing  fluid  enough  to  allow  the  heart  to  work  and  to  maintain  its 
own  nutrition  and  that  of  the  nervous  system. 

Crushing  of  tissues  seems  especially  likely  to  be  followed  by  severe  shock, 
and  so  too  does  the  re-establishment  of  the  circulation  through  tissues 
which  have  long  been  cut  off  from  their  blood-supply;  something  forms  in 
crushed  muscles  or  in  injured  tissues  which  is  later  distributed  by  the  cir- 
culating blood  and  acts  as  a  poison.  Dale  recognized  this,  and  stated  that 
from  its  effects  it  must  be  a  body  resembling  the  histamine  or  beta-imido- 
azolylethylamine  which  he  had  extracted  from  ergot.  Dr.  Abel  finds  that  he 
can  extract  histamine  itself  from  practically  every  tissue  and  thinks  that  it 
may  well  be  the  substance  actually  concerned.  The  effects  of  injection  of 
histamine  are  exactly  those  of  shock.  It  causes  a  sinking  of  blood-pressure 
through  paralysis  of  the  walls  of  the  capillaries  which  widen  and  receive 
most  of  the  blood  and  become  more  permeable  so  that  much  of  its  fluid  is 
lost  into  the  tissues.  Dale  does  not  claim  that  this  is  the  only  factor  in  the 
production  of  shock,  but  Cannon,  Bayliss,  McNee,  and  others  bring  great 
support  to  the  idea  from  their  observations  of  the  effect  of  experimentally 


382  TEXT-BOOK    OF    PATHOLOGY 

crushing  muscle  and  other  tissues.  They  speak,  therefore,  of  traumatic 
toxsemia  as  the  important  underlying  condition  in  shock. 

(Dale,  Wallace,  Bayliss,  Cannon,  McNee,  Keith,  and  others,  Report  of 
the  Special  Investigation  Committee  on  Surgical  Shock  and  Allied  Con- 
ditions, National  Health  Insurance,  Special  Report  Series  Nos.  25,  26,  27, 
London,  1919.) 

All  of  these  studies  are  very  recent,  and  while  they  seem  to  offer  a 
very  plausible  explanation  of  shock,  difficulties  encountered  in  attempt- 
ing to  observe  directly  changes  in  the  calibre  of  the  capillaries  under  the 
influence  of  histamine  and  related  substances,  incline  us  to  accept  them 

with  some  reserve. 

LITERATURE 

Abel  and  Kubota:  Jour.  Phar.  and  Exp.  Therap.,  1919,  xiii,  243. 

Crile:  Exp.  Inquiry  into  Surgical  Shock,  Philadelphia,  1899. 

Janeway,  H.  H.,  and  Ewing,  E.  M.:  Annals  of  Surgery,  1914,  lix,  158. 

Keen,  Mitchell,  and  Morehouse:  Circular  No.  6,  Surgeon  General's  Office,  1864. 

Malcolm:   Lancet,  1905,  ii,  573;    Med.  Chir.  Trans.,  1907,  xc,  563;    Clin.  Jour.,  1909, 

xxxiv,  328. 

Mann:  Johns  Hopkins  Hosp.  Bull.,  1914,  xxv,  205. 
Meltzer:  Archives  Internal  Med.,  July,  1908,  i,  571. 
Seelig  and  Lyon:    Jour.  Amer.  Med.  Assoc.,  1909,  lii,  p.  45,  Surg.,  Gyn.  and  Obst.,. 

1910,  xi,  146. 
Yandell  Henderson:  Amer.  Jour.  Physiol.,  1908-1910,  xxi-xxvi;   Johns  Hopkins  Hosp, 

Bull.,  1910,  xxi,  235. 

INJURIES  FROM  HEAT 

Animals  can  live  only  within  certain  temperature  limits,  which  are  different 
for  different  forms.  Lambert  has  shown,  by  culture  of  tissue  in  vitro,  that 
there  is  a  definite  temperature  at  which  cells  grow,  while  growth  decreases 
toward  certain  extremes  at  which  it  ceases.  Nevertheless,  these  extremes 
may  be  passed  without  the  actual  death  of  the  cell.  Marchand  and  others 
have  found  that  a  temperature  of  50°  to  51°  C.  (about  122°  F.)  is  sufficient 
to  cause  heat  coagulation  of  leucocytes.  So,  too,  distortion  and  fragmenta- 
tion of  red  corpuscles  occur  at  that  temperature,  and  even  the  necrosis  of 
epidermis  and  deeper  layers  of  the  skin.  Actual  haemolysis  is  produced  by 
a  higher  temperature — 59°  to  60°  C. — or  by  longer  exposure  at  the  lower 
point. 

Burns. — Actual  burning  or  scalding  through  exposure  to  much  higher 
temperatures  causes  various  degrees  of  alteration  in  the  skin,  according  to 
the  intensity  and  duration  of  the  action  of  the  heat;  the  skin  may  be 
reddened,  or  blistered,  or  finally  it  may  be  actually  roasted  or  charred. 
Burning  of  extensive  skin  surfaces  usually  causes  death  within  twenty-four 
hours,  but  more  limited  burns  and  those  of  slighter  intensity  may  be  sur- 
vived for  a  longer  time  or  even  permanently.  The  patient  suffers  the  most 
excruciating  pain,  becomes  delirious  or  stuporous,  but  extremely  restless, 
and  finally  passes  into  coma  which  ends  in  death.  The  pulse  is  small, 
respiration  rapid  and  shallow,  and  the  blood-pressure  sinks,  producing  the 
whole  symptom-complex  of  shock,  such  as  follows  great  trauma. 


INJURIES   FROM   HEAT  383 

At  autopsy  nothing  is  found  except  congestion  of  the  brain  and  meninges, 
and  occasional  small  haemorrhages  in  the  mucosa  of  the  digestive  tract. 
The  duodenal  ulcers  so  often  mentioned  are  really  rare.  Bardeen  empha- 
sized swelling  and  focal  necroses  in  the  lymphoid  structures,  but  these  seem 
to  be  not  especially  characteristic.  There  is  a  good  deal  of  fragmentation 
of  the  red  corpuscles  and  some  laking  of  the  blood.  Haemoglobin  is  ex- 
creted through  the  glomeruli  and  precipitated  in  irregular,  globular  masses 
in  the  tubules  of  the  kidney;  but  although  the  haemoglobinuria  is  marked, 
it  does  not  indicate  blood  destruction  enough  to  account  for  death.  The 
blood  is  concentrated  by  the  loss  of  plasma,  evidently  through  great  evapor- 
ation from  the  skin.  Thrombosis  of  the  minuter  vessels  has  been  described 
by  several,  but  others  have  failed  to  demonstrate  any  such  occlusion,  and 
it  can  hardly  play  an  important  part.  The  suggestion  has  been  made 
very  frequently  that  some  toxic  material  may  be  absorbed  from  the  burnt 
skin  which  could  account  for  the  collapse  and  death,  but  there  is  no  direct 
evidence  of  this.  It  seems  possible  that  since  the  symptoms  resemble  so 
closely  those  of  traumatic  shock,  the  same  poisons,  histamine  or  related 
substances,  may  be  concerned.  Extracts  of  such  burnt  skin  have  had  little 
or  no  poisonous  effect.  In  this  uncertain  state  of  knowledge  it  is  generally 
believed  that  death  is  actually  due  to  shock  produced  by  the  extreme  insult 
to  the  nervous  system. 

Injurious  Effects  of  High  Temperatures. — The  temperature  of  the  so- 
called  cold-blooded  animals  varies,  as  does  that  of  any  other  object,  with 
the  temperature  of  the  surrounding  air,  but  in  man  and  warm-blooded 
animals  in  general,  the  heat-regulating  mechanism  is  effective  to  maintain 
the  body-temperature  at  a  fairly  constant  level.  Clothes  and  other 
artificial  protections  are  important  in  aiding  this  in  the  case  of  man,  but 
even  without  them  the  mechanism  will  suffice  for  brief  periods  of  exposure 
to  extremes  of  heat  and  cold.  There  are  numerous  experiments  (Blagden 
and  others)  to  show  that  a  man  may  remain  for  many  minutes  without 
any  serious  discomfort  in  a  room  the  air  of  which  is  heated  to  many  degrees 
above  the  boiling-point  of  water  (120°  C.  or  248°  F.).  Saturation  of  the  air 
with  moisture,  so  that  the  cooling  evaporation  from  the  skin  cannot  take 
place,  or  a  longer  stay  will  finally  break  down  this  protection,  with  serious 
or  fatal  results. 

Heat-stroke;  Heat  Prostration. — In  very  hot  weather,  especially  in 
places  where  the  air  is  heavily  saturated  with  moisture,  it  is  not  uncommon 
for  persons  here  and  there,  to  fall  unconscious  in  convulsions,  and  sometimes 
to  die,  as  a  direct  effect  of  overheating.  These  are  usually  debilitated 
people,  or  those  who  make  great  muscular  exertion  in  clothing  which  pre- 
vents the  rapid  evaporation  of  moisture  from  the  skin  surface.  Occasion- 
ally in  periods  of  extreme  heat  and  humidity  great  numbers  of  people  may 
be  prostrated,  as  though  the  affection  were  epidemic  (Alex.  Lambert). 
The  mildest  effect  (heat  prostration)  consists  in  headache,  moderate  rise 
in  temperature,  pains  in  back  and  limbs,  and  extreme  exhaustion.  More 


384  TEXT-BOOK   OF   PATHOLOGY 

severe  is  the  asphyctic  form,  in  which  great  dyspnoea  and  cyanosis,  with 
delirium  or  unconsciousness,  are  added  to  these  symptoms.  Still  more 
severe,  and  very  frequently  fatal,  is  the  hyperpyretic  type,  in  which  un- 
consciousness and  collapse  come  on  suddenly,  or  after  several  days  of  vague 
premonitory  symptoms.  There  are  convulsions,  delirium,  or  profound 
coma,  with  shallow  and  gasping  or  very  deep  respiration,  and  finally  failure 
and  stoppage  of  the  heart.  The  skin,  at  first  covered  with  sweat,  becomes 
hot  and  dry,  and  the  temperature  rises  to  phenomenal  levels.  Lambert 
describes  one  case  in  which  the  rectal  temperature  reached  117.6°  F. 
Another  which  we  observed  reached  108°  F.  before  death,  but  after  death 
continued  to  rise  to  nearly  120°  F.  In  that  case  the  most  advanced  putre- 
faction with  great  distension  of  the  body  appeared  within  twenty-four  hours 
after  death,  and  this  is  a  phenomenon  regularly  observed  and  worthy  of 
study. 

Nothing  definite  is  found  at  autopsy  to  explain  such  a  death.  There  is 
intense  rigor  mortis,  which  sets  in  at  once;  the  blood  is  fluid,  but  thick  and 
dark  from  the  asphyctic  phenomena  of  the  last  hours.  No  infection  nor 
intoxication  has  been  demonstrated.  It  is  thought  that  the  centres  of  the 
medulla  are  directly  impaired,  and  that  the  extreme  hyperpyrexia  which 
follows  the  disordering  of  the  regulating  mechanism,  as  well  as  the  dis- 
turbances of  respiration  and  circulation,  are  of  central  origin.  McKenzie 
and  LeCount  found  oedema  of  the  brain  and  meninges  in  such  cases;  there 
was  swelling  of  the  brain  with  flattening  of  the  convolutions,  and  upon 
extraction  a  high  percentage  of  fluid.  The  lungs  were  oedematous,  there 
was  cloudy  swelling  of  the  liver,  kidneys,  and  myocardium,  with  petechial 
haemorrhages.  These  features  together  with  the  acute  splenic  tumor 
suggest  the  type  of  changes  usually  found  in  an  acute  infection. 

Sunstroke  or  insolation  must  be  distinguished  from  this,  since  it  is  the 
effect  of  exposure,  especially  of  the  head  and  neck,  to  the  direct  rays  of 
the  sun.  Violent  headache,  with  excitement  reaching  to  maniacal  out- 
bursts, convulsions,  and  loss  of  consciousness  characterize  the  attack,  and 
if  it  does  not  end  fatally  in  this  acute  stage  or  some  days  later,  there  may 
remain  permanent  mental  and  nervous  disturbances. 

Nothing  is  found  at  autopsy  except  congestion  and  swelling  of  the  face 
and  scalp,  and  a  similar  hypersemia  and  oedema  of  the  brain  and  meninges. 
It  is  thought  (Schmidt)  that  it  is  rather  the  bright  rays  of  the  sun  than 
the  ultraviolet  rays  which  penetrate  the  skull  and  cause  these  injuries  to 
the  brain — an  opinion  which  seems  open  to  question. 

LITERATURE 

Bardeen:  Jour.  Exp.  Med.,  1897,  ii,  501;  Johns  Hopkins  Hosp.  Rep.,  1898,  vii,  135. 

Lambert,  Alex.:  Medical  News,  1897,  Ixxi,  97. 

Marchand:  Handb.  d.  allg.  Path.,  1908,  i,  49. 

McCrae,  J.:  Trans.  Assoc.  Amer.  Phys.,  1901,  xvi,  153. 

McKenzie,  P.,  and  LeCount:  Jour.  Amer.  Med.  Assoc..  1918,  Ixxi,  260. 

Schmidt,  P. :  Arch,  f .  Hygiene,  1903,  xlvii,  292. 


INJURIES    PRODUCED    BY    COLD  385 

INJURIES  PRODUCED  BY  COLD 

The  heat-regulating  mechanism  in  the  case  of  man  is  rather  less  effective 
in  exposure  to  cold  than  to  high  temperatures,  and  since  it  works  only 
through  retention  of  the  body-heat,  it  fails  when  lowering  of  the  oxidative 
processes  reduces  the  production  of  heat.  Our  artificial  means  of  protec- 
tion have  become  absolutely  necessary  to  us,  since  we  are  not  hardened  to 
the  exposure  of  the  whole  body  to  cold,  and  are  no  longer  thickly  covered 
with  hair. 

With  prolonged  exposure  to  extreme  cold  there  are  at  first  excitement 
and  unrest,  but  later  the  skin  becomes  livid  or  pale,  blood  is  driven  back  into 
the  interior  of  the  body,  the  temperature  sinks,  metabolism  is  slowed  in  all 
the  organs,  and  their  activity  consequently  reduced,  the  limbs  become  stiff 
and  weak,  the  person  is  overcome  by  an  irresistible  desire  to  sleep,  the 
respiration  grows  shallow,  and  the  pulse  small  and  weak — the  temperature 
still  sinks,  and  when  it  reaches  20°  to  18°  C.  the  heart  stops  beating  and 
death  follows.  Nothing  distinctive  is  found  at  autopsy,  and  it  seems  prob- 
able that  death  is  due  to  just  these  changes  which  have  been  mentioned, 
just  as  a  perfused  heart,  beating  well  upon  Ringer's  fluid  at  body-tempera- 
ture, slows  down  and  stops  if  the  fluid  is  cooled  to  18°  C.  As  to  the  possi- 
bility of  recovery,  it  is  easy  enough  to  start  the  perfused  heart  beating 
again  by  warming  the  fluid,  but  the  resuscitation  of  a  person  is  a  different 
matter. 

There  has  been  much  discussion  and  experiment  as  to  the  resuscitation 
of  lower  animals  which  have  been  frozen,  and  the  most  divergent  results 
have  been  obtained.  It  seems  pretty  clear,  from  many  apparently  trust- 
worthy reports,  that  all  sorts  of  animals  and  plants  may  be  exposed  to 
extremely  low  temperatures  for  a  limited  time,  and  then  resume  their  vital 
activities  when  they  are  warmed  again.  But  it  is  generally  objected  that 
they  are  not  actually  frozen — that  is,  their  fluids  do  not  actually  crystallize, 
for  when  this  occurs,  the  injury  is  too  great  to  allow  of  recovery.  Even 
when  freezing  does  not  take  place,  prolonged  exposure  to  great  cold  kills. 
Lambert  has  shown  this  accurately  with  tissue  grown  in  vitro;  whereas  by 
placing  it  in  relatively  concentrated  plasma  or  salt  solution  it  may  be  kept 
alive  and  ready  to  grow  at  —  4°  to  —  6°  C.  for  five  days,  it  is  quickly  killed  in 
a  less  concentrated  plasma,  in  which  it  actually  freezes  at  this  temperature. 
Even  if  it  does  not  freeze,  it  is  killed  by  ten  days'  exposure  and  by  lower 
temperatures  in  a  far  shorter  time,  so  that  it  cannot  survive  exposure  to 
-20°  C.  for  twenty  minutes. 

The  noxious  effect  of  the  freezing  is  explained  either  as  due  to  mechani- 
cal tearing  of  the  cell  as  the  ice  crystals  are  formed,  or  to  the  concentration 
of  salt  around  the  crystals,  or  to  the  withdrawal  of  water  from  the  cell  to 
form  the  ice.  It  appears  that  the  injury  to  the  cell  is  the  direct  effect  of 
the  cold,  and  independent  of  the  rate  at  which  the  tissue  is  thawed  out. 
Rischpler  describes  in  detail  the  anatomical  changes,  which  consist  in 
vacuole  formation  in  the  protoplasm  and  disintegration  of  the  nucleus, 
26 


386  TEXT-BOOK    OF    PATHOLOGY 

and  finally  of  the  whole  cell-body.  It  is  easy  to  see  that  this  must  be  fol- 
lowed by  serious  inflammatory  reaction  or  by  gangrene.  This  is  indeed 
the  case,  but  it  must  be  stated  at  once  that  the  gangrene  of  extremities 
which  follows  such  chilling  is  by  no  means  always  directly  due  to  the  cold. 
On  the  contrary,  it  is  the  result  of  protracted  ischsemia  from  extreme  con- 
traction of  the  blood-vessels  or  their  obstruction  by  thrombi.  Frozen  feet 
or  toes  become  livid  or  cyanotic,  somewhat  swollen,  and  pulseless,  and  turn 
purple  and  finally  greenish  black.  The  process  is  quite  like  the  gangrene 
described  in  other  connections,  and  the  necrotic  areas  become  sharply 
demarcated  and  dry  up,  or  disintegrate  or  putrefy  if  they  are  not  removed 
by  the  surgeon.  Repeated  freezing  for  very  short  periods  at  intervals 
is  not  so  harmful  as  such  long-continued  freezing.  Instead  of  necrosis,  it 
tends  to  produce  a  remarkable  hyperplasia  of  the  tissue,  with  giant-cell 
formation  in  the  epidermis. 

Exposure  to  less  extreme  cold  with  moisture  produces,  especially  in  cer- 
tain susceptible  persons,  slighter  injuries,  evidently  largely  dependent  on 
the  contraction  of  the  vessels  and  the  resulting  anemia.  The  fingers  or 
toes  are  livid  or  cyanotic,  and  when  brought  back  into  the  warmth,  remain 
purplish,  but  swell  and  become  painful  and  disabled  (chilblains).  After 
some  days  the  epidermis  may  peel  oft7  in  patches,  while  the  normal  color 
comes  back  gradually.  Another  exposure  to  cold  will  bring  on  another 
attack. 

It  is  a  matter  of  common  experience  with  many  people  that  if  they  sit 
in  a  draft  or  get  wet  and  are  chilled  they  "catch  cold."  This  means  that 
an  infection  of  the  respiratory  tract  occurs  by  bacteria  which  are  present 
there  during  perfect  health,  but  which  gain  a  foothold  and  multiply  be- 
cause of  favorable  conditions  produced  by  the  chilling  of  the  skin.  Exactly 
what  those  conditions  are  is  not  clear,  although  it  is  generally  vaguely 
stated  that  chilling  of  the  skin  causes  congestion  of  the  internal  organs. 
This  seems  an  inexact  explanation,  since  congestion  is  usually  rather  inimi- 
cal, than  otherwise,  to  bacterial  invasion  (Bier).  The  investigations  of 
Mudd  and  Grant  have  shown,  however,  that  if,  when  the  skin  is  experimen- 
tally chilled,  a  thermopyle  is  applied  to  the  mucosa  of  the  nasopharnyx  it 
shows  a  corresponding  fall  in  temperature,  indicating  that  the  chilling  of 
the  skin  causes  a  reflex  vasoconstriction  in  the  mucosae.  This  anaemic 
condition  is  much  more  compatible  with  the  invasion  of  bacteria  than  the 
congestion  which  we  formerly  assumed  to  occur.  That  some  definite 
change  is  brought  about  is  plain,  however,  from  the  fact  that  the  same  sort 
of  exposure  will  cause  painful  stiffness  in  the  muscles  of  the  neck  or  back, 
which  must  be  of  inflammatory  character  (muscular  rheumatism),  while 
in  other  persons  it  brings  on  an  attack  of  diarrhoea.  Probably  in  all 
instances  the  chilling  acts  as  a  predisposing  factor,  favoring  the  invasion 
of  bacteria,  but  it  must  be  remembered  that,  although  it  is  common  in 
pneumonia,  coryza,  etc.,  it  is  by  no  means  an  indispensable  factor,  and 
every  one  realizes  that  it  is  perfectly  possible  to  catch  a  cold  from  some 
one  who  is  already  suffering, without  having  been  chilled. 


LIGHT   AND    OTHER   RADIANT  ENERGY:   ELECTRICITY  387 

LITERATURE 

Lambert:  Jour.  Exp.  Med.,  1913,  xviii,  406. 
Marchand:  "Die  Kalte  als  Krankheitsursache,"  Krehl  and  Marchand,  Handb.  d.  allg. 

Path.,  1908,  i,  541. 

Mudd,  S.,  and  Grant,  S.  B.:  Jour.  Med.  Research,  1919,  xl,  53. 
Rischpler:  Ziegler's  Beitrage,  1900,  xxviii,  541. 

LIGHT  AND  OTHER  RADIANT  ENERGY:    ELECTRICITY 

No  attempt  can  be  made  here  to  discuss  in  detail  this  subject,  which  be- 
comes daily  more  complex  with  the  astounding  discoveries  in  the  realm 
of  physics.  References  to  recent  works  which  present  the  subject  from  its 
physical  aspect  are  given,  so  that  the  student  may  consult  the  literature. 

Nature  of  Different  Rays.— Radiant  energy  takes  the  form  of  rays  moving  with  the 
same  velocity,  but  with  different  wave  lengths,  according  to  which  its  peculiar  character 
varies.  Analyzed  into  a  complete  spectrum,  it  appears  that  the  rays  of  greatest  wave 
length  are  electric;  then  follow  thermic,  optically  visible,  and  finally  chemically  active, 
rays,  which  have  the  minimal  wave  length.  The  atoms  of  each  substance  contain 
electrons  which  are  positively  and  negatively  charged.  The  vibrations  of  these  electrons 
communicate  electromagnetic  vibrations  to  the  ether.  These  waves,  impinging  upon 
other  bodies,  are  absorbed  by  their  electrons,  which  vibrate  at  the  same  rate,  and  since 
the  electromagnetic  vibrations  of  the  negative  electrons  have  the  wave  length  of  the 
ultraviolet  rays,  the  latter  are  readily  absorbed. 

Some  substances  have  the  power,  when  thus  influenced  by  certain  radiations,  of  giving 
forth  light-rays  of  another  quality.  This  so-called  fluorescence  is  of  great  biological 
significance. 

Other  forms  of  radiant  energy,  different  from  the  electromagnetic  transverse  vibrations 
of  the  ether,  are  the  so-called  corpuscular  rays,  which  consist  in  an  actual  bombardment 
of  negative  electrons  at  a  velocity  somewhat  less  than  that  of  light.  Where  they  impinge 
upon  metals,  they  produce  the  Rontgen-rays.  The  positively  charged  electrons  pass  in 
the  other  direction,  and  correspond  to  the  a-rays  of  radium.  The  shower  of  negative 
electrons,  the  kathode  rays,  correspond  with  the  /3-rays  of  radium.  Where  kathode 
rays  strike  upon  metal  or  glass,  there  are  produced  the  7-rays,  which  are  emanated  from 
radium  and  are  related  to  the  Rontgen-rays.  Like  the  electromagnetic  rays,  these 
corpuscular  rays  may  produce  electric,  thermic,  optic,  and  chemical  changes  (Aschoff). 

Effect  of  Light  Upon  the  Tissues. — General. — Ordinarily  we  meet  with 
conditions  in  which  the  tissues  are  acted  upon  by  a  whole  series  of  different 
forms  of  radiant  energy  at  once,  and  until  recently  no  attempt  has  been 
made  to  analyze  accurately  these  effects,  and  to  experiment  with  them  by 
separating  the  waves  of  different  length  and  allowing  them  to  act  alone. 
Of  the  visible  or  optically  active  rays,  it  has  been  said  that  those  toward 
the  red  end  have  the  longer  waves  and  are  associated  with  effects  of  heat — 
beyond  the  red  rays  are  invisible  rays  with  long  waves,  which  are  merely 
heat-waves.  On  the  other  hand,  toward  the  blue-violet  end  the  waves  are 
shorter,  and  their  photochemical  action  is  intense;  far  beyond  the  violet 
are  invisible  rays  spread  out  in  the  spectrum  which  have  the  greatest  power 
of  influencing  chemical  action.  These  very  short-waved  rays  correspond 
most  closely  with  the  vibration  of  the  negative  electrons  of  the  tissues,  and 
are  quickly  absorbed  by  the  most  superficial  layers,  especially  when  they 


388  TEXT-BOOK   OF    PATHOLOGY 

are  colored  by  pigment  deposits.  The  red  and  infra-red  rays  penetrate 
much  deeper. 

Little  effect  is  produced  by  the  red  rays  as  compared  with  the  violet 
and  ultraviolet.  They  are  capable  of  producing  an  influence  upon  cells 
only  in  the  presence  of  oxygen.  The  ultraviolet  rays  have  a  really  intense 
effect  on  the  tissues,  in  which  they  seem  to  act  as  catalytic  agents.  It  is 
not  quite  clear  how  they  produce  their  peculiar  influence,  but  it  is  appar- 
ently through  inducing  intense  chemical  decomposition  and  oxidation. 
Their  relation  to  the  lipoid  substances  is  peculiar  in  that  the  rays  sensi- 
tize them  and  prepare  them  for  oxidation  or  fermentative  decomposition. 
An  intracellular  oxidation  is  brought  about  without  the  advent  of  extra 
oxygen,  through  the  facilitation  of  decomposition  of  the  lipoid  substances 
by  the  action  of  the  light.  For  this  the  red-yellow  rays  require  an  actual 
excess  of  oxygen.  Ferments  are  affected  also,  but  perhaps  only  secondarily, 
by  way  of  the  altered  lipoids,  which  themselves,  under  the  influence  of  light, 
acquire  a  photoactivity. 

Such  effects  may  appear  in  extraordinarily  contrasting  forms,  according 
to  their  intensity,  so  that  at  times  a  new  impulse  to  growth  is  conferred, 
at  other  times  the  tissues  are  disintegrated  and  destroyed.  A  peculiar 
influence  is  exerted  by  fluorescent  bodies,  which  may  depend  upon  the  new 
rays  set  free  by  them  when  exposed  to  light  or  to  their  acting  in  some  way 
as  sensitizers.  In  the  dark  their  presence  has  no  significance,  but  if  bac- 
teria in  a  fluid  containing  eosin  are  exposed  to  sunlight,  they  are  killed  very 
rapidly.  Enzymes,  hsemolytic  substances,  venoms  and  toxins,  etc.,  are 
weakened  or  destroyed  in  the  same  way.  The  tissues  of  higher  animals 
seem  to  be  exposed  to  a  new  intensity  of  action  of  light-rays  if  they  are 
impregnated  with  eosin  or  some  similar  fluorescent  material  (cf.  Flexner, 
Noguchi). 

Sittenfield  found,  as  Tappeiner  and  others  had  already  observed,  that 
animals  injected  with  minute  quantities  of  hsematoporphyrin  remained 
normal  when  kept  in  the  dark,  but  died  quickly  when  exposed  to  sunlight 
or  to  the  rays  of  an  arc  lamp.  In  the  kidneys  and  other  organs  of  these 
animals  there  were  to  be  found  distinct  lesions  in  which  fragmentation  of 
nuclei  and  disintegration  of  cells  were  conspicuous.  The  part  played  by 
the  fluorescence  is,  however,  still  uncertain,  for  some  of  the  most  highly 
fluorescent  substances  are  but  slightly  toxic  under  exposure  to  light.  Mrs. 
Clark,  after  studying  the  effect  of  such  substance  as  eosin  on  rennin,  inclines 
to  the  idea  that  the  inhibition  of  the  action  of  the  rennin  is  due  to  the  de- 
composition of  the  eosin  with  the  liberation  of  its  halogen  constituents,  but 
v.  Tappeiner  showed  that  paramcecia  were  killed  and  disintegrated  in  an 
illuminated  solution  of  eosin  even  when  it  was  neutralized,  but  maintained 
their  form  for  hours  in  a  solution  in  which  free  acid  had  killed  them.  It  is 
evident,  as  Sellards  says,  that  the  subject  is  as  yet  comparatively  unde- 
veloped. 


LIGHT  AND   OTHER   RADIANT  ENERGY:   ELECTRICITY  389 

LITERATURE 

Bering:  Lubarsch  u.  Ostertag  Ergebn.,  1914,  xvii,  790. 
v.  Tappeiner  and  Jodlbauer:  Wirkung  fluoreszierender  Stoffe,  Leipzig,  1907. 
Clark:  Amer.  Jour.  Physiol.,  1918,  xlvii,  251. 
Sellards:  Jour.  Med.  Research,  1918,  xxxiii,  293. 

Effects  of  Ultraviolet  Rays. — The  sun's  light  contains  the  ultraviolet 
rays,  together  with  all  the  others,  but  they  are  produced  much  more  abun- 
dantly by  the  electric  arc  and  other  artificial  light.  We  may  consider  their 
pathological  effects  and  their  therapeutic  use  in  pathological  conditions. 

Exposure  to  the  sun  or  its  reflected  rays  (from  the  surface  of  water  or 
snow)  produces  the  familiar  sunburn.  This  is  far  more  intense  upon  the 
tops  of  high  mountains  than  at  the  sea-level,  where  the  ultraviolet  rays  are 
to  a  great  extent  absorbed  by  the  thick  layer  of  the  atmosphere. 

The  effect  is  not  noticed  at  once,  but  after  some  hours  there  comes 
on  an  intense  inflammatory  reaction  which  is  painful  and  often  accompanied 
by  blisters.  The  conjunctive  also  become  inflamed.  Evidently  there  is 
definite  injury  to  the  skin,  for  layers  of  it  peel  off  after  the  inflammation 
has  subsided.  The  blisters  may  leave  white,  scarred  patches  with  pig- 
mented  border.  Pigment  is  increased  in  the  skin,  and  is  recognized  as 
distinctively  protective  in  its  function.  Every  one  is  familiar  with  the 
people  who  burn,  others  who  acquire  freckles,  and  stilt  others  who  tan 
gradually  to  a  dark  brown  without  much  suffering.  The  dark  pigmenta- 
tion of  southern  races  and  of  negroes  is  evidently  a  protective  adaptation 
for  those  living  in  hot  countries. 

Histologically,  the  epidermis  in  the  sunburned  place  is  found  loosened 
and  vacuolated,  exudate  permeates  the  corium,  blood-vessels  are  widened, 
and  in  every  respect  the  inflammatory  reaction  is  like  that  produced  by 
some  mild  chemical  irritant.  Occasionally  the  repetition  of  such  sunburn 
in  certain  persons  produces  a  chronic  condition  of  pigmentation  and  ex- 
cessive keratinization  which  may  lead  to  cancer  formation  (the  so-called 
xeroderma  pigmentosum) .  In  other  persons  the  subject  of  certain  diseases, 
such  as  smallpox,  pellagra,  etc.,  the  sensitiveness  to  the  effects  of  light  is 
much  intensified,  and  the  example  of  buckwheat  rash  h*  cattle  seems  to 
make  it  probable  that  this  susceptibility  is  due  to  the  existence  of  a  sensi- 
tizing or  fluorescent  substance  in  the  tissues  in  those  diseases. 

Therapeutic  use  of  ultraviolet  and  other  rays  is  made  in  virtue  of  their 
more  or  less  specific  destructive  influence  upon  pathological  tissue  elements. 
The  epithelioid  cells  of  cutaneous  tuberculosis  (lupus  vulgaris)  are  especially 
susceptible  to  this  effect.  On  the  other  hand,  smallpox  patients  are  kept  in 
rooms  from  which  the  ultraviolet  rays  are  excluded  by  red  glass  in  order  to 
protect  their  sensitized  skin. 

The  Effects  of  x-rays  and  Radium  on  the  Tissues. — In  an  x-ray  tube  the  rays  which 
start  from  the  kathode  and  play  on  the  anode  (kathode  rays)  are  really  streams  of  nega- 
tive electrons  which  impinge  upon  the  metallic  anode,  and  there  cause  the  production  of 
electromagnetic  vibrations  of  the  ether  which  are  very  short,  very  irregular,  and  dis- 


390  TEXT-BOOK    OF    PATHOLOGY 

continuous.  These  are  the  Rontgen-rays.  There  is  a  stream  of  positively  charged 
electrons  passing  in  the  opposite  direction,  which,  if  the  kathode  is  perforated,  pass 
through  the  holes  and  are,  therefore,  called  channel  rays.  From  radium  there  are  given 
off  analogous  rays,  the  a-rays,  which,  like  the  channel  rays,  are  really  a  corpuscular 
stream  of  positively  charged  electrons  swung  off  from  the  decomposing  atom,  while  the 
similarly  discharged  stream  of  negatively  charged  electrons  constitutes  the  /3-rays, 
which  correspond  with  the  kathode  rays.  These,  through  striking  on  metal  or  glass, 
produce  7-rays,  in  just  the  same  way  as  the  kathode  rays  produce  the  Rontgen-rays. 
They  are  like  the  Rontgen-rays,  but  have  a  much  greater  power  of  penetration. 
By  the  use  of  adequate  niters  the  effect  of  the  different  rays  can  be  analyzed. 

Rontgen-rays  have  little  injurious  effect  upon  bacteria,  but  the  a-  and 
0-rays  from  radium  kill  them  directly,  although  they  do  not  render  the 
medium  in  which  they  grow  poisonous  to  them,  as  light-rays  do.  Toxins 
are  variously  affected,  but  the  toxalbumins,  such  as  snake  venoms,  are 
weakened  by  radium-rays. 

In  the  case  of  animals  and  man,  the  action  of  Rontgen-rays  and  radium- 
rays  is  very  similar,  the  /3-rays  behaving  like  the  kathode  rays.  Their 
effects  have  been  studied  especially  in  certain  susceptible  persons,  in  whom 
the  so-called  x-ray  burns  have  appeared  after  a  relatively  short  exposure 
for  diagnostic,  or  therapeutic  purposes,  and  also  in  radiologists  who  have 
been  careless  in  exposing  their  hands  in  operating  the  apparatus.  Now  that 
protection  is  afforded  the  radiologist  by  leaden  screens,  and  the  patient 
screened  by  a  thick  aluminum  plate,  the  corpuscular  rays  which  seem 
responsible  for  the  injurious  effects  are  eliminated,  and  burns  are  becoming 
a  matter  of  history. 

The  Skin. — Although  in  some  cases  a  reddening  of  the  skin  appears  at 
once,  this  is  usually  due  to  heat,  and  the  real  effects  of  the  burn  become 
evident  only  after  a  long  latent  period  of  about  two  weeks.  Then  the  skin 
becomes  swollen  and  reddened,  the  hairs  fall  out,  and  a  pigmentation  ap- 
pears. Blisters  and  excoriations  with  fibrinous  exudate  may  persist  for  a 
time,  or  the  skin  becomes  a  necrotic  slough  over  the  affected  area.  Such 
ulcers  as  result  from  the  discharge  of  this  dead  tissue  show  only  slow  at- 
tempts at  healing,  and  repair  is  never  complete,  as  is  pointed  out  by  Wol- 
bach  in  some  of  his  cases  examined  many  years  after  the  last  exposure. 

The  hands  of  radiologists  show  best  the  chronic  effects  of  long-repeated 
brief  exposure,  the  lesions  dating  usually  from  the  early  days  of  radiology, 
when  they  neglected  or  were  ignorant  of  screens.  Really  dreadful  distor- 
tion and  disfigurement  have  resulted  in  many  of  these  men.  The  skin  is 
dry,  reddened,  and  scaly,  with  painful  fissures  and  cracks  here  and  there 
which  refuse  to  heal,  or  after  healing  give  place  to  others.  The  hairs  are 
lost,  and  with  the  later  atrophy  of  the  skin  sweat-glands  also  disappear. 
More  extensive  ulcerations,  which  are  likewise  very  persistent,  occur. 
The  nails  are  thin  and  brittle,  and  are  usually  badly  split  and  broken. 

Wolbach  has  described  the  histological  changes  in  many  cases,  and  finds 
that  the  epidermis  in  places  produces  excessive  dense  keratinized  layers; 
in  other  places  the  cells  maintain  their  plump,  deeply  staining  nucleus, 


LIGHT   AND    OTHER   RADIANT   ENERGY!   ELECTRICITY  391 

and  show  no  tendency  to  keratinization.  At  times  vacuolated  and  evi- 
dently in  process  of  downfall,  the  epidermal  cells  are  often  found  in  active 
mitosis  growing  downward  into  the  cor  him.  The  cor  mm  is  indurated  in 
its  depths,  rarefied  in  the  more  superficial  layers,  where  it  becomes  poor  in 
cells  and  blood-vessels,  and  may  show  areas  of  necrosis.  The  capillaries 
which  are  there  often  become  greatly  distended,  and  are  even  so  much 
widened  as  to  give  the  appearance  of  telangiectases,  through  the  skin. 
Such  wide  capillaries  often  become  thrombosed,  and  Wolbach  describes 
the  invasion  of  these  by  the  growing  epithelial  cells.  Obliteration  of  ar- 
teries and  veins  and  of  capillaries  in  these  layers  of  the  skin  by  changes  in 
the  endothelium  and  by  thrombosis  and  later  organization,  seems  to  him 
responsible  for  much  of  the  necrosis  in  the  corium  and  the  inability  to  heal. 
With  the  destruction  of  the  corium  in  foci,  the  epidermis  is  stimulated  to 
grow  down,  invading  unusual  positions.  It  is  not  surprising,  therefore,  to 
find  that  this  brings  about  actual  epithelial  tumor  growth.  There  are 
many  cases  in  which  a  proliferation  of  the  epithelium,  at  first  indefinite, 
later  becomes  recognizable  as  an  actively  growing  skin  cancer,  which  de- 
stroys the  tissues  in  its  line  of  progress  and  metastasizes  into  other  organs. 
More  will  be  said  of  this  later,  as  it  offers  a  point  at  which  the  study  of 
cancer  development  seems  promising. 

The  Blood-forming  Organs. — Prolonged  exposure  to  x-rays  quickly  di- 
minishes the  number  of  lymphocytes  in  circulation;  the  other  leucocytes 
are  affected  slightly,  but  the  red  corpuscles  seem,  if  anything,  to  increase 
in  number.  Brief  exposure,  on  the  contrary,  causes  an  increase  in  the 
lymphocytes.  Cases  of  leukaemia  treated  with  x-rays  sometimes  show  an 
extraordinary  reduction  of  the  white  cells  in  the  blood,  while  the  red  cor- 
puscles are  unaffected.  Doubtless  the  influence  is  upon  the  blood-forming 
organs,  which  are  especially  sensitive  to  these  rays.  The  spleen  is  quickly 
reduced  in  size  and  becomes  much  pigmented.  In  the  thymus  the 
lymphocytes  disappear  rapidly,  and  even  the  framework  of  epithelial  cells 
is  injured.  Lymph-glands  lose  their  lymphocytes  and  become  mere 
skeleton  frameworks.  In  the  bone-marrow  the  red  corpuscles  do  not 
suffer,  but  the  lymphocytes  and  myelocytes  are  destroyed. 

An  animal  thus  deprived  of  its  lymphocytes  has  been  shown  by  Murphy 
to  be  far  more  than  normally  susceptible  to  tumor  implantations  and  also 
to  tuberculosis.  On  the  other  hand,  Sittenfield  and  Kessel  have  thought 
they  observed  a  retardation  of  the  invasion  of  tubercle  bacilli  after  exposure 

to  x-rays. 

Genital  Glands.— Testes  and  ovaries  are  also  highly  susceptible  to  the 
injurious  influence  of  the  radiation,  the  cells  of  the  testicular  tubules  which 
produce  the  spermatozoa  being  especially  affected  there,  while  interstitial 
cells  of  Leydig  and  Sertoli  cells  are  apparently  resistant.  After  sufficiently 
long  exposure  the  spermatic  fluid  is  found  to  be  devoid  of  spermatozoa. 

In  the  same  way  the  Graafian  follicles  in  the  ovary  suffer,  although  it  is 
less  easy  to  determine  whether  complete  sterility  is  produced  in  that  way. 


392  TEXT-BOOK   OF   PATHOLOGY 

Other  Organs.— In  all  the  other  organs  similar,  if  less  definite,  changes  are 
produced,  destructive  when  the  exposure  is  intense  enough,  but  rather 
stimulating  to  proliferation  and  cell  division  when  less  intense.  Experi- 
mental radiation  of  developing  eggs  and  embryos  usually  produces  either 
death  or  the  development  of  malformations  of  all  sorts. 

Pathological  tissues  seem  to  be  especially  susceptible  to  destruction  by 
these  rays,  whether  derived  from  radium  or  the  z-ray  tube,  and  a  great 
deal  of  work  has  been  done  upon  their  application  in  the  case  of  cancers 
and  other  tumors,  as  well  as  in  the  treatment  of  various  skin  diseases  and 
in  leukaemia,  Hodgkin's  disease,  and  other  affections  of  the  blood-forming 
apparatus.  This  is  not  the  place  to  discuss  the  results,  but  it  may  be  said 
that  while  the  effects  are  only  palliative  in  advanced  tumors  and  those  in 
which  metastases  have  already  formed,  there  are  some  tumors,  especially 
those  of  sarcomatous  or  lymphosarcomatous  nature,  such  as  occur  commonly 
in  the  nasopharynx,  which  melt  away  as  though  by  magic  under  their  in- 
fluence. Janeway  comments  on  this  and  also  refers  to  good  results  in  cu- 
taneous epitheliomas.  In  leukemia  a  temporary  improvement  may  be 
produced,  but  I  saw  one  case  recently  in  which  the  irradiation  of  a  mediasti- 
nal  lymphosarcoma  coincided  with  the  appearance  of  leuksemic  changes 
in  the  blood,  soon  followed  by  death.  The  destructive  changes  in  the  cells 
of  tumors  exposed  to  these  rays  have  been  studied  by  Alter. 

LITERATURE 

Janeway,  H.  H.:  Surg.,  Gyn.,  and  Obst.,  1918,  xxvi,  233. 
Boggs,  R.  H.:  Amer.  Jour.  Med.  Sci.,  1918,  clvi,  690. 
Alter,  N.:  Jour.  Med.  Research,  1919,  xl,  241. 

EFFECTS  OF  ELECTRICITY 

Electric  waves,  such  as  the  Hertzian  waves,  are  not  known  to  have  any 
effect  upon  living  beings.  Most  important  are  the  effects  of  the  passage, 
through  the  body,  of  powerful  currents  of  electricity  from  artificial  sources 
or  from  lightning. 

Judicial  electrocution  or  the  accidental  contact  of  the  body  with  the 
conductors  of  some  light  or  power  current  furnishes  examples  of  the  former. 
In  electrocution  the  contact  is  carefully  arranged,  so  that  the  current  will 
pass  through  the  nervous  system.  In  accidents  it  usually  happens  that 
the  person  touches  an  overhanging  conductor  and  allows  the  escape  of  the 
current  through  his  body  to  the  ground,  or  forms  with  his  body  a  short 
circuit  between  two  conductors.  In  the  case  of  lightning  he  becomes  in 
the  same  way  a  conductor  through  which  the  discharge  from  the  cloud 
passes  to  the  earth. 

Except  for  the  so-called  lightning  figures,  which  Jellinek  ascribes  to 
paralysis  of  blood-vessels,  and  which  are  branching  red  lines  radiating  over 
the  skin,  the  effects  of  lightning  and  the  passage  of  the  electric  current  are 
the  same. 


EFFECTS   OF   ELECTRICITY  393 

Fatal  shocks  may  be  produced  by  a  direct  current  with  electromotive 
force  of  500  volts.  With  alternating  currents  the  effect  depends  partly 
upon  the  rapidity  of  alternation,  and  when  this  is  extremely  rapid,  as  in 
the  Tesla  currents,  its  passage  may  become  quite  harmless.  The  effect  of 
such  electric  shocks  depends  largely  upon  the  resistance  of  the  skin  and  of 
the  whole  body,  and  differs  in  different  animals.  Horses  whose  resistance 
to  conduction  is  very  slight  are  especially  sensitive. 

The  pathological  effects  are  most  evident  in  the  skin  and  underlying 
tissues,  where  at  the  point  of  contact  deep  burns  are  produced,  often  de- 
stroying the  tissue  down  to  the  bone.  At  the  point  where  the  current 
leaves  the  body  a  similar  charred  wound  may  be  found,  with  an  appearance 
almost  like  that  of  a  gunshot  wound,  a  resemblance  which  is  often  inten- 
sified by  the  singeing  of  the  neighboring  skin  and  by  the  radiating  tears 
in  the  tissue.  These  wounds  in  non-fatal  cases  are,  like  x-ray  burns,  extra- 
ordinarily persistent  and  hard  to  heal.  The  exact  cause  of  death  is  not 
clear,  since  little  is  to  be  observed  in  the  internal  organs  aside  from  small 
haemorrhages  and  the  curious,  irregular  streaks  of  contraction  and  hyaline 
change  in  the  muscles  described  by  Schmidt.  There  are  great  changes  in 
blood-pressure  and  evidences  of  shock,  but  whether  these  are  due  to 
changes  in  the  medulla  oblongata  or  to'  direct  action  upon  the  heart  it  is 
impossible  to  say. 

LITERATURE 

Aschoff:  Krehl  and  Marchand,  Handb.  d.  allg.  Path.,  1908,  i,  144. 
Councilman  and  Magrath:    "Xeroderma  pigmentosum,"  Jour.  Med.  Research,  1909, 

xxi,  331. 
Flexner  and  Noguchi;  Noguchi:   Jour.  Exp.  Med.,  1906,  viii,  1,  252,  268;    1907,  ix,  281, 

291;   1908,  x,  30. 

Heineke:  Mitth.  a.  d.  Grenz.  d.  Med.  u.  Chir.,  1905,  xiv,  21. 
Jellinek:  Elektropathologie,  Stuttgart,  1903. 
Murphy:   Jour.  Exp.  Med.,  1914,  xx,  397. 
Porter:  Jour.  Med.  Research,  1909,  xxi,  357. 
v.  Schlapfer:  Pfluger's  Arch.,  1905,  cviii,  537;   1906,  cxiv,  301. 
Schmidt:  Verh.  d.  Deutsch.  path.  Gesellsch.,  1910,  xiv,  218. 
Wolbach:  Jour.  Med.  Research,  1909,  xxi,  415. 


CHAPTER  XIX 
TYPES  OF  INJURY  (Continued).— CHEMICAL  INJURIES 

Nature  of  poisons:  their  varying  effects.  Reaction  of  organism;  elimination,  detoxica- 
tion,  resistance.  Auto-intoxication.  Poisoning  by  illuminating  gas,  corrosive  substances, 
cyanides.  Chloroform,  alcohol,  metallic  poisons,  etc. 

CHEMICAL  INJURIES 

Nature  of  Poisons. — Injurious  chemical  substances  or  poisons  are  those 
which  enter  into  chemical  reaction  with  the  tissues  in  such  a  way  as  to 
injure  them.  All  the  activities  of  the  body  are  based  on  chemical  reac- 
tions, and  many  substances  which  we  regard  as  foods  are  necessary  and 
helpful  to  these  chemical  processes.  Others  which  prevent  them  or  actually 
destroy  the  structure  of  the  cells  are  poisons. 

Many  of  the  substances  which  derange  the  activities  of  the  cells  do  so 
only  temporarily,  and  are  changed  into  some  harmless  form  or  excreted 
completely  before  long.  It  is  difficult  to  say,  therefore,  in  many  cases, 
whether  or  not  we  should  call  them  poisons,  but  in  some  instances  the  repe- 
tition, through  years,  of  the  slight  effects  of  single  doses  leaves  the  organs 
much  altered,  and  we  realize,  in  recognizing  this  chronic  poisoning,  that 
each  dose  had  its  own  injurious  effect. 

It  is  essential  to  the  complete  understanding  of  the  action  of  a  poison 
that  we  should  know  its  chemical  composition,  and  that  of  the  protoplasm 
with  which  it  comes  into  relation,  as  well  as  the  nature  of  the  interaction. 
Perhaps  even  more  important  is  a  knowledge  of  the  chemical  process 
through  which  the  cell  carries  on  its  function,  and  in  which  the  poison  inter- 
feres at  some  point,  but  at  present  it  is  only  in  the  rarest  instances  that  we 
possess  all  this  information  in  accurate  detail. 

The  study  of  all  types  of  poisons  is  the  province  of  toxicology,  but  it  is 
equally  interesting  to  the  student  of  pathology  for  whom  the  structural 
changes  and  alterations  of  function  form  the  subject  of  investigation. 
These  are  so  manifold  that  no  attempt  can  be  made  to  describe  them  here, 
and  we  must  be  content  with  an  outline  of  the  principles  involved. 

Varying  Effects  of  Poisons. — Without  knowing  why,  we  realize  that  the 
effects  of  many  poisons  vary  greatly  with  their  quantity  and  concentra- 
tion, so  that  while  small  doses  stimulate  the  tissues  to  intensified  biological 
activity,  larger  or  more  concentrated  doses  have  the  opposite  effect,  prob- 
ably because  they  render  impossible  some  part  of  this  activity.  Often 
this  is  effected  through  making  the  tissue  at  first  more  sensitive,  and  then 
less  sensitive,  to  the  normal  stimuli. 

When  a  poison  produces  definite  structural  changes  in  the  cells,  its 

394 


CHEMICAL   INJURIES  395 

effect,  so  far  as  those  cells  are  concerned,  is  permanent,  although  the 
animal  may  recover  in  virtue  of  the  great  reserve  power  of  every  organ, 
which  can,  with  the  remnant  of  its  tissue,  carry  on  the  whole  function 
long  enough  to  tide  over  the  crisis  and  allow  new  cells  to  form  and  repair 
the  loss.  But  if,  as  is  so  common,  the  poisoning  is  repeated  frequently, 
the  efforts  at  compensation  and  repair  finally  become  inadequate,  and  the 
man  with  advanced  chronic  nephritis  dies  from  the  effects  of  renal  in- 
sufficiency. 

The  extraordinary  resources  in  the  face  of  such  attacks,  and  the  long  life 
that  may  be  dragged  out  with  such  injured  organs,  are  very  striking,  in 
contrast  with  the  sudden  violent  symptoms  and  death  which  follow  a 
rapid  and  extensive  destruction  of  their  tissues.  Of  course,  in  the  latter 
case  the  margin  of  safety  is  overstepped,  and  there  is  not  enough  tissue 
left  alive  to  carry  on  the  organ's  function,  but  in  the  former,  where  the 
destruction  is  gradual,  there  is  a  chance  for  accommodation  to  the  reduced 
efficiency  of  the  organ. 

Unlike  these  poisons,  there  are  others  whose  action  is  a  temporary  or 
invisible  one;  the  functions  of  the  tissue  elements  are  disturbed  only  while 
the  poison  is  dissolved  in  their  fluids,  and  quickly  return  to  the  normal 
when  it  is  washed  away.  A  familiar  example  is  found  in  the  awakening 
from  narcosis,  during  which  the  ether  or  chloroform  is  thought  to  be  dis- 
solved in  the  lipoids  of  the  brain-cells. 

The  body  has  numerous  fairly  effective  methods  of  removing  poisonous 
substances,  or  even  of  protecting  itself  against  their  action.  Irritating 
corrosive  substances  are  vomited  from  the  stomach,  which  throws  out  a 
thick,  tough  layer  of  tenacious  mucus  to  protect  its  mucosa  -against  what 
remains.  Elimination  of  poisons  is  hurried  by  the  development  of 
diarrhoea,  but  also  occurs,  in  the  case  of  volatile  substances,  through  the 
breath,  and  in  the  case  of  many  others  through  the  kidneys  or  the  in- 
testinal mucosa. 

In  the  case  of  some  poisons,  such  as  arsenic,  opium,  cocaine,  alcohol, 
etc.,  it  is  a  matter  of  common  knowledge  that  habitue's  become  able  to 
take  far  larger  doses  than  other  people  without  any  poisonous  effect.  The 
explanations  attempted  for  this  are  very  unsatisfactory,  especially,  perhaps, 
with  regard  to  the  hunger  for  morphine  and  alcohol  which  these  people 
develop  when  the  drugs  are  denied  them,  and  which  often  produces  such 
stormy  symptoms.  No  such  theory  as  Ehrlich  has  devised  for  the  immu- 
nity or  resistance  which  comes  after  poisoning  with  bacterial  or  animal 
poisons  will  apply  here,  for  the  mechanism  seems  to  be  quite  different  and 
is  still  to  be  discovered.  In  the  case  of  arsenic  it  is  said  that  the  larger  and 
larger  doses  of  the  drug  fail  to  poison  because  the  intestinal  mucosa  acquires 
the  power  of  refusing  to  absorb  it,  so  that  even  in  a  person  able  to  swallow 
an  enormous  dose  without  any  ill  effects  the  subcutaneous  injection  of  the 
same  material  is  just  as  poisonous  in  small  doses  as  it  would  be  to  the  most 
unaccustomed  person. 


396  TEXT-BOOK   OF   PATHOLOGY 

The  mechanism  of  resistance  to  bacterial  toxins,  snake  venoms,  and 
some  related  plant  poisons,  such  as  ricin  and  abrin,  has  been  detailed  else- 
where. (Cf.  Zinsser.)  Its  far-reaching  importance  cannot  be  over- 
estimated, but  even  this  mechanism  may  be  turned  to  unfortunate  use  at 
times,  as  it  seems  to  be  in  producing  the  anaphylactic  poisoning  and  injury 
to  the  tissues  (Longcope,  Jobling). 

On  the  other  hand,  there  are  some  poisons,  such  as  strychnine  and  digi- 
talis, which  have  a  so-called  cumulative  effect,  in  that  successive  doses 
seem  to  build  up  their  effect  upon  those  which  have  gone  before,  and  act 
with  increasing  intensity. 

While  rapid  elimination  and  variously  acquired  resistance  thus  work 
toward  the  warding-off  of  the  effects  of  many  poisons,  there  are  many 
which  are  neutralized  in  other  ways  by  losing  their  chemical  characters 
under  the  influence  of  the  body.  Inorganic  poisons,  when  they  are  simple 
combinations  in  the  form  of  a  salt,  are  dissociated  as  electrolytes  in  the 
body  fluids,  and  the  action  is  an  action  of  separate  ions.  Arsenic,  mer- 
cury, and  lead  act  in  this  way,  as  kations,  in  virtue  of  their  metallic  pecu- 
liarities, while  the  anion  in  sodium  bromide  or  fluoride  or  iodide  is  the  one 
which  appears  as  a  poison.  When  the  combination  is  very  stable  and  com- 
plex, these  metals  may  be  introduced  in  forms  in  which  they  are  not 
easily  dissociated,  and  then  fail  to  unfold  their  characteristic  poison- 
ous effects.  It  is  further  true  that  combinations  of  atoms,  in  themselves 
innocuous,  may  acquire,  in  virtue  of  their  peculiar  arrangement,  toxic 
characters  of  the  greatest  intensity.  Therefore  it  is  not  surprising  that 
mere  processes  of  oxidation  may  sometimes  be  capable  of  disarranging 
this  fatal  combination  and  rendering  the  poison  inert.  Similarly,  syn- 
thetic combinations  may  occur  with  the  same  result — carbolic  acid,  in 
itself  a  violent  poison,  becomes  harmless  in  the  form  of  a  double  ethereal 
sulphate,  while  other  substances  are  decomposed,  sometimes  to  render 
them  innocent,  at  other  times  only  to  liberate  a  more  poisonous  combi- 
nation. 

Interesting  and  complex  antagonisms  between  various  inorganic  sub- 
stances occur  in  their  action  upon  cells,  and  in  so  far  as  they  are  not  mere 
precipitations  of  the  poison,  are  very  hard  to  explain.  Meltzer  has  shown 
that  the  injection  of  a  calcium  salt  will  awake  instantly,  from  the  deepest 
coma,  a  rabbit  poisoned  with  magnesium,  and  the  papers  of  J.  Loeb  throw 
much  light  upon  similar  antagonistic  action  between  calcium  and  sodium 
or  potassium  salts,  and  many  others,  as  tested  on  developing  eggs,  muscular 
activity,  etc.  He  at  least  proves  that  it  is  not  merely  the  neutralization 
of  differently  charged  ions. 

No  effort  shall  be  made  here  to  give  a  classification  of  poisons;  the  stu- 
dent is  referred  to  text-books  on  toxicology  and  pharmacology.  In  general 
poisons  are  derived  from  inorganic  or  mineral  sources,  from  plants, 
including  bacteria  and  fungi,  and  from  animals.  Of  the  inorganic  sub- 
stances, the  most  familiar  poisons  are  the  salts  of  heavy  metals,  such  as 


ABSORPTION   AND    GENERAL   EFFECTS   OF   POISONS  397 

lead,  arsenic,  antimony,  mercury,  chromium,  manganese,  etc.,  and  the 
halogen  group,  fluorine,  bromine,  iodine.  From  plants  come  great  num- 
bers of  highly  poisonous  alkaloids  and  glucosides,  oils,  terpenes,  alco- 
hols, and  coal-tar  products,  as  well  as  all  the  enormously  complex  toxins 
produced  by  bacteria  and  moulds,  which  have  the  special  peculiarity  of 
stirring  up  resistance  and  immunity  in  the  poisoned  animals.  Quite 
similar  in  this  respect  are  those  other  plant  poisons  of  which  ricin  and  abrin 
have  already  been  mentioned.  From  animals  there  originate  many  vehe- 
ment poisons,  of  which  those  specially  secreted  in  glands  for  offensive  pur- 
poses (snake  venoms,  etc.)  are  the  most  interesting.  Other  animal  products, 
especially  the  partly  digested  or  disintegrated  proteins,  such  as  albumoses, 
seem  to  be  poisonous  when  introduced  subcutaneously  or  intravenously; 
although  they,  like  snake  venoms,  are  innocuous  if  swallowed.  These 
protein  materials,  including  the  venoms,  also  have  the  power  of  inciting  a 
reaction  of  immunity,  and,  indeed,  one  can,  by  injecting  frequently  the 
proteins  or  the  cells  of  one  animal  into  another  of  a  different  species,  pro- 
duce in  the  blood  of  that  second  animal  a  substance  which  would  be  dis- 
tinctly poisonous  if  now  injected  into  the  body  of  the  first.  Such  cyto- 
toxins,  which  include  hsemolytic  sera,  have  already  been  referred  to. 

Different  in  principle  is  the  development  of  poisonous  substances  in 
putrefying  fish  or  flesh.  Although  part  of  these  familiar  sudden  and  vio- 
lent poisonings,  which  may  end  fatally  in  whole  groups  of  people  who  have 
partaken  of  stale  shellfish,  fish,  meats,  or  milk  products,  have  long  been 
ascribed  to  ptomaine-poisoning,  it  is  possible  that  in  most  cases  such  epi- 
demics are  really  due  to  infection  with  certain  bacteria  (B.  botulinus  of 
Van  Ermengen,  B.  enteritidis  of  Gartner,  and  allied  forms). 

Much  is  written  of  autointoxication,  or  the  absorption  of  poison  from 
some  place  where  it  is  formed  in  the  body  itself.  In  so  far  as  the  proper 
evacuation  of  the  excreta  is  interfered  with  by  obstruction  or  disease  of 
the  excretory  organs,  this  is  easily  comprehended.  Obstruction  of  the  in- 
testine may  be  rapidly  fatal,  and  so,  too,  may  such  disease  of  the  kidneys, 
or  obstruction  to  the  outflow  from  ureters  and  bladder  as  can  stop  or 
greatly  decrease  the  excretion  of  urine.  Ursemic  poisoning  falls  into  this 
latter  class.  The  absorption  of  bacterial  poisoning  from  the  unobstructed 
and  otherwise  not  diseased  intestine  has  long  been  widely  accepted,  but 
must  be  taken  with  caution,  while  it  seems  more  confusing  than  helpful  to 
class  the  alterations  of  metabolism  which  follow  disease  of  the  organs  of 
internal  secretion  as  autointoxication.  Most  of  these  are  in  reality  the 
effect  of  the  lack  of  some  secretion  proper  to  the  injured  gland,  although, 
of  course,  in  the  imperfect  metabolism,  toxic  substances  may  arise,  as  in 
the  case  of  /3-oxybutyric  acid  in  diabetes  (q.  v.}. 

ABSORPTION  AND  GENERAL  EFFECTS  OF  POISONS 

Most  poisons  are  taken  into  the  digestive  tract,  although  volatile  or  gaseous 
poisons  may  be  absorbed  in  the  lungs,  and  other  substances,  such  as  mer- 


398  TEXT-BOOK    OF    PATHOLOGY 

cury,  may  penetrate  the  skin,  or,  as  in  the  case  of  snake-venoms  or  the 
drugs  administered  in  a  hypodermic  syringe,  be  introduced  directly  into 
the  tissue  or  the  blood-stream. 

They  act  locally,  as  when  strong  acids  or  alkalies  or  caustic  metallic 
salts  corrode  and  kill  the  tissues,  or  else  they  are  absorbed  into  the  blood 
and  then  exercise  a  more  general  effect.  When  poisons  are  introduced 
into  the  streaming  blood,  they  disappear  very  rapidly  and  are  not  to  be 
quantitatively  recovered  from  the  blood,  nor  equally  from  all  organs,  but 
often  concentrate  themselves  in  certain  tissues  with  a  markedly  selective 
action.  Under  such  circumstances  the  poison  often  reaches  the  nervous 
system  or  other  vital  organs  in  greater  concentration  than  after  the  slower 
absorption  from  the  alimentary  tract.  Naturally,  in  the  case  of  bacterial 
toxins  and  the  less  denned  products  of  protozoan  and  other  animal  para- 
sites, the  distribution  of  the  parasites  determines  to  a  great  degree  the 
spread  of  the  poison,  although  there  are,  at  least,  two  bacterial  infections 
(diphtheria  and  tetanus)  in  which  the  bacteria  grow  locally  on  a  mucous 
surface  or  in  a  wound,  and  diffuse  their  poison  throughout  the  body. 

It  has  been  said  that  most  poisons  seem  to  show  a  certain  selective 
action  in  the  way  they  affect  especially  one  organ  or  another.  It  would  be 
better  to  say  that  those  organs  exhibit  a  special  affinity  for  certain  poisons, 
but  it  is  usual  to  classify  poisons  as  cardiac  poisons,  renal  poisons,  blood- 
poisons,  etc.  Since  there  is  little  in  common  among  the  members  of 
such  groups,  the  classification  seems  hardly  rational,  and  we  must  be- 
lieve that  the  organ  absorbs  them  and  is  affected  by  them  for  different 
reasons.  For  example,  of  the  poisons  which  affect  the  central  nervous 
system,  narcotics,  strychnine,  and  magnesium  salts  must  behave  very 
differently. 

Here,  if  anywhere,  it  should  be  easy  to  carry  out  the  general  aim  of  this 
book  and  set  in  order  the  pathological  results  on  the  basis  of  aetiology,  but 
the  number  of  poisons  is  so  limitless,  and  their  effects  are  so  variegated,  that 
any  classification,  to  be  at  all  accurate,  must  include  an  immense  number 
of  headings.  For  this  space  at  least  is  lacking,  and  once  more  the  student 
must  be  referred  to  works  on  toxicology  and  pharmacology.  It  is  desir- 
able, however,  to  discuss  briefly  the  very  common  forms  of  poisoning  which 
are  found  at  autopsy,  and  which  occur  nowadays  usually  in  cases  of  suicide 
or  in  persons  who  have  worked  with  poisonous  materials  in  one  of  the  dan- 
gerous industries.  Doubtless  in  the  old  days,  when  poisoning  was  a  fine 
art,  the  subject  was  vastly  more  interesting. 

Persons  committing  suicide  by  poison  are  generally  ignorant  of  the  pain- 
ful effects  of  the  poison  which  they  choose  to  take,  but  are  impelled,  by  the 
lurid  descriptions  in  the  newspapers,  to  swallow  what  some  other  suicide 
is  said  to  have  taken.  Hence  whole  epidemics  of  poisoning  with  bichloride 
of  mercury  have  occurred  recently.  Many  other  substances  are  used 
because  they  can  be  obtained  easily,  and  this  is  true  of  carbolic  acid  and 
cyanide  of  potassium,  and  of  the  ever-accessible  illuminating  gas. 


ABSORPTION   AND   GENERAL  EFFECTS   OF   POISONS 


399 


Illuminating-gas  Poisoning. — The  essential  factor  in  this  is  the  carbon 
monoxide,  which  is  present  in  greater  concentration  in  the  so-called  water- 
gas  than  in  the  other  types  of  illuminating  gas.  Breathed  into  the  lungs, 
it  quickly  replaces  oxygen  in  the  red  corpuscles,  by  virtue  of  its  very  much 
greater  affinity  for  haemoglobin  and  the  tenacity  with  which  it  holds  to  this 
combination.  It  can  be  gradually  washed  away  by  prolonged  breathing 
of  pure  air  or  oxygen,  so  that  carbon  monoxide  haemoglobin  is  not  a  perma- 
nent and  stable  combination.  The  blood,  and  consequently  all  the  organs, 
assume  a  bright,  cherry-red  color,  which  is  little  affected  by  the  condition 
of  asphyxia  of  the  tissues,  for  it  is  as  difficult  for  carbon  dioxide  to  dislodge 


Fig.  195.— Carbon  monoxide  poisoning;    symmetrical  necroses  in  lenticular  nuclei. 

the  carbon  monoxide  as  it  is  for  the  oxygen.  There  are  usually  fever  and 
leucocytosis,  but  no  direct  injury  to  the  lungs,  nor,  as  a  rule,  pneumonia. 
It  is  common  to  find  at  autopsy  symmetrical  areas  of  softening  with  minute 
haemorrhages  in  the  corpora  striata  and  lenticular  nuclei  of  the 

Corrosive  Poisons.— Strong  acids  and  alkalies  and  some  metallic  salts, 
swallowed  usually  with  suicidal  intent,  produce  deep  lesions  in  the  stomach 
wall  which,  while  very  characteristic  when  fresh,  are  more  difficult  to 
recognize  as  the  typical  effect  of  a  particular  poison  when  the  persons  sur- 
vive long  enough  to  allow  the  digestive  action  of  the  gastric  juice  to  reduce 
them  all  to  a  similar  appearance. 


400 


TEXT-BOOK    OF    PATHOLOGY 


Nitric  add  produces  deep  necroses  in  the  stomach-wall  which  are  dis- 
colored and  mottled  with  white  and  black  debris,  but  characteristically 
colored  in  places,  at  least,  by  the  bright  orange  yellow  of  the  xantho- 
proteic  reaction.  Hydrochloric  acid  fails  to  produce  this  color,  while  strong 
sulphuric  acid  chars  the  mucosa  into  a  crumbly  black  mass. 

In  all  these  cases  the  immediate  effect  is  to  make  the  stomach  contract  sharply,  so 
that  the  crests  of  the  folds  of  mucosa  are  pressed  together  and  form  a  smooth  surface, 
while  the  depths  between  are  protected  and  secrete  much  thick  mucus  for  their  further 

protection.  Distension  of  the  stomach  tends 
to  make  the  effect  more  diffuse,  but  food,  when 
present,  aids  in  the  protection  of  the  mucosa. 

Carbolic  acid  is  much  favored  by 
suicides,  and  is  usually  swallowed  in 
concentrated  form.  White  eschars 
about  the  mouth  and  in  the  oesophagus 
prepare  one  for  the  appearance  of  the 
stomach,  in  which  again  the  crests  of 
the  folds  suffer  most  intensely  (Fig. 
196).  They  are  covered  with  a  white, 
opaque  layer  of  necrotic  tissue.  Car- 
bolic acid  is  an  excellent  fixing  fluid, 
and  in  microscopical  preparation  these 
areas  of  the  mucosa  seem  perfectly 
normal.  The  fixation  or  coagulation 
may  extend  through  the  wall  of  the 
stomach  and  involve  adjacent  organs, 
which  look  as  though  they  had  been 
cooked.  Lysol  poisoning  produces  a 
peculiar  effect  in  the  stomach,  and 
here,  as  in  the  case  of  carbolic  acid,  the 
deeper  cells  of  the  mucosa,  killed  but 
not  fixed  by  the  poison,  are  digested  by 
the  ferments  of  the  stomach  (Fig.  197). 
Uyeno  has  described  extensive  changes 
in  the  kidney  from  long-continued  car- 
bolic-acid poisoning.  These  are  hardly 
to  be  found  in  the  acutely  fatal  cases. 

Caustic  alkalies  are  generally  swallowed  by  mistake,  and  this  accident  is 
especially  common  among  children  in  the  south,  where  concentrated 
lye  is  sometimes  used  for  household  purposes.  If  they  die,  the  gastric 
mucosa  is  found  greatly  swollen  and  haemorrhagic,  and  often  rather  gelatin- 
ous, from  the  direct  effect  of  the  alkali.  If  they  survive,  the  destructive 
changes  which  are  commonly  produced  in  the  wall  of  the  oesophagus  lead 
to  narrowing  of  its  lumen  by  scar  tissue.  Such  strictures  must  be  dilated 
to  prevent  starvation. 


Fig.  196. — Carbolic-acid  poisoning. 
Coagulation  of  crests  of  the  folds  of 
mucosa  in  the  stomach. 


ABSORPTION   AND   GENERAL   EFFECTS   OF   POISONS 


401 


Prussic  add  and  cyanides  have  no  corrosive  effect  in  the  stomach,  but 
the  mucosa  assumes  a  bright,  chestnut-brown  color  which  is  characteristic. 
Here,  as  in  carbolic-acid  poisoning,  the  odor  of  the  stomach-contents  and 
tissue  is  a  very  great  help  in  recognizing  the  nature  of  the  poison.  The 
cyanides  cause  death  by  their  action  on  the  nervous  sytem  and  heart,  and 
by  their  wide-spread  interference  with  oxidation  and  ferment  processes 
throughout  the  body. 

Fumes  from  nitric  acid,  which,  according  to  Wood,  are  essentially  nitro- 
gen tetroxide,  although  mixed  with  other  oxides,  may  be  inhaled  in  acci- 


. 


~*i.  *^'T"lAltt3  m        '  ^& 

^»v^ 


Fig.  197.— Lysol  poisoning.     Superficial  necrosis  and  partial  digestion  of  the  gastric 


mucosa. 


dents,  explosions,  etc.,  and  may  cause  death,  as  in  one  case  which  we 
studied,  with  extensive  desquamation  of  the  lining  epithelium  of  the 
lungs,  with  lobular  pneumonia  and  oedema  of  the  lungs.  Strong  ammo- 
nia and  chlorine  vapors  have  a  somewhat  similar  corrosive  effect,  asso- 
ciated with  other  more  general  evidences  of  intoxication. 

It  is  impossible  to  discuss  here  all  the  manifold  effects  of  the  poison- 
ous gases  used  in  the  war,  and  the  student  must  be  referred  to  the 
special  literature  upon  the  subject.  The  most  important  gases  used  were 
mustard  gas,  the  phosgene,  chlorpicrine,  chlorine  group,  and  the  arsme 
compounds.  In  brief,  the  lesions  produced  are  summarized  by  Pappei 
27 


402  TEXT-BOOK   OF   PATHOLOGY 

heimer  as  follows:  No  data  are  available  on  the  lesions  in  human  beings 
from  the  arsine  compounds.  Mustard  gas  (dichlorethylsulphide)  produces 
blisters  on  the  skin  after  a  long  latent  period.  Its  inhalation  causes 
necrosis  of  the  respiratory  mucosa  with  formation  of  a  diphtheritic  mem- 
brane extending  deep  into  the  bronchi,  and  followed  by  purulent  bron- 
chitis with  regeneration  of  the  epithelium,  usually  with  squamous  meta- 
plasia. All  types  of  lobular,  hsemorrhagic,  and  interstitial  pneumonia 
follow,  sometimes  resulting  in  gangrene,  extensive  organization,  or 
bronchiectasis.  Intestinal  and  cerebral  haemorrhages  have  been  found, 
and  there  is  aplasia  of  the  bone-marrow  resulting  in  leucopenia.  The 
changes  caused  by  phosgene,  chlorine,  etc.,  consist  essentially  of  extreme 
oedema  of  the  lungs,  coming  on  after  a  latent  period  with  areas  of 
atelectasis  and  emphysema.  When  recovery  is  not  immediate,  various 
types  of  pneumonia  follow.  No  other  visceral  changes  are  observed. 

Other  volatile  substances  can  be  absorbed  through  the  enormous  capil- 
lary surface  exposed  in  the  lungs,  and  take  effect  with  a  rapidity  almost 
as  great  as  though  they  had  been  injected  into  the  veins.  Among  these 
chloroform,  ether,  and  the  other  narcotics  are  most  prominent. 

Chloroform  has  a  distinctly  poisonous  effect,  as  is  shown  by  the  necrosis 
and  fat  accumulation  which  it  produces  in  the  liver.  Its  more  rapidly  fatal 
effects  seem  to  be  due  to  the  paralysis  of  the  heart  which  it  brings  about 
when  administered  in  too  great  concentration.  Evarts  Graham  states 
that  the  poisonous  effect  of  chloroform  is  due  to  its  decomposition  within 
the^  cell  with  liberation  of  free  hydrochloric  acid. 

Alcohol  is,  of  course,  the  commonest  of  poisons  that  affect  human 
beings.  Methyl-alcohol  in  relatively  small  doses  produces  coma  and  death, 
or  recovery  with  blindness.  Its  action  is  in  part  due  to  the  fact  that  it  is 
changed  to  formic  acid  in  the  tissues.  Ethyl-alcohol  has  the  well-known 
effect  of  producing  drunkenness,  and  after  protracted  habitual  use  seems  to 
give  rise  to  many  anatomical  changes  in  the  organs.  The  proof  of  this 
connection  is  not  so  clear  as  it  should  be,  and  is  questioned  by  many, 
especially  since  such  changes  cannot  be  produced  experimentally  with  any 
degree  of  constancy.  This  is  true  of  cirrhosis  of  the  liver,  which  can  be 
caused  by  so  many  other  kinds  of  injury  and  which  is  absent  in  such  a  large 
percentage  of  those  who  have  abused  alcohol  to  the  last  degree  for  many 
years.  Nevertheless,  it  is  unreasonable  to  deny  its  part  in  this  process, 
since  it  undoubtedly  has  poisonous  qualities  and  seems  capable  of  such  a 
banal  effect.  Probably  it  acts  in  this  respect  in  combination  with  some 
other  poisons.  The  destructive  effects  upon  the  brain  are  more  evident 
in  the  functional  disturbances  which  are  clearly  traceable  (delirium  tremens; 
alcoholic  insanity,  etc.).  With  regard  to  the  relation  of  alcohol  to  chronic 
nephritis,  arteriosclerosis,  etc.,  the  same  may  be  said  as  for  cirrhosis  of  the 
liver. 

Mention  may  be  made  of  a  few  poisons  absorbed  by  workers  in  various 
dangerous  industries.  This  subject  is  so  broad  that  the  reader  is  referred 
to  the  special  literature  upon  occupational  diseases. 


ABSORPTION   AND   GENERAL   EFFECTS   OF   POISONS  403 

Lead. — Chronic  lead  poisoning  (saturnism)  among  painters  occurs  in 
pottery  workers,  white-lead  workers,  and  many  others  who  constantly  deal 
with  dusty  operations  with  lead  in  various  combinations,  and  is  so  common 
as  to  assume  great  importance  among  industrial  poisonings.  Acute  lead- 
poisoning  is  rare. 

Anaemia,  intestinal  colic,  a  bluish  line  along  the  gums  of  those  who  neg- 
lect the  cleanliness  of  their  teeth,  paresis  of  the  extensor  muscles,  resulting 
in  the  so-called  wrist-drop  and  toe-drop,  and  occasionally  outspoken  mental 
disturbances  are  characteristic  of  this  affection.  Lead  may  be  found  in 
the  brain,  bones,  kidneys,  and  liver  in  proportion  varying  according  to  differ- 
ent investigators.  It  is  excreted  in  urine,  faeces,  saliva,  bile,  etc. 

In  the  blood  there  is  decrease  of  red  corpuscles,  which  show  a  baso- 
philic  granulation,  and  there  may  be  jaundice  (icterus  saturninus).  The 
colic,  which  is  very  painful,  is  thought  by  Kobert  to  be  due  to  an  irritation 
of  the  motor  nerve  elements  of  the  intestinal  muscles  and  blood-vessels. 
A  form  of  gout  associated  with  chronic  saturnism  may  be  partly  due  to  de- 
posits of  a  lead  combination  with  uric  acid.  Local  anaesthesia  and  blind- 
ness occur.  Cerebral  disease,  the  so-called  "lead  encephalopathy,"  with 
depression,  delirium,  convulsions,  and  even  general  paralysis,  is  found  to 
be  due  to  chronic  degenerative  changes  in  the  cortical  cells,  vascular 
changes,  scarring,  and  meningeal  thickening,  together  with  pigmentation 
and  small  hemorrhages.  The  condition  resembles  in  some  respects  that 
found  in  dementia  paralytica. 

The  motor  paralysis  affects  some  cranial  nerves,  but  more  especially 
the  spinal  motor  nerves,  musculo-spiral,  peroneal,  etc.  It  is  a  peripheral 
neuritis,  not  primarily  an  affection  of  the  anterior  horn  cells,  and  the 
muscles  show  a  secondary  degeneration,  although  retaining  for  a  time  their 
excitability.  Chronic  diffuse  nephritis  of  the  arteriosclerotic  type,  with 
extensive  scarring,  obliteration  of  blood-vessels  and  glomeruli,  is  char- 
acteristic of  lead  poisoning,  and  evidently  depends  largely  upon  the  effect 
of  the  poison  upon  the  smaller  blood-vessels. 

Arsenic. — Once  most  extensively  used  for  purposes  of  murderous  poison- 
ing and  for  suicide,  arsenic  poisoning  is  now  accidental  or  connected  with 
its  absorption  from  adulterated  foods  or  from  various  paints,  and  dyes  used 
in  coloring  wall-papers,  cloths,  etc.  There  may  be  expected,  therefore, 
acute  and  slow  chronic  poisoning.  Acute  Form—When  taken  into  the 
stomach  in  poisonous  doses,  the  effect  may  be  rapid  death  from  direct 
influence  upon  the  brain  and  heart,  but  more  often  the  symptoms  are 
referable  to  the  digestive  tract,  where  the  lesions  are  accentuated  by  the 
reexcretion  of  absorbed  arsenic  through  the  mucosa.  Swelling,  haemor- 
rhage, diphtheritic  inflammation  with  ulceration,  are  characteristic,  and 
in  the  mucosa  of  the  stomach  crystals  or  particles  of  the  swallowed  arsenic 
persist.  When  Paris  green  or  some  other  brightly  colored  combination  is 
swallowed,  this  is  a  conspicuous  feature.  Fat  accumulation  in  liver,  kid- 
neys, and  other  intestinal  organs  is  common.  Chronic  Poisoning.— In 


404  TEXT-BOOK    OF    PATHOLOGY 

the  chronic  forms  which  may  appear  late,  after  even  one  severe  poisoning, 
the  nervous  system  suffers  especially,  but  conspicuous  changes  are  found  in 
the  skin.  The  cutaneous  lesions  are  manifold,  the  most  extreme  being 
forms  of  excessive  keratinization  and  deep  pigmentation.  The  nervous 
changes  have  the  character  of  a  neuritis,  with  paralyses,  followed  by  mus- 
cular atrophy  and  contractures.  There  may  be  also  cerebral  disturbances 
of  varying  degree.  Most  important  is  the  danger  of  blindness  from 
arsenical  destruction  of  the  optic  nerves,  after  the  careless  use  of  salvarsan 
and  others  of  the  newer  synthetic  arsenical  remedies.  Arsenic  is  finally 
lodged  in  the  bones,  and  may  long  be  recognized  there. 

Phosphorus. — As  an  industrial  poisoning  in  those  who  work  in  match 
factories,  and  as  a  poison  accessible  to  all  for  suicidal  purposes  in  the  heads 
of  old-fashioned  matches,  phosphorus  is  more  important  in  Europe  than 
in  this  country.  Acute  poisoning,  with  vomiting,  depression,  jaundice, 
haemorrhages,  swelling  of  the  liver,  etc.,  may  lead  to  death.  Aside  from 
the  haemorrhages,  which  may  be  widely  scattered,  one  finds  intense  icterus 
and  great  enlargement  of  the.  liver,  with  wide-spread  necrosis  and  autolytic 
disintegration  of  the  cells.  Whatever  cells  are  left  are  distended  with  fat 
and  lipoid  globules.  With  recovery,  the  liver  decreases  in  size  and  may 
become  greatly  scarred.  Kidneys,  heart  muscle,  and  even  skeletal  muscles 
are  loaded  with  fat.  Chronic  poisoning  occurs  especially  in  those  exposed 
to  vapors  of  phosphorus,  and  is  particularly  characterized  by  producing 
necrosis  of  the  jaws.  This  begins  with  suppuration  at  the  root  of  a  tooth, 
which  sets  free  a  quantity  of  pus,  when  it  finally  loosens  and  drops  out. 
The  destruction  with  suppuration  does  not  cease  there,  but  progresses, 
to  destroy  the  whole  jaw  or  even  to  extend  into  the  neck.  Evidently 
the  aid  of  bacterial  infection  is  necessary  to  the  process. 

Mercury. — Suicidal  poisoning  with  mercuric  bichloride  is  at  present  in 
favor,  since  the  public  imagination  is  stirred  by  the  detailed  reports  of 
several  cases.  A  few  years  ago  there  were  cases  of  the  same  sort  of  poison- 
ing due  to  the  inordinate  irrigation  of  wounds  with  this  substance,  which 
was  used  as  an  antiseptic.  The  poisoning  from  careless  use  of  mercurial 
drugs  or  from  the  inunction  of  syphilitics  with  mercurial  ointments  is 
usually  milder  and  more  chronic  in  its  course,  and  since  it  shows  itself  in 
salivation,  the  loosening  of  teeth,  and  fcetor  from  the  mouth,  is  likely  to  be 
checked  before  producing  a  fatal  result.  Industrial  poisoning  with  mer- 
cury is  not  uncommon  in  such  trades  as  mirror  making,  gilding,  ther- 
mometer making,  etc. 

The  acute  poisoning  provokes  intense  gastro-intestinal  symptoms,  with 
pain,  metallic  taste,  vomiting,  diarrhoea,  etc.  The  stomach  shows  various 
lesions,  according  to  the  nature  of  the  poison  and  the  dose.  A  large 
quantity  of  a  solution  of  mercuric  bichloride  may  fix  the  mucosa  so  that 
it  appears  normal  micriscopically,  although  white  and  opaque  to  the 
naked  eye.  A  solid  tablet  may,  it  seems,  act  intensely  on  one  spot  and  cause 
the  death  of  the  tissue,  with  subsequent  ulceration.  If  this  be  survived, 


ABSORPTION    AND    GENERAL   EFFECTS    OF    POISONS 


405 


the  symptoms  may  practically  disappear,  but  later  others  ensue — anuria 
and  evidences  of  inflammation  in  the  colon.  Death  follows  days  or  even 
weeks  later  from  renal  insufficiency.  Since  mercury  once  absorbed  is 
reexcreted  through  the  mucosa  of  the  intestine,  it  is  surprising  to  find  at 
autopsy  the  most  intense  diphtheritic  and  hsemorrhagic  enteritis  (Fig.  198). 
Mercury  can  be  recognized  by  appropriate  tests  in  the  necrotic  mass  lying 


Fig.  198.— Mercuric  chloride  poisoning.     Diphtheritic  and  hsemorrhagic  colitis 

upon  the  mucosa,  and  in  the  mucosa  itself.  The  kidneys  present  most 
extensive  necrosis  of  the  epithelium  of  the  tubules,  with  deposition  of  cal- 
cium in  and  about  the  dead  cells.  Later,  with  the  liquefaction  of  these 
cells  or  their  disintegration  by  phagocytes,  the  calcium  becomes  coalescent 
in  irregular  masses  within  the  tubules  (Fig.  127).  The  remaining  epithelial 
cells  proliferate  rapidly,  to  replace  those  which  were  lost,  and  often  be- 
come large  protoplasmic  masses  with  many  nuclei,  which  act  as  phagocytes 


406  TEXT-BOOK    OF    PATHOLOGY 

and  engulf  those  which  are  in  process  of  disintegration  (Fig.  128).     (Cf. 
Heineke.) 

It  does  not  fall  within  the  scope  of  this  book  to  treat  of  the  multi- 
farious effects  of  poisons  of  plant  and  animal  origin.  They  might  be 
classified  according  to  their  point  of  action,  as  in  other  text-books  of  pathol- 
ogy, and  mentioned  by  name,  but  except  for  their  discussion  in  other  con- 
nections, it  seems  better  to  refer  the  student  to  works  on  toxicology  where 
they  are  satisfactorily  treated. 

LITERATURE 

Boehm:   Krehl  and  Marchand,  Handb.  d.  allg.  Path.,  1908,  i,  198. 
Ford:    "Plant  Poisons  and  Antibodies,"  Centralbl.  f.  Bakt.  u.  Paras.,  1913,  Iviii,  129. 
Heineke:    "Sublimate  Poisoning,"  Ziegler's  Beitrage,  1909,  xlv,  197. 
Jobling:  Jour.  Exp.  Med.,  1914,  xx,  37. 
Robert:    Lehrb.  der  Intoxikationen,  1902-1906,  Stuttgart. 
Loeb:  "Antagonistic  Salt  Action,"  Biochem.  Zeitschr.,  1911,  xxxvi,  275.     Jour.  Biol. 

Chem.,  1914,  xix,  431. 

Longcope:    Jour.  Exp.  Med.,  1913,  xviii,  678. 
Meyer  and  Gottlieb:   Lehrb.  d.  exp.  Pharmakologie,  Berlin,  1914. 
Schall:    "Aetzgifte,"  Ziegler's  Beitrage,  1908,  xliv,  458. 
Thompson:    "Illuminating  Gas  Poisoning,"  Med.  Record,  1904,  Ixvi,  41;  Occupation 

Diseases,  New  York,  1914. 

Uyeno:    "Exp.  Carbolic  Acid  Poisoning,"  Ziegler's  Beitrage,  1910,  xlvii,  126. 
Wood:    Trans.  Assoc.  Amer.  Phys.,  1912,  xxvii,  407. 
Peterson  and  Haines:  Text-book  Legal  Medicine,  Philadelphia,  1903. 
Welch:  Pathological  Effects  of  Alcohol,  Boston,  1903. 
War  Gases: 

Marshall,  Lynch,  and  Smith:  Jour.  Pharm.  and  Exp.  Therap.,  1918,  xii,  265. 
Mackenzie:  U.  S.  Naval  Med.  Bull.,  1918,  xii,  173. 
Winternitz:  Mil.  Surgeon,  1919,  xliv,  476. 

War  thin  and  Weller:  Jour.  Lab.  and  Clin.  Med.,  1918,  iii;  1919,  iv. 
Pappenheimer  and  Vance:  Proc.  Soc.  Exp.  Biol.  and  Med.,  1919,  xvi,  92. 


CHAPTER  XX 

TYPES    OF    INJURY    (Continued).— EFFECTS    OF    OBSTRUCTION 
OF  THE  FLOW  OF  CONTENTS  OF  HOLLOW  ORGANS.    OB- 
STRUCTION IN  THE  ALIMENTARY  TRACT 

Salivary  ducts:  bile-ducts  (gall-stones,  cholecystitis,  jaundice).  Pancreatic  ducts  (pan- 
creatic cirrhosis,  acute  pancreatitis).  Obstruction  of  digestive  tract.  (Esophagus,  stomach 
(gastric  ulcer).  Intestine;  varying  mechanism  of  obstruction  (hernias,  intussusception, 
volvulus,  compression  or  kinking  by  adhesions,  paralysis,  stenosis). 

THE  possession  of  a  duct  or  canal  for  the  discharge  of  secretions,  or  for  the 
reception  and  transmission  of  fluid,  gaseous,  or  even  solid  materials,  is 
an  arrangement  common  to  a  great  many  organs.  Wherever  this  plan  is 
made  use  of,  there  may  arise  obstruction  of  the  canal,  and  the  effects  which 
follow  are  so  much  alike  that  it  seems  desirable  to  consider  them  together, 
and  to  regard  this  as  one  of  the  types  of  injury  which  underlie  pathological 
processes.  The  mechanical  principles  are  very  nearly  the  same  in  all, 
although  it  may  at  first  glance  seem  absurd  to  bring  together  in  any  way 
such  processes  as  bronchiectasis  and  hydronephrosis.  As  a  rule,  an 
accumulation  of  material  occurs  on  one  side  of  the  obstruction,  which  causes 
the  gradual  widening  of  that  part  of  the  canal,  while  the  part  on  the  other 
side  remains  normal  or  even  shrinks  together.  This  and  the  general 
behavior  of  the  organ  depend,  however,  very  largely  upon  whether  the 
obstruction  is  complete  or  only  partial.  Some  organs  can  go  on  secreting 
for  a  while,  attempting  to  force  their  secretion  into  the  duct  against  a  com- 
plete obstruction,  but  in  many  cases  they  quickly  stop  all  activity  under 
those  conditions  and  the  duct  never  becomes  distended.  On  the  con- 
trary, when  the  obstruction  is  only  partial  or  intermittent,  secretion  or 
the  entrance  of  material  into  the  canal  goes  on  until  it  becomes  greatly 
dilated.  Examples  from  various  parts  of  the  body  will  make  these  princi- 
ples clear,  and  show  further  many  modifying  influences.  These  conditions, 
varying  as  they  do,  afford  a  large  proportion  of  the  operable  disturbances 
which  may  be  treated  by  the  surgeon. 

RESULTS  OF  OBSTRUCTION  IN  THE  ALIMENTARY  TRACT 

Naturally,  since  the  glands  of  the  stomach  and  intestine  open  by  indi- 
vidual canals,  it  is  rare  to  find  any  obvious  effect  of  their  obstruction, 
although  it  is  quite  true  that  in  some  old  inflammatory  changes  in  the 
mucosa  they  may  be  constricted  at  their  orifice  or  obliterated  by  healing 
processes  so  that  their  continued  secretion  distends  them  into  tiny  cysts. 
This  is  more  frequent  in  the  colon  than  elsewhere.  But  the  accessory 

407 


408  TEXT-BOOK   OF   PATHOLOGY 

glands,  which  empty  into  the  alimentary  tract,  are  often  victims  of  some 
form  of  occlusion  of  their  ducts. 

In  the  salivary  glands  this  is  not  especially  common,  but  there  do  occur 
calculous  concretions  in  the  salivary  ducts  which  partly  or  completely  oc- 
clude them  and  cause  inflammation  and  dilatation  of  the  duct,  with  gradual 
atrophy  of  the  gland.  Such  calculi  are  rough  and  irregular  and  white,  and 
are  composed  chiefly  of  calcium  phosphate  and  carbonate. 

Bile-ducts. — In  the  case  of  the  liver,  the  canal  giving  exit  to  the  biliary 
secretion  is  somewhat  complicated  by  the  presence  of  a  reservoir,  the  gall- 
bladder, joined  on  laterally.  Obstruction  of  the  canal  may,  therefore,  take 
place  at  such  a  point  as  to  affect  the  whole  system,  only  the  lateral  reservoir, 
or  only  the  liver  or  portions  of  the  liver.  The  obstruction  may  be  caused 
by  compression  of  these  ducts  from  the  outside  at  any  point;  by  changes  in 
their  own  walls,  which,  becoming  thickened,  encroach  upon  the  lumen, 
or  by  some  solid  plug  which  may  lodge  at  any  point  in  their  lumen.  Not 
uncommonly  these  factors  are  found  combined,  as  when  there  arises  about 
an  obstructing  gall-stone  an  inflammatory  thickening  of  the  wall  of  the 
duct  or  even  a  tumor. 

Much  has  been  said  in  discussing  the  rather  broader  topic,  jaundice, 
about  the  important  part  played  by  various  forms  of  obstruction  in  its 
development,  and  this  need  not  be  repeated.  The  principles  underlying 
such  obstruction  are,  however,  well  exemplified  in  the  variegated  phenomena 
which  are  associated  with  the  formation  of  gall-stones  (cholelithiasis) . 

Gall-stones. — In  the  first  place,  it  is  becoming  clearer  in  later  years  that  the  primary 
formation  of  gall-stones  is  itself  largely  dependent  upon  stagnation  of  bile,  such  as  may 
arise  in  the  gall-bladder  if  an  intermittent  or  incomplete  closure  of  the  cystic  duct  be 
brought  about  by  such  things  as  tight  lacing,  pregnancy,  or  even  the  unequal  sagging  of 
the  abdominal  viscera.  Then,  although  some  bile  moves  in  and  out  of  the  gall-bladder, 
there  is  stagnation,  and  even  in  the  clear,  uninfected  fluid,  cholesterine  crystals  may  sepa- 
rate out  and  cluster  about  a  central  point  until  there  is  formed  a  solitary  round  or  oval, 
slightly  roughened,  stone-like  mass,  which  usually  lies  loose  in  the  neck  of  the  gall- 
bladder.* This  is  the  first  type  named  by  Aschoff  and  Bacmeister,  the  radiate  choles- 
terine stone  (Fig.  199),  because  it  is  found  on  cross-section  to  be  composed  of  coarse, 
radiately  arranged  crystals  of  nearly  pure  cholesterine,  which  project  to  produce  the 
roughened  surface  of  the  stone.  There  is  so  little  admixture  of  other  materials  that  such 
calculi  are  quite  clear  or  only  pale  yellow.  Pure  crystalline  masses  of  this  sort  are  not 
very  common,  for  usually  they  become  covered  with  yellow,  brown,  or  greenish  material 
by  a  secondary  deposit.  This  happens  when,  after  the  stone  has  lain  in  the  gall-bladder 
for  some  time,  infection  with  bacteria  arises  around  it  and  causes  inflammation  of  the 
gall-bladder  wall  (cholecystitis).  With  the  appearance  of  the  inflammatory  exudate, 
which  is  rich  in  calcium,  there  are  deposited  on  the  surface  layer  after  layer  of  a  com- 
bination of  calcium  and  bilirubin.  It  may  be  emphasized  that,  whereas  the  cholesterine 
is  a  constituent  of  the  bile  and  crystallizes  out  from  it  calcium  appears  in  appreciable 
quantities  only  in  the  course  of  inflammation.  Such  a  mixed  stone  with  a  nucleus 

*  Recent  investigations  of  Stewart,  Hermann  and  Neumann,  and  others  show  that, 
during  pregnancy,  the  blood  and  bile  are  rich  in  cholesterine.  Doubtless  this  is  important 
in  the  production  of  gall-stones,  which  are  so  common  in  women  who  have  borne  several 
children.  Rothschild  and  Wilensky  support  this  in  their  studies  of  the  cholesterin  con- 
tent of  the  blood  in  this  and  other  conditions,  but  there  are  others  who  deny  the  relation. 


RESULTS   OF   OBSTRUCTION   IN   THE   ALIMENTARY   TRACT       409 


Fig.  199. — Two  large  radiate  cholesterine  gall-stones,  one  of  which  is  broken,  together 
with  several  small,  mixed  pigment  and  cholesterine  stones  with  outer  covering  of  cho- 
lesterine. 


Fig.  200.— Subacute  and  chronic  cholecystitis  with  gall-stones.  There  is  one  rounded 
stone  of  pure  cholesterine,  together  with  nine  faceted  mixed  pigment  calculi.  The 
small  irregular  mass  was  found  in  the  duct. 


410  TEXT-BOOK   OF   PATHOLOGY 

formed  of  cholesterine  and  a  mantle  of  calcium  bilirubin  may  be  regarded  as  the  second 
type.  The  mode  of  its  formation  by  apposition  is  shown  hi  sections  by  the  fact  that 
each  projecting  crystal  of  the  cholesterine  nucleus  is  separately  covered  by  a  layer  or 
two  of  the  brown  mantle  before  the  depressions  are  sufficiently  filled  up  to  allow  the 
next  layer  to  be  laid  on  smoothly. 

There  are  other  types,  such  as  the  laminated  calcium  cholesterine  stones,  and  the  soft, 
blackish  green,  calcium  bilirubin  concretions,  which  are  usually  formed  in  the  hepatic 
ducts,  and  more  rarely  get  into  the  gall-bladder;  but  all  these  are  rarer  and  of  less 
importance  than  the  last  form,  which  is  the  common  mixed  calcium  bilirubin-cholesterine 
stone  (Fig.  200).  These  form  the  great  majority  of  all  gall-stones,  and  occur  sometimes 
in  hundreds  or  thousands  in  a  single  case,  although  there  may  be  only  two  or  three  large 
ones  filling  up  the  gall-bladder.  These  large  ones  are  rounded  or  barrel-shaped  and 
faceted  where  they  abut  on  one  another.  The  smaller  ones  vary  in  color  from  pure, 
silky  white  through  yellow,  brown,  and  green  to  black.  They  may  be  so  small  as  to  be 
almost  like  sand,  or  a  centimetre  or  two  in  diameter.  Often  a  great  number  of  stones 
of  almost  exactly  the  same  size  may  be  found  together.  Usually  they  are  faceted  against 
one  another,  and  fit  together  by  their  polished  surfaces  like  dice.  Sometimes,  indeed, 
they  seem  to  show  the  effects  of  rubbing,  for  several  laminae  may  be  exposed.  On  cut- 
ting through  and  polishing  one  of  these  there  is  found  to  be  a  soft,  greenish-brown  or 
yellow  central  mass  which  is  composed  of  conglomerate  crystals  with  much  organic 
material  and  pigment,  and  then,  surrounding  this,  there  are  laminae,  often  alternating 
in  color,  of  a  much  denser  consistence,  and  composed,  as  stated  above,  of  a  mixture  of 
cholesterine  with  calcium  bilirubin  (Fig.  201). 

Ribbert's  interesting  study  of  these  stones  gives  many  details  of  their  structure, 
showing  that  the  central  portion  contracts  upon  drying  in  such  a  way  that  sharp  clefts 
extend  radially  as  far  as  the  laminated  outer  part.  He  devised  a  new  way  of  studying 
them  in  section,  and  finds  that  the  part  played  by  the  calcium  is  perhaps  less  than  gen- 
erally supposed. 

All  the  types  of  gall-stones  described  contain  a  great  deal  of  organic  material  derived 
from  desquamated  epithelial  cells  and  coagulated  albuminous  matter,  as  well  as  pigment. 
Many  of  them  contain  bacteria,  and  are  formed  in  infected  bile  and  within  a  gall-bladder 
which  is  inflamed,  because  in  this  vicious  circle  the  presence  of  the  stone  aids  in  giving  a 
foothold  to  bacteria,  while  they  in  turn,  through  the  inflammation  they  set  up,  aid  hi 
the  growth  of  the  stone. 

The  bacteria  are  of  many  sorts,  but  the  typhoid  and  colon  bacilli  are  common  invaders, 
and  doubtless  the  pyogenic  cocci  are  important  in  causing  the  acuter  forms  of  inflamma- 
tion. How  they  enter  has  been  much  discussed.  Probably  the  typhoid  bacilli,  since 
they  are  distributed  everywhere  by  the  blood-stream,  might  reach  the  gall-bladder  in 
that  way,  but  they  may  also  be  excreted  from  the  liver  in  the  bile,  and  may  be  found 
there  for  months  after  convalescence  from  typhoid  fever.  There  is  some  evidence  that 
they  may,  by  being  agglutinated  in  clumps,  produce  nuclei  upon  which  gall-stones  may 
form,  but  this  evidence  is  not  conclusive,  since  it  has  been  shown  that  bacteria  may 
quickly  wander  into  such  stones.  The  lower  end  of  the  common  duct  is  always  infected, 
so  that,  especially  when  calculi  lodge  in  the  duct  and  obstruct  the  stream,  bacteria  may 
wander  up  in  that  way.  The  occurrence  of  cholecystitis  following  appendicitis  seems  to 
suggest  the  possibility  that  bacteria  may  be  carried  from  the  appendix  by  way  of  the 
portal  vein,  and  back  into  those  branches  which  drain  the  gall-bladder. 

Cholecystitis. — There  is  nothing  peculiar  about  the  inflammatory  process 
in  cholecystitis.  The  beginnings  are  seldom  seen,  but  apparently  infection 
takes  place  in  the  so-called  Luschka's  crypts,  or  under  gall-stones  which 
press  on  the  wall.  It  commonly  produces  diffuse,  abscess-like  infiltration 
of  the  wall  (acute  phlegmonous  cholecystitis),  often  with  extensive  ulceration 
of  the  mucosa.  Gall-stones  may  come  to  lie  in  these  deep  ulcers,  or  even 


18 


Fig.  201. — Gallstones  of  various  types  cut  and  polished.  4,  7,  13,  14  and  17  show 
primary  gallstones  at  first  composed  of  almost  pure  cholesterine,  later  covered  with 
pigment.  3,  5,  6  and  11  are  facetted  secondary  stones.  9  and  19  show  well  the  thin 
laminae  found  under  the  facetted  surfaces. 


RESULTS   OF   OBSTRUCTION   IN   THE    ALIMENTARY   TRACT        411 

to  pass  through  perforations  in  the  wall  if  the  ulcer  goes  deep  enough, 
sometimes  into  a  neighboring  hollow  organ,  like  the  colon,  if  there  have 
been  adhesions,  at  other  times  into  the  open  peritoneum.  I  have  seen 
one  case  in  which  recovery  took  place  after  such  a  discharge  of  stones, 
and  long  afterward  they  were  found  hanging  in  fibrous  capsules  from  the 
omentum  like  so  many  cherries. 

Occasionally  the  acute  forms  of  cholecystitis  heal  completely,  but  usually 
there  are  many  recurrences,  especially  when  stones  persist  and  bile  is  stag- 
nant, and  the  ulcerated  mucosa,  as  well  as  the  whole  thickness  of  the  wall, 
becomes  much  occupied  by  scar  tissue  (chronic  recurring  cholecystitis) 
(Figs.  202,  203,  204).  The  remnants  of  mucosa  are  thrown  up  into  relief, 
and  attempts  at  repair  on  the  part  of  the  epithelium  result  in  the  formation 
of  distorted,  gland-like  structures,  or  even  complicated,  adenoma-like 
masses.  Enormous  thickening  with  rigidity  of  the  connective-tissue  walls 
may  take  place,  and  in  these  walls  accumulations  of  wandering  cells 
loaded  with  lipoid  substances  and  bile-pigments  give  the  whole  a  dull, 
ochre-yellow  color. 

The  mechanical  effects  of  the  gall-stones  are  manifold,  for  by  no  means 
all  of  them  are  passed  down  through  the  cystic  duct  to  escape  into  the 
intestine.  Some  do  make  this  descent,  causing  great  pain,  and  may  lodge 
at  various  points.  Occluding  the  cystic  duct  completely,  they  prevent 
ingress  and  egress  of  bile.  That  which  remains  in  the  gall-bladder  is  soon 
absorbed,  but  the  sac  does  not  collapse,  for  it  is  full  of  a  clear,  glairy  mucoid 
secretion  from  its  own  walls.  When  there  are  other  stones  in  the  gall- 
bladder, it  often  happens  that  its  thickened  wall  shrinks  down  about 
them  until  there  is  no  lumen  left,  and  the  whole  gall-bladder  is  reduced  to 
a  mass  of  stones  tightly  bound  in  a  fibrous  covering. 

When  the  calculus  passes  into  the  common  duct,  jaundice  results — a 
jaundice  which  may  be  lasting  until  the  gall-stone  is  removed  by  opera- 
tion, or  by  its  escape  into  the  intestine,  or  until  the  death  of  the  patient. 
In  those  cases  where  the  stone  is  not  large  enough  to  occlude  the  duct 
completely,  the  jaundice  may  vary  in  intensity,  but  usually  the  accom- 
panying inflammation  is  enough  to  complete  the  obstruction. 

When  the  ampulla  of  Vater  is  large  and  receives  both  bile-duct  and  pan- 
creatic duct,  and  opens  by  a  narrow  orifice,  the  occlusion  of  this  orifice 
by  a  small  stone  may  cause  the  retro jection  of  bile  into  the  pancreatic 
duct,  an  occurrence  which  is  followed  by  acute  hsemorrhagic  necrosis  of 
the  pancreas,  with  all  its  sequelae.  Large  gall-stones  which  escape  into 
the  intestine  may  become  impacted,  and  even  be  sufficient  to  cause  an 
obstruction  of  the  intestine.  Other  mechanical  effects  may  be  produced 
by  these  large  stones  if  they  remain  in  an  adherent  gall-bladder  through 
the  pressure  which  they  exert  upon  the  adjacent  organs;  and  there 
are  a  number  of  cases  reported  in  which  great  dilatation  of  the  stomach 
has  followed  the  partial  obstruction  of  the  pylorus  produced  in  this 
way. 


412 


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!  ,  |.i  l.i.l.l  1,1.1  I  ! .|.'l.|.|',l,l.h-l.l.; 
Fig.  202. — Acute  and  chronic  cholecystitis  with  many  faceted  gall-stones. 


Fig.  203.— Large  gall-stone  impacted  in  neck  of  gall-bladder.     Subacute  and  chronic 

cholecystitis. 


RESULTS  OF  OBSTRUCTION  IN  THE  ALIMENTARY  TRACT   413 

Finally,  the  persistent  presence  of  the  gall-stones  in  one  position  in  the 
gall-bladder  may  stir  up  a  change  in  the  character  of  the  mucosa,  so  that 
a  cancerous  growth  appears  there  and  tightly  clasps  the  gall-stone.  In 
one  case  I  saw  a  round,  radiate  cholesterine  stone  held  as  in  a  cup  in  the 
fundus  of  the  gall-bladder  by  the  thickened  cancerous  wall,  which  passed 
over  abruptly  into  the  thin,  unaffected  wall  of  the  rest  of  the  sac.  One 
could  hardly  escape  the  impression  that  the  presence  of  the  gall-stone 


Fig.  204. — Chronic  cholecystitis  with  scarring  and  diverticula. 

had  produced  this  change  in  the  mucosa,  although  this  idea  is  by  no  means 
accepted  by  every  one. 

In  the  liver  itself  obstruction  to  the  escape  of  bile. soon  causes  rupture 
of  the  walls  of  the  bile-capillaries  by  destroying  the  liver-cells  which  form 
those  walls.  This  is  probably  not  merely  a  mechanical  effect,  but  due  to 
the  poisonous  action  of  the  bile,  as  well  as  to  the  enforced  inactivity  of  the 
cells.  Indeed,  Steinhaus,  Beloussow,  and  others  have  described  rather 
extensive  necroses  in  the  liver  following  in  the  wake  of  obstructive  jaundice, 
and  think  that  they  may  underlie  the  scarring  seen  in  the  so-called  biliary 


414 


TEXT-BOOK    OF    PATHOLOGY 


cirrhosis.  It  is  precisely  in  the  liver,  however,  that  obstruction  of  the 
:  ducts  may  be  survived  by  the  organ  for  a  long  time  in  spite  of  the  most 
intense  jaundice.  Is  it  possible  that  this  is  because  the  cells  are  so  actively 
engaged  in  carrying  on  functions  which  have  nothing  to  do  with  bile 
production,  so  that,  even  when  that  is  stopped,  they  are  not  entirely 
inactive?  At  any  rate,  the  effect  of  obstruction  is  far  less  obvious  than  in 


Fig.  205.— Margin  of  cholangitic  abscess  of  liver,  showing  compression  of  liver-cells 
and  layer  of  fat-laden  phagocytes.  There  were  multiple  bile-stained  abscesses  resulting 
from  obstruction  by  gall-stones  and  infection. 


the  case  of  other  glands.  In  those  cases  in  which  obstruction  of  the  bile- 
ducts  is  accompanied  by  infection  of  their  stagnating  contents  it  is  common 
to  find  numerous  abscesses  (Fig.  205)  scattered  through  the  liver  and  evi- 
dently formed  about  the  bacteria  which  have  penetrated  into  the  smallest 
ducts.  These  cholangitic  abscesses  may  become  quite  large  and  contain  pus 
which  is  deeply  bile  stained. 


RESULTS   OF   OBSTRUCTION   IN   THE   ALIMENTARY   TRACT        415 

LITERATURE 

Aschoff  and  Bacmeister:   Die  Cholelithiasis,  Jena,  1909. 
Bacmeister:  "Aufbau  und  Entstehung  d.  Gallensteine, "  Ziegler's  Beitrage,  1908,  xliv, 

528. 

Naunyn:    Klinik  d.  Cholelithiasis,  Leipzig,  1892. 
Riedel:  Pathogenese,  etc.,  d.  Gallensteinleidens,  Jena,  1903. 
Ogata:  Ziegler's  Beitrage,  1913,  Iv,  236. 
Ribbert:  Virchow's  Archiv,  1915,  ccXx,  20. 
Rothschild  and  Wilensky:  Amer.  Jour.  Med.  Sci.,  1918,  clvi,   239,  404. 

Obstruction  of  the  Pancreatic  Ducts. — Usually  there  are  two  ducts 
opening  separately,  and  sometimes  hardly  anastomosing  in  the  substance 
of  the  pancreas.  One  of  these,  the  duct  of  Wirsung,  which  usually  opens 
with  the  ductus  communis  choledochus,  is  much  more  exposed  to  influ- 
ences which  might  block  it  than  the  other,  the  duct  of  Santorini,  which 
opens  separately.  Tumors,  especially  adenocarcinomata  of  the  head  of 
the  pancreas,  gall-stones  in  the  common  bile-duct,  aneurysms  m  neighbor- 
ing vessels,  and  pancreatic  calculi  in  the  duct  itself  are  the  commonest 
causes  of  its  occlusion,  and  exert  their  effect  upon  that  part  of  the  gland 
which  it  drains.  The  rest,  which  is  drained  by  the  duct  of  Santorini, 
may  remain  quite  normal.  Of  all  these  causes,  probably  the  tumor  growths 
most  commonly  produce  the  completer  forms  of  occlusion,  while  with  the 
passage  of  gall-stones  temporary  and  incomplete  obstruction  may  arise. 
Occasionally,  whether  from  infection  of  the  duct  or  other  causes,  the 
mucosa  lining  the  smaller  ducts  may  proliferate  into  such  voluminous  folds 
as  to  plug  the  duct  and  set  up  the  most  intense  changes  in  its  drainage  area 
(Winternitz).  Pancreatic  calculi  are  like  irregular,  rough  bits  of  marble, 
and  are,  as  their  appearance  suggests,  composed  chiefly  of  calcium  carbon- 
ate. Their  impaction  in  the  duct  may  again  give  a  foothold  for  bacteria, 
and  when  they  are  surrounded  by  an  abscess-like  area  of  inflammation,  the 
obstruction  is  usually  complete.  When  some  pancreatic  juice  can  escape, 
the  duct  is  apt  to  become  greatly  dilated,  and  even  when  none  can  pass, 
one  usually  finds  that  the  duct  is  widened  behind  the  obstruction,  perhaps 
from  an  earlier  stage  in  which  it  was  incomplete. 

When  the  duct  has  been  stopped  up  for  a  long  time  its  drainage  terri- 
tory is  usually  found  extremely  shrunken,  hard,  and  leathery,  in  sharp  con- 
trast to  the  well-preserved,  lobulated  part,  which  is  still  free  to  discharge 
its  pancreatic  juice  by  way  of  the  other  duct.  Microscopically,  one  finds 
that  the  lobules  have  lost  most  of  their  acini  and  are  hardly  to  be  outlined. 
The  remaining  acini  show  a  dilatation  of  their  lumen  and  a  thinning  or  flat- 
tening of  the  epithelial  cells,  and  the  whole  of  this  persisting  pancreatic 
tissue  is  embedded  in  abundant  scar  tissue,  which  has  grown  to  replace 
those  acini  which  are  lost.  It  is  evident  that  the  damming-up  of  secretion 
under  some  tension  and  the  enforced  inactivity  have  led  to  the  gradual 
disappearance  of  the  secreting  cells  and  their  replacement  by  scar  tissue 


416 


TEXT-BOOK    OF    PATHOLOGY 


(Fig.  206).  Here  and  in  many  other  instances  it  will  be  observed  that  there 
is  no  evidence  that  the  scar  tissue  is  the  cause  of  the  destruction  of  the 
pancreatic  cells.  On  the  contrary,  there  is  every  reason  to  regard  its 
presence  as  an  attempt  to  heal  the  gap  left  by  the  loss  of  those  cells,  be- 
cause the  islands  of  Langerhans,  which  occur  in  most  of  the  lobules,  and 
which  are  not  connected  with  the  pancreatic  ducts,  remain  uninjured,  and 
finally  stand  out  conspicuously  as  about  the  only  intact  tissue  left.  Ex- 


Fig.  206.— Chronic  pancreatitis  following  obstruction  of  the  ducts.     Fat  and  fibrous 
tissue  have  replaced  many  lobules  of  the  gland. 

perimentally,  we  have  ligated  the  duct  of  a  large  part  of  the  pancreas  in 

a  dog,  and  found,  after  a  year,  that  this  portion  was  reduced  to  a  thin 

film— a  mere  opalescence  in  the  transparent  mesentery  in  which  pan- 

c  acini  had  disappeared  and  only  islands  of  Langerhans  were  left.* 

*  MacCallum:  Johns  Hopkins  Hosp.  Bull,  1909,  xx,  265. 
Kirkbride:  Jour.  Exp.  Med.,  1912,  xv,  p.  101. 


RESULTS   OF   OBSTRUCTION   IN   THE   ALIMENTARY   TRACT        417 

Acute  Pancreatitis. — There  are  several  forms  of  acute  destructive  changes  in  the 
pancreas  in  which  obstruction  in  some  sense  plays  a  part,  if  only  by  allowing  the  intro- 
duction of  the  injurious  agent  into  the  gland.  These  are  acute  hsemorrhagic  pancreatitis, 
with  its  less  common  sequel,  gangrenous  pancreatitis,  and  the  more  localized  suppurative 
pancreatitis. 

Fitz,  in  1889,  made  clear  the  existence  of  these  three  affections,  and  described  many 
cases.  Since  that  time  much  anatomical  and  experimental  work  has  shed  light  on  their 
nature,  but  even  yet  there  are  many  obscurities. 


Fig.  207.— Acute  hgemorrhagic  necrosis  of  pancreas:  cholelithiasis  and  impaction  of 
a  small  gall-stone  in  the  common  duct  and  in  the  ampulla  of  Vater.  Abundant  fat 
necrosis. 

Acute  Hcemorrhagic  Pancreatitis —This  condition  arises  suddenly  with  violent  symp- 
toms of  pain,  collapse,  cyanosis,  and  vomiting.  In  these  respects  it  resembles  rather 
closely  obstruction  of  the  intestines  at  a  high  level.  Death  follows  quickly  with  general 
intoxication  in  most  cases.  If  the  abdomen  is  opened,  there  is  a  blood-stained  fluid  in 
the  peritoneum,  and  in  the  fat  of  the  omentum  and  mesentery  there  are  found  opaque 
white  patches  of  pasty  consistence.  These  are  areas  of  necrosis  in  the  fat,  and  are  indica- 
28 


418 


TEXT-BOOK    OF    PATHOLOGY 


live  of  pancreatic  disease.  The  pancreas  is  swollen  and  deep  red  or  purplish-black  in 
patches  (Figs.  207,  208).  On  section,  the  brown  or  black  patches  are  found  to  be  rather 
dry  and  dull  looking,  and  extend  widely  through  the  substance  of  the  gland  surrounded 
by  hemorrhage  In  places  they  may  be  softened.  Opaque,  white,  necrotic  patches 
are  found  in  the  fat  in  the  interstices  of  the  pancreas.  Microscopically,  the  dark  areas 
are  found  to  be  patches  of  necrotic  pancreas,  infiltrated  with  changed  blood,  and  showing 
about  the  margins,  at  least,  an  intense  acute  inflammatory  reaction.  Sometimes  nearly 
the  whole  pancreas  may  have  undergone  this  coagulative  necrosis  with  haemorrhage 


Fig.  208. — Pancreatic  fat  necrosis  in  the  omentum. 


and  inflammation.     Occasionally  the  process  is  so  fresh  that  there  is  but  little  inflam- 
mation, and  Chiari  suggests  the  name  "acute  haemorrhagic  necrosis"  of  the  pancreas. 

The  cause  of  this  was  quite  obscure,  until  Opie  discovered  a  case  in  which  a  small 
gall-stone  had  become  impacted  in  the  orifice  of  the  ampulla  of  Vater  in  such  a  way  that 
neither  bile  nor  pancreatic  juice  could  escape,  although  bile  could  run  back  from  the 
common  bile-duct  into  the  pancreatic  duct.  Naturally,  if  the  ducts  had  opened  side  by 
side  instead  of  into  a  common  ampulla,  or  if  the  stone  had  been  too  large  to  obstruct  the 
orifice  of  the  ampulla  only,  no  such  access  of  bile  to  the  pancreatic  duct  would  have  been 
possible.  Opie  readily  showed  that  injection  of  bile  into  the  pancreatic  duct  would  pro- 
duce acute  haemorrhagic  pancreatitis  in  animals,  and  Flexner  showed  that  gastric  juice 
and  many  other  irritating  substances  would  do  so  too.  He  found  that  fresh  bile  was 


OBSTRUCTION   OF   THE    LUMEN   OF   THE    INTESTINAL  TRACT      419 

most  effective,  that  much  mucus  rendered  its  action  far  milder  and  produced  rather 
chronic  effects.  Several  other  cases  have  been  found  in  which  exactly  the  same  un- 
fortunate combination  of  circumstances  has  led  to  the  results  found  by  Opie,  but  there 
are  many  cases  in  which  no  such  good  explanation  is  to  be  found. 

Any  injury  to  the  pancreas  which  causes  the  death  of  cells  and  allows  the  escape  of 
pancreatic  juice  into  the  tissues  seems  to  be  capable  of  causing  a  little  of  such  haemor- 
rhagic  necrosis,  and  it  is  probable  that  this  is  at  the  root  of  the  formation  of  those 
areas  of  gangrene  which  are  sometimes  found  in  its  substance.  Doubtless  if  the  person 
could  live  after  an  extensive  haemorrhagic  necrosis,  infection  would  follow  by  way  of  the 
ducts,  and  a  putrefactive  liquefaction  of  the  dead  tissue  might  occur.  Whether  such 
necrosis  and  self-digestion  form  the  basis  upon  which  localized  infection  and  abscess 
formation  occur  in  the  gland  is  not  so  clear.  The  fact  remains,  however,  that  abscesses 
of  considerable  size  are  occasionally  discovered  there  in  cases  in  which  intense  symptoms 
point  to  their  existence. 

The  fat  necroses  (Fig.  208)  are  due  to  the  dissemination  of  the  ferments  of  the  pan- 
creas, which  are  able,  by  the  lipolytic  action,  to  decompose  the  fat  in  the  fat-cells  which 
they  have  rendered  necrotic.  The  neutral  fats  break  up  into  free  fatty  acids  and  glycerin, 
and  usually  bunches  of  needle-shaped  crystals  of  fatty  acids  are  visible  in  these  areas. 
Combinations  with  calcium  salts  often  produce,  in  those  situations,  the  insoluble  white 
calcium  soaps  which  add  to  the  whiteness  and  opacity  of  the  foci.  Any  injury  to  the 
pancreas  which  tears  its  tissue  allows  the  dissemination  of  the  ferments.  In  one  case 
in  which  a  small  incision  was  made  into  a  pancreas  by  accident  in  the  course  of  an  opera- 
tion there  appeared  a  crop  of  fat  necroses  in  the  neighborhood.  Ligation  of  the  duct 
usually  produces  them.  In  the  cases  of  acute  hsemorrhagic  pancreatitis  they  are  very 
wide-spread,  and  in  animals  in  which  this  condition  is  produced  experimentally  they  are 
found  in  the  subcutaneous  abdominal  fat,  and  even  in  that  of  the  pericardium  and 
pleura.  Lipases  have  been  demonstrated  in  these  areas,  and  also  in  the  urine  in  such 
cases. 

Of  course,  there  is  nothing  in  common  between  these  forms  of  hsemorrhagic  pan- 
creatitis and  the  so-called  pancreatic  apoplexy,  which  is  a  rapidly  fatal  haemorrhage  into 
and  about  the  pancreas  from  a  large  diseased  artery.  In  one  case  at  autopsy  I  found  a 
retropancreatic  haemorrhage  of  almost  two  liters  which  came  from  the  rupture  of  the 
sclerotic  pancreatico-duodenal  artery  as  it  passed  through  the  head  of  the  pancreas. 

LITERATURE 

Balch  and  Smith:   Boston  Med.  and  Surg.  Jour.,  1910,  clxiii,  384. 
Fitz:   "Acute  Pancreatitis,"  Boston  Med.  and  Surg.  Jour.,  1889,  cxxi,  607. 
Opie:  Johns  Hopkins  Hosp.  Bull.,  1901,  xii,  182. 
Watts:  Southern  Med.  Jour.,  1913,  vi,  174. 

OBSTRUCTION  OF  THE  LUMEN  OF  THE  INTESTINAL  TRACT 

The  most  extraordinary  variety  of  phenomena,  based  on  slight  modifica- 
tions of  a  few  underlying  principles,  occur  here,  and  one  might  foretell 
easily  enough  the  effect  of  obstruction  at  any  given  point.  The  same 
general  types  of  occluding  agent  appear,  but  there  are  some  modifications, 
owing  to  the  strong  muscular  character  of  the  wall  of  the  canal.  Foreign 
bodies  in  the  lumen,  tumors  in  the  walls  sometimes  encircling  the  canal, 
constricting  scars  resulting  from  healing  ulcers,  twists  and  kinks  and  com- 
pression from  outside  by  tumors  or  by  constricting  bands,  the  escape  of  a 
loop  of  intestine  through  a  narrow  hole  in  the  abdominal  wall,  or  the 
telescoping  of  a  part  of  the  intestine  into  itself — all  these  things  and  many 


420  TEXT-BOOK   OF    PATHOLOGY 

others  may  impede  the  flow  of  the  intestinal  contents  in  the  normal  direc- 
tion. Even  the  mere  lack  of  propulsive  muscular  contractions  over  a 
length  of  intestine  may  be  enough  to  allow  the  contents  to  stagnate  and 
give  the  symptoms  of  obstruction  (paralytic  ileus). 

(Esophagus. — Two  common  causes  of  cesophageal  obstruction  exist, 
namely,  the  narrowing  of  the  lumen  by  the  shrinkage  of  scar  tissue  formed 
in  the  healing  of  an  ulcer  caused  by  the  swallowing  of  some  corrosive  poison, 
such  as  concentrated  lye,  and,  secondly,  the  encroachment  of  a  cancerous 
tumor  growing  from  the  mucosa.  Other  things,  such  as  the  pressure  of  a 
tumor  or  an  aneurysm  from  the  outside,  may  have  a  similar  effect,  and 
make  it  difficult  or  impossible  for  food  to  pass  into  the  stomach.  Extreme 
narrowing,  usually  at  the  cardiac  end  of  the  oesophagus,  may  be  produced, 
in  the  stricture  following  ulceration,  but  since  the  food  is  easily  regurgitated, 
there  is  usually  no  great  dilatation  of  the  canal  above  the  closure,  nor  any 
very  marked  hypertrophy  of  its  muscular  walls. 

On  the  contrary,  in  some  rare  cases,  of  which  we  have  recently  seen  one, 
without  any  apparent  obstruction  the  oesophagus  may  be  found  enormously 
lengthened  and  widened,  so  that  it  sags  and  kinks,  and  food  is  regurgitated 
unchanged  without  ever  entering  the  stomach.  There  seems  to  be  no 
explanation  except  that  this  may  be  a  congenital  anomaly.  More  local- 
ised dilatations  are  the  traction  and  pulsion  diverticula.  The  traction  di- 
verticula  are  common,  and  usually  small  and  funnel  shaped;  they  arise 
from  the  persistence  of  connections  between  the  oesophagus  and  trachea, 
or  from  the  adhesion  and  contraction  of  adjacent  inflamed  lymph-glands. 
The  pulsion  diverticula  are  the  outcome  of  local  weakening  of  the  wall  and 
the  forcing  out  of  a  hernia-like  sac.  These  may  become  quite  large,  and 
are  annoying  in  that  they  receive  the  food  until  they  are  full,  and  may, 
by  their  bulk,  offer  obstruction  to  the  main  channel. 

Obstruction  in  the  Stomach. — The  same  types  of  obstruction  are  met 
with  in  the  stomach,  and  the  occlusion  may  be  at  the  cardiac  orifice  or  at 
the  pylorus.  In  the  first  instance,  in  which  the  growth  of  a  cancerous  tumor 
is  the  common  cause,  the  individual  tends  to  starve,  because  food  does 
not  easily  reach  the  stomach.  In  the  second  case,  in  which  the  cause 
is  a  cancerous  growth  or  the  contracting  scar  of  a  round  ulcer  at  the 
pylorus,  the  orifice  of  the  pylorus  may  be  reduced  to  a  very  narrow  channel 
(Fig.  209).  Stagnation  and  accumulation  of  the  stomach-contents  follow, 
with  great  changes  in  the  gastric  juice,  which  often  loses  its  antiseptic 
acidity.  Putrefaction  of  all  this  material  produces  poisonous  substances, 
which  are  absorbed,  to  the  great  detriment  of  the  patient.  Besides,  the 
frequent  vomiting  causes  the  loss  of  much  water  and  the  normal  con- 
stituents of  the  gastric  juice,  and  one  might  surmise  that  this,  as  well  as 
the  absorption  of  poison,  could  give  rise  to  the  symptoms  which  sometimes 
follow.  Not  uncommon  among  these  symptoms  is  the  development  of 
tetany,  with  greatly  heightened  nerve  excitability  and  violent  convulsions. 
The  stomach  may  become  hugely  dilated,  so  as  to  be  capable  of  holding 


OBSTRUCTION   OF   THE   LUMEN   OF   THE   INTESTINAL   TRACT    421 

four  or  five  litres,  and  the  most  incredible  mass  of  material,  dating  from 
meals  long  past,  may  accumulate  there.  The  wall  becomes  thick,  the 
muscular  coat  hypertrophic,  in  the  attempt  to  drive  the  contents  through 


Fig.  209. — Scarred  ulcer  of  the  pylorus,  dilatation  and  hypertrophy  of  the  stomach. 


Fig.  210. — Gastric  ulcer  (round  or  peptic  ulcer). 

the  pylorus,  and  the  mucosa  seems  to  hypertrophy  by  the  production  of  new 
glands  to  comply  with  the  necessity  for  covering  all  that  increased  space. 
There  are  other  ways  in  which  such  gastrectasis  can  be  set  up,  as  by  the 


422  TEXT-BOOK   OF   PATHOLOGY 

pressure  of  outside  tumors  or  by  the  sagging  of  the  stomach  and  the  kink- 
ing of  the  pylorus,  but  the  two  causes  mentioned  are  by  far  the  more 
common.  The  symptoms  are  not  acute  in  these  cases,  nor  do  they  quickly 
end  fatally,  because  vomiting  is  capable  of  relieving  them  to  some  extent. 

Gastric  Ulcer. — There  are  several  types  of  ulceration  of  the  gastric  wall  produced  in 
as  many  ways,  and  distinguished  by  nothing  specially  characteristic.  For  while  the 
intact  living  mucosa  resists  perfectly  the  digestive  action  of  the  gastric  juice,  anything 
like  a  strong  corrosive  poison  which  can  kill  the  tissue,  or  even  anything  like  a  haemor- 
rhage, which  may  interrupt  the  circulation  of  a  patch  of  mucosa  for  a  time,  exposes  that 
area  to  the  liquefying  power  of  the  juice,  and  in  an  incredibly  short  time  there  is 
produced  an  ulcer  which  extends  to  the  depth  reached  by  the  anaemia  or  coagulation 
of  the  tissue.  Even  the  little  ecchymotic  haemorrhages  which  appear  after  violent 
vomiting  present  themselves  very  shortly  a.s  pits  of  pinhead  size  in  the  mucosa.  Emboli 
in  the  larger  vessels  have  no  such  consequences,  since  the  intercommunication  of  the 
arteries  is  so  extremely  rich.  If  we  try  experimentally  to  produce  an  area  of  anemia 
hi  the  wall  of  the  stomach  of  an  animal,  we  fail,  even  though  we  tie  several  large  vessels. 
Their  current  is  instantly  supplied  backward,  if  necessary,  from  other  arteries.  It  is 
only  by  injecting  a  suspension  of  coarse  particles  which  plug  all  the  small  vessels,  or  by 
causing  a  spasmodic  contraction  of  the  muscular  wall,  which  clamps  down  the  col- 
lateral arteries,  that  we  can  produce  an  anaemia  of  the  mucosa  serious  enough  to  allow 
the  gastric  juice  to  attack  and  digest  it,  and  thus  form  an  ulcer.  But  although  many 
things  will  produce  an  ulcer,  the  mucosa  is  surprisingly  capable  of  healing  it  over.  I 
have  removed  large  squares  of  the  mucosa  of  the  dog's  stomach,  only  to  find,  a  short 
time  later,  such  complete  healing  that  it  was  impossible  to  say  where  the  ulcer  had  been. 

It  is  perhaps  a  peculiarity,  therefore,  of  the  so-called  peptic  or  round  ulcers  of  the 
stomach  that  they  persist  as  such.  Most  of  them  do  heal,  and  we  find  only  the  scar,  but 
others,  although  they  are  the  seat  of  energetic  efforts  at  healing,  not  only  persist,  but 
progress,  boring  deeper  and  deeper  into  the  thickening  stomach-wall.  Very  similar 
ulcers  are  found  in  the  duodenum,  where  they  follow  a  course  much  like  that  of  the 
gastric  ones.  All  the  theories  as  to  their  origin  seem  inadequate,  from  that  of  Virchow, 
who  thought  them  to  be  due  to  the  embolic  occlusion  of  the  artery  supplying  that  area, 
to  the  mor^  recent  ones,  which  attempt  to  incriminate  bacteria  and  other  parasites,  or, 
as  in  the  case  of  van  Yzeren  and  Palma,  ascribe  them  to  changes  in  the  innervation  of 
the  stomach,  which  maintains  part  of  its  wall  in  a  bloodless  state  through  cramp  of  the 
muscle.* 

They  occur  in  relatively  young  persons,  usually  in  association  with  hyperacidity  of 
the  gastric  juice,  and  cause  a  peculiar  pain.  There  may  be  only  one  or  several.  Many 
of  them  are  irregular  in  outline,  and  there  are  small  ulcers,  as  well  as  wide-spread  erosions, 
but  the  name  arises  from  the  fact  that  many  of  them  are  quite  round  and  smooth  (Fig. 
210).  Such  ulcers  look  as  though  they  had  been  cut  out  with  a  gunwad  cutter,  except 
that  their  base  is  terraced  and  funnel  shaped,  and  may  run  slantingly  into  the  stomach- 
wall,  or  else  their  edges  are  undermined.  All  around  such  an  ulcer  the  wall  becomes  very 
thick  and  hard,  so  as  to  be  easily  recognized  from  the  outside  when  the  stomach  is 
exposed.  Often  there  are  adhesions  formed  over  it,  so  that  in  case  the  ulcer  extends  quite 
through  the  wall,  it  is  likely  to  encounter  first  the  adhesions  and  then  the  adherent  organ. 
Since  they  often  perforate  the  posterior  and  inner  curvature  of  the  stomach,  the  pan- 
creas is  likely  to  be  the  bulwark  and  to  be  rapidly  excavated,  until,  sometimes,  the  splenic 
artery  is  cut  into.  The  liver  may  sometimes  form  this  buffer,  but  it  is  not  very  uncom- 
mon to  have  the  gastric  contents  emptied  through  the  perforated  ulcer  directly  into  the 
peritoneum.  Microscopically,  the  edge  of  such  an  ulcer  shows  an  abrupt  cessation 

*Stromeyer:  Ziegler's  Beitrage,  1912,  liv,  1. 


OBSTRUCTION   OF   THE    LUMEN   OF   THE   INTESTINAL  TRACT     423 

of  the  mucosa.  The  precipitous  walls  are  lined  with  a  thin  layer  of  formless,  hyaline 
material,  and  pass  through  the  greatly  thickened  submucosa,  the  musculature,  and  even 
the  thickened  subserous  tissue.  There  is  often  not  much  infiltration  with  wandering 
leucocytes  to  indicate  any  active  inflammatory  process.  On  the  contrary,  the  ulcer 
may  look  as  if  bored  through  a  dense,  hard,  fibrous  tissue.  In  the  floor  of  the  depression 
one  may  sometimes  see  an  artery  laid  bare,  or  even  find  its  exposed  wall  so  thinned 
that  the  blood-pressure  has  been  sufficient  to  bulge  it  out  into  an  aneurysmal  sac.  It  is 
obvious,  though,  that  one  would  be  more  likely,  under  such  circumstances,  to  find  the 
little  sac  burst  into  shreds  after  an  alarming  or  fatal  haemorrhage  had  called  attention  to 
the  ulcer. 

Aside  from  these  two  dangers,  the  most  serious  effect  of  the  ulcer  may  arise  in  the 
course  of  its  healing,  if  it  happens  to  encircle  the  pylorus.  It  is  then  that  the  contrac- 
tion of  the  scar  may  produce  the  most  extreme  narrowing  of  that  orifice,  and  a  conse- 
quent enormous  dilatation  of  the  stomach. 

Duodenal  ulcers  are  similar  in  their  course  and  even  hi  their  general  effects,  for  they 
may  perforate  into  the  peritoneum  or  into  blood-vessels  or  adjacent  organs.  They  some- 
times appear  when  gastro-enterostomy  has  been  performed  at  the  point  where  gastric 
juice  pours  into  the  intestine,  and  I  have  recently  seen  a  case  in  which  five  ulcers  bur- 
rowing and  connected  in  the  most  tortuous  way  were  formed  in  this  manner. 

Intestinal  Obstruction. — Although  there  are  many  different  iways  in 
which  the  lumen  of  the  intestine  may  be  closed  so  that  nothing  can  pass, 
the  result  is  in  one  sense  the  same  in  all.  Still,  the  effects  of  such  obstruc- 
tion vary  according  to  the  point  in  the  intestinal  tract  at  which  it  occurs, 
its  completeness,  and  the  condition  of  the  intestinal  wall. 

In  general,  when  the  occlusion  is  produced  by  a  foreign  body  which  acts 
as  a  plug,  the  symptoms  are  rather  less  violent  than  when  the  canal  is 
closed  from  outside,  as  it  might  be  with  a  ligature.  More  important  in 
this  respect,  however,  is  the  fact  that  obstructions  high  up  in  the  small 
intestine  are  usually  accompanied  by  far  more  violent  symptoms  than  those 
in  the  rectum  or  sigmoid  flexure.  Perhaps  the  fact  that  impaction  of 
faeces  in  the  rectum,  with  no  discharge  for  days  or  even  weeks,  may  cause 
nothing  more  serious  than  headache,  will  illustrate  this,  for  sudden  closure 
of  the  small  intestine  is  very  quickly  followed  by  vomiting,  pain,  abdom- 
inal distension,  and  evidences  of  shock,  with  death  in  a  few  days  if  not 
relieved.  These  symptoms  (grouped  under  the  term  ileus)  are  often  es- 
pecially fulminant,  when  something  occurs  to  cut  off  the  blood  supply 
from  the  wall  of  the  obstructed  intestinal  loop. 

The  actual  cause  of  these  extraordinarily  intense  symptoms  has  been 
searched  for  experimentally,  and  by  other  means,  for  years,  but  even  yet 
it  is  far  from  being  clearly  understood.  The  intestine  above  the  point 
of  closure  becomes  distended  with  gas  and  a  very  foul-smelling  fluid  which 
swarms  with  bacteria.  Even  when  there  is  no  outward  obstruction  to  the 
circulation,  its  wall  is  soon  so  stretched  as  to  interrupt  the  free  flow  of 
blood  in  the  capillaries,  and  necrosis  and  ulceration  of  the  mucosa  appear, 
often  with  actual  tears  in  the  muscular  wall  and  serous  covering  of  the  gut. 
Kocher  has  called  these  ulcers  distension  ulcers.  It  is  evident  that  poison- 
ous materials  are  absorbed  from  this  sac-like  loop  of  intestine,  which  is 
practically  like  one  huge  bouillon  culture  of  bacteria,  and  in  many  cases 


424  TEXT-BOOK   OF   PATHOLOGY 

it  is  clear  enough  that  the  bacteria  themselves  have  passed  into  and  through 
the  intestinal  walls,  and  have  caused  not  only  an  acute  peritonitis,  but  a 
generalized  infection. 

In  other  cases,  though,  with  just  as  intense  symptoms,  there  may  be  no 
definite  peritonitis  nor  general  infection,  and  these  make  it  necessary  to 
find  some  other  explanation.  Whipple  finds  that,  from  the  contents  of  the 
obstructed  intestine,  he  can  extract  a  material  which,  on  being  injected 
into  veins  of  other  animals,  produces  all  the  symptoms  which  follow  acute 
intestinal  obstruction.  This  substance  is  derived  from  the  mucosa  of  the 
obstructed  intestine,  its  production  being  stimulated  by  the  bacteria  present 
in  such  numbers,  and  is  purified  by  being  precipitated  with  alcohol  and 
washed.  Davis  and  Stone  found  that  the  duodenal  secretion  from  which  the 
pancreatic  juice  was  excluded  is  not  toxic  so  long  as  it  is  kept  from  bacterial 
decomposition.  Dragstedt  and  his  co-workers  agree  with  this,  and  emphasize 
the  importance  of  the  presence  of  bacteria,  which  decompose  proteins,  arid 
of  the  injured  state  of  the  mucosa.  Whatever  is  absorbed  leads  to  no 
production  of  antibodies  and  is,  therefore,  probably  not  a  protein.  The 
symptoms  produced  in  intestinal  obstruction  are  so  like  those  of  shock 
that  it  is  difficult  to  escape  the  temptation  of  assuming  that  the  poisonous 
material  is  the  decomposition  product  of  proteins  which  Dr.  Abel  recognizes 
as  histamine.  Dale  refers  shock  and  the  related  phenomena  to  histamine- 
like  bodies  derived  from  the  disintegration  of  injured  tissues,  and  the  con- 
ditions presented  in  an  obstructed  loop  of  intestine  seem  ideal  for  the 
formation  of  a  quantity  of  this  material.  Possibly  the  origin  of  histamine 
from  the  protein  contents  of  the  intestine  may  explain  its  greater  abundance 
in  the  upper  intestine,  for  there  is  relatively  little  protein  left  to  decompose 
in  the  contents  of  the  colon.  Should  this  explanation  prove  true  it  would 
also  account  for  the  paralysis  of  the  smooth  muscle  of  the  wall  of  the  com- 
pletely obstructed  loop  after  sufficient  time  has  elapsed. 

MECHANISM  OF  INTESTINAL  OBSTRUCTION 

Ordinarily  the  contents  of  the  small  intestine  are  quite  fluid,  and  the 
musculature  of  the  colon,  aided  by  that  of  the  abdominal  wall,  is  strong 
enough  to  expel  the  more  solid  contents  of  that  part  of  the  intestine.  Still 
it  occasionally  happens  that  a  foreign  body  which  was  swallowed  and  has 
passed  through  the  stomach  sticks  somewhere  in  the  intestine.  This  is 
true,  too,  of  the  so-called  enteroliths,  which  may  be  very  large,  and  partly 
composed  of  hair  and  of  large  gall-stones,  as  well  as  of  the  indurated  masses 
of  faces  which  sometimes  become  impacted  in  the  colon  and  obstruct  it. 
Tumors  or  aneurysms  outside  the  intestine  rarely  compress  it  enough  in 
the  yielding  abdominal  cavity  to  produce  obstruction,  unless  the  tumors 
have  surrounded  it  and  involved  it  in  their  growth.  After  abdominal 
operation,  however,  in  which  the  intestines  have  been  roughly  handled  and 
displaced,  and  especially  when  there  exists  a  focus  of  infection  and  inflam- 
mation of  long  standing,  such  as  an  abscess  around  the  appendix,  or  a  gen- 


MECHANISM   OF   INTESTINAL   OBSTRUCTION  425 

eral  infection  of  the  peritoneum,  adhesions  are  apt  to  bind  the  intestinal 
coils  together.  Then  the  symptoms  of  obstruction  commonly  appear,  and 
the  surgeon  must  separate  and  loosen  and  straighten  out  such  loops.  Usu- 
ally in  such  a  case  the  occlusion  is  produced  by  the  angular  kinking  of  the 
gut,  but  sometimes  the  most  extraordinary  long  bands  of  fibrous  tissue  are 
found  stretching  from  one  point  to  another,  entangling,  as  in  a  ligature, 
a  loop  of  intestine.  Doubtless  this  latter  condition  is  brought  about  by 
the  peristaltic  and  passive  movements  of  the  intestine,  which  entangle 
it  in  the  adhesions. 

Hernias. — Quite  analogous  to  this  method  of  obstruction  is  that  found 
in  the  various  sorts  of  hernias,  where  again  the  movements  of  the  intestines 
(this  time  chiefly  the  passive  movements,  caused  by  the  press  of  the  abdom- 
inal muscles)  forcibly  intrude  them  into  compromising  situations.  The 
omentum,  and  in  some  forms  of  hernias,  even  other  abdominal  organs,  may 
be  forced  to  accompany  the  intestinal  loops.  These  structures  pass  through 
a  weak  point  in  the  abdominal  wall,  pushing  ahead  of  them  a  sac  composed 
of  the  peritoneum,  usually  with  accompanying  layers  of  the  tissues  which 
lie  outside  it  in  that  area.  When  the  violent  muscular  effort  is  over  and 
the  heightened  intra-abdominal  pressure  is  relaxed,  the  intestine  may 
slip  back  or  be  pushed  back  by  the  surgeon.  But  the  sac  remains,  and  the 
intestine  is  easily  forced  into  it  again — the  more  so  as  with  each  time  it 
grows  larger  and  receives  more  and  larger  loops  of  the  gut,  which  may 
remain  there  without  causing  any  trouble.  Such  a  sac  often  contains  serous 
fluid,  and  is  subject  to  inflammations,  just  as  is  the  peritoneum  in  general. 

Inguinal  hernias  are  those  in  which  the  sac  is  pushed  through  the  abdominal  wall  just 
above  Poupart's  ligament.  Those  which  pass  through  the  internal  abdominal  ring, 
that  is,  outside  the  deep  epigastric  artery,  pass  along  the  track  of  the  inguinal  canal  or 
through  the  unobliterated  inguinal  canal,  when  that  has  remained  open,  into  the  scrotum. 
They  are  the  oblique  inguinal  hernias.  Those  which  push  through  to  the  inner  side  of 
the  epigastric  artery  and  likewise  project  through  the  external  abdominal  ring  into  the 
scrotum  are  the  direct  inguinal  hernias. 

Femoral  hernias  are  such  as  arise  from  the  propulsion  of  a  peritoneal  sac  through  the 
space  between  the  femoral  vein  and  Gimbernat's  ligament,  beneath  Poupart's  ligament, 
to  project  through  the  saphenous  opening. 

Umbilical  hernias  are  often  of  great  extent  when  congenital,  and  may  contain  most 
of  the  abdominal  viscera.  They  are  acquired  in  later  life  through  the  protrusion  of  a  sac 
through  the  weakened  scar  tissue  about  the  navel,  and  are  common  in  women  who  have 
borne  many  children.  Hernias  through  the  abdominal  wall  may  occur  anywhere  where 
a  large  operation  wound  has  resulted  in  delayed  healing,  and  the  scar  has  remained  as 
a  weak  place. 

Other  hernias  which  are  less  conspicuous  and  far  less  common  occur,  and  some  of 
these  are  the  so-called  internal  hernias.  Thus  the  left  side  of  the  diaphragm  may  be 
thinned  and  stretched  into  a  sac,  and  in  a  case  which  we  recently  observed  nearly  the 
whole  of  the  stomach,  the  spleen,  and  the  splenic  flexure  of  the  colon  lay  in  this  sac  far 
up  in  the  thoracic  cavity.  The  most  unexpected  places  may  be  pitched  upon  by  the 
intestinal  loops  for  invasion,  and  extraordinary  results  follow.  For  example,  the  fossae 
about  the  junction  of  the  duodenum  and  jejunum,  which  are  ordinarily  quite  small 
recesses,  may  become  distended  into  great  sacs  in  which  numerous  loops  of  intestine 


426  TEXT-BOOK   OF    PATHOLOGY 

are  found  ensconsed  The  same  is  true  of  the  fossae  about  the  caecum  and  at  the  root  of 
the  sigmoid,  and  I  have  recently  reported  a  case  in  which  a  notoriously  weak  place  in 
the  root  of  the  mesentery  of  the  jejunum  was  attacked,  and  just  as  a  flock  of  sheep  in  a 
street,  left  for  a  moment  to  themselves,  will  hurry  into  any  open  door,  the  whole  of  the 
small  intestine  had  become  inclosed  in  a  sac  which  hung  to  the  right  of  the  midline. 

All  this  seems  to  have  little  to  do  with  intestinal  obstruction,  but  it  is 
precisely  in  these  hernias  that  a  common  form  of  obstruction  takes  place. 
For  although  ordinarily  the  neck  of  the  sac  is  wide  and  the  intestinal  con- 
tents circulate  through  the  loop  in  the  sac  without  hindrance,  more  intes- 
tine than  usual  may  sometimes  be  forced  into  the  sac.  All  these  hernias 
tend  to  grow  in  this  way,  and  it  may  even  happen  that  the  abdomen  is  so 
emptied  of  its  contents  and  contracted  and  the  sac  so  large  that  it  is 
impossible  to  reduce  the  hernia,  that  is,  to  replace  its  contents  in  the 
abdominal  cavity.  The  formation  of  adhesions  between  the  intestine  and 
the  wall  of  the  sac  may  also  make  the  hernia  irreducible.  Such  a  condition 
may  exist  for  a  long  time. 

If,  through  a  sudden  violent  exertion,  a  loop  of  intestine  be  forced  through 
a  very  narrow  orifice,  or  if  an  excessive  amount  of  intestine  or  too  much  of 
the  intestinal  contents  be  forced  into  the  sac,  the  afferent  and  efferent  por- 
tions as  they  pass  through  the  neck  of  the  sac  become  compressed.  Then 
not  only  is  it  impossible  to  reduce  the  hernia,  but  the  intestine  is  obstructed 
and  all  the  symptoms  of  an  acute  ileus,  distension  of  the  loops  above  the 
constriction,  faecal  vomiting,  etc.,  make  their  appearance  (incarcerated 
hernia).  This  is  not  all,  however,  for  the  compression  of  the  veins  of  the 
mesentery  of  the  incarcerated  loops  soon  causes  oedema  of  those  loops,  and 
increases  still  further  the  bulk  of  the  contents  of  the  sac  until  the  flow  of  the 
circulation  is  quite  stopped,  and  the  whole  included  loop  becomes  the  seat 
of  a  haemorrhagic  infarction  (strangulated  hernia).  The  wall  becomes 
greatly  thickened  and  infiltrated  with  blood,  and  dies,  after  which  the 
bacteria  in  the  lumen  pervade  the  dead  tissue  and  set  up  an  inflammation 
in  the  sac.  If  some  time  elapses  before  the  sac  is  cut  open  by  the  surgeon, 
the  intestine  is  found  to  be  purple  or  greenish  black,  but  if  relief  is  rapid, 
circulation  may  be  reestablished  and  the  loop  saved  alive. 

Somewhat  similar  in  principle  to  this  process  is  the  prolapse  of  the  rec- 
tum, in  which  the  relaxation  of  the  tissue  in  and  about  the  rectal  wall 
allows  its  mucous  surface  to  be  everted  through  the  anus  until  a  consider- 
able length  has  been  turned  outside  and  protruded. 

Intussusception. — Higher  up  in  the  intestine  one  portion  of  the  wall 
may  be  telescoped  into  the  next  section  below.  This  invagination  or  intus- 
susception is  frequently  found  to  take  place  in  the  irregular  peristalsis  which 
arises  just  after  death,  perhaps  more  often  in  children  than  in  adults. 
But  it  does  occur  also  during  life,  and  quickly  leads  to  complete  obstruc- 
tion of  the  intestine  and  all  the  acute  symptoms  of  ileus.  For,  as  will  be 
seen  in  the  drawing  (Fig.  16,  p.  38),  the  portion  which  is  invaginated  drags 
with  it  its  mesentery,  while  the  portion  which  receives  it  is  stretched  until 


MECHANISM   OF   INTESTINAL   OBSTRUCTION  427 

it  constricts  its  contents  closely.  Especially  at  its  beginning  or  upper  end, 
where  the  mesenteric  mass  at  least  is  most  bulky,  it  forms  a  tight  ring  con- 
stricting the  mesenteric  veins.  The  result,  as  in  the  strangulated  hernia, 
is  the  production  of  a  hsemorrhagic  infarction  in  the  two  internal  folds,  which 
thereby  become  even  more  swollen.  It  is  said  to  have  happened  that  the 
normal  entering  intestine,  by  healing  to  the  upper  end  of  the  outer  or  receiv- 
ing intestine,  allowed  the  whole  of  the  invaginated  portion  to  be  sloughed 
off  and  discharged  per  rectum,  but  this  must  be  a  rare  occurrence.  In  the 
early  stages,  before  circulation  has  been  interrupted  too  long,  the  sur- 
geon may  pull  out  the  intussuscepted  part  and  relieve  the  whole  condi- 
tion. But  after  the  infarction  of  the  invaginated  part  is  complete,  a 
more  radical  operation  is  necessary.  Irregular  peristalsis  is  held  responsi- 
ble for  this  process,  but  sometimes  there  is  a  stalked  polypoid  tumor  hang- 
ing from  the  mucosa  which  is  forced  along  the  intestinal  canal  and  drags 
the  wall  with  it.  Once  started,  the  invagination  tends  to  increase  rapidly. 

Volvulus. — Volvulus  is  another  type  of  constriction  from  without  which 
depends  upon  the  twisting  of  a  loop  of  intestine  through  more  than  180 
degrees,  so  that  the  two  ends  of  the  loop  compress  each  other  as  in  a  knot. 
For  this  there  must  be  a  long  loose  mesentery,  and  the  condition  is  most 
common  in  the  sigmoid  flexure.  Complete  obstruction  occurs,  with  the 
isolation  of  a  loop.  When  the  twist  is  tight  enough  to  embarrass  the  cir- 
culation, the  condition  comes  to  resemble  closely  that  in  the  strangulated 
hernia. 

Instances  of  post-operative  obstruction  due  to  adhesions  which  compress 
or  kink  the  intestine,  or  among  which  the  intestine  can  entangle  and 
strangle  itself,  are  not  very  uncommon,  but  almost  as  common  are  those 
cases  in  which  evidences  of  obstruction  arise  very  soon  after  the  operation, 
when  there  has  been  no  time  for  dense  adhesions  to  form,  and  in  which, 
at  a  second  exploration,  the  intestine  is  found  bent  on  itself  at  a  sharp  angle 
above  which  it  is  greatly  distended.  These  are  rather  hard  to  explain, 
but  they  seem  to  be  due  to  a  combination  of  a  paralysis  of  the  intestinal 
wall  with  any  slight  mechanical  displacement,  which,  after  the  first  hand- 
ling of  the  intestines,  is  maintained  even  by  weak  fibrinous  adhesions.  The 
capability  of  mere  paralysis  of  peristalsis  in  a  length  of  the  intestine  to 
produce  the  symptoms  of  obstruction  is  well  known  (paralytic  ileus),  and 
the  inert  segment  which  does  not  help  in  the  propulsion  of  the  intestinal 
contents  will,  if  it  is  long  enough,  prove  to  be  as  effective  a  barrier  as  a 
ligature.  It  is  not  always  easy  to  explain  how  the  paralysis  is  produced. 
Sometimes,  as  in  a  phlegmonous  inflammation  of  the  intestinal  wall,  when 
the  infiltrated  wall  becomes  rigid,  the  cause  is  clear,  and  so,  too,  are  those 
in  which  thrombosis  or  embolism  of  the  mesenteric  vessels  causes  the 
death  of  a  whole  length  of  the  intestine,  with  haemorrhagic  infarction,  but 
at  other  times  we  are  reduced  to  the  idea  that  the  nervous  controlling 
mechanism  is  disturbed.  I  have  already  mentioned  one  instance  in  which 
a  dissecting  aneurysm  had  ruptured  into  the  tissues  about  the  aorta,  so 


428 


TEXT-BOOK   OF   PATHOLOGY 


that  there  was  a  great  clot  of  blood  stretching  from  the  upper  thoracic 
to  the  lumbar  region.  The  most  striking  symptoms  were  those  of  in- 
testinal obstruction,  for  the  relief  of  which  an  operation  was  per- 
formed. The  man  died,  and  at  the  autopsy  the  intestines  were  dis- 
tended with  fluid  and  gas  to  a  colossal  size,  so  that  from  the  stretching 
the  muscular  wall  showed  numerous  tears,  but  there  was  no  obstruction 

except  from  the  paralysis  of  the  intes- 
tines. 

It  seems  possible  that  in  many  cases 
this  may  be  the  effect  of  some  toxic 
agent  acting  directly  upon  the  smooth 
muscle  of  the  intestinal  wall,  and  as  in 
the  case  of  mechanical  obstructions 
the  poison  which  suggests  itself  is  that 
derived  from  the  bacterial  decompo- 
sition of  proteins  or  from  the  injured 
tissues  themselves. 

Stenosis  and  Stricture. — Finally, 
obstruction  may  be  gradually  produced 
by  the  development  of  a  tumor  encir- 
cling the  lumen  of  the  intestine,  or  by 
the  contraction  of  a  scar  produced  in 
the  healing  of  a  girdle  ulcer.  Cancer- 
ous tumors  of  this  sort  are  most  com- 
mon in  the  large  intestine,  and  they 
may  produce  obstruction  by  their  in- 
creasing bulk  or  by  the  scar  tissue 
formed  after  their  partial  degenera- 
tion. In  the  small  intestine  annular 
lymphosarcomata,  and  more  rarely 
carcinomata,  may  cause  the  same 
thing.  Ulcers  of  tuberculous  origin 
rarely  heal  far  enough  to  cause  strict- 
ure, but  syphilitic  ulcers,  especially  in 

the  rectum,  frequently  do  so.  All  these  things  produce  a  gradual  narrow- 
ing with  slowly  advancing  incomplete  obstruction,  so  that  the  symptoms 
are  not  the  acute  and  violent  symptoms  of  ileus.  Instead,  the  intestine 
above  the  stenosis  becomes  greatly  distended  and  also  greatly  thickened 
through  the  hypertrophy  of  the  muscular  wall,  which  attempts  constantly 
to  drive  materials  through  the  narrow  opening  (Fig.  211).  Below  the 
stricture  the  intestine  is  collapsed  and  thin  walled.  An  almost  continu- 
ous stream  of  fluid  intestinal  contents  is  driven  through  the  stricture,  and 
may  cause  the  so-called  paradoxical  diarrhoaa.  Above  the  stricture  the 
mucosa  of  the  distended  intestine  often  presents  extensive  ulcerations, 
which  are  thought  to  be  due  partly  to  its  disturbed  nutrition,  partly  to 


Fig.  211. — Carcinoma  of  the  rectum 
encircling  the  gut  and  producing  a 
stricture. 


MECHANISM    OF   INTESTINAL   OBSTRUCTION  429 

the  stagnation  of  masses  of  infected  faecal  material  in  contact  with  it 
(stercoraceous  ulceration).  Sometimes  an  acute  diphtheritic  inflammation 
of  the  mucosa  of  this  area  is  produced  in  the  same  way. 

Thus  if  we  look  back  over  this  review  of  intestinal  obstructions,  we  find 
that  no  matter  what  the  mechanism  by  which  occlusion  of  the  intestine 
is  produced,  the  effect  is  fairly  constant,  and  varies  only  with  the  com- 
pleteness and  situation  of  the  obstruction.  It  differs  from  the  effects 
of  the  occlusion  of  the  duct  of  a  gland  on  account  of  the  immediate  vital 
importance  of  the  intestine,  its  circulatory  relations,  and  its  abundant 
content  of  bacteria. 

LITERATURE 

Lichtwitz:  Ergeb.  d.  innere  Medizin  u.  Kinderh.,  1914,  xiii,  1. 
Opie:  Diseases  of  the  Pancreas,  Philadelphia,  1903. 

Wilms:   " Ileus,"  Handb.  d.  prakt.  Chir.  (Brims,  Garre,  Kuttner),  1913,  iii,  336. 
Graser:   "Hernias,  etc.,"  ibid.,  421. 

Whipple,  Stone,  and  Bernheim:  Jour.  Exp.  Med.,  1913,  xvii,  286,  307. 
Brooks,  Schumacher,  and  Wattenberg:  Ann.  Surg.,  1918,  Ixvii,  210. 
Davis  and  Stone:  Jour.  Exp.  Med.,  1917,  xxvi,  687. 

Dragstedt,  Moorhead  and  Burcky,  and  others:  Ibid.,  1917,  xxv,  421;  1919,  xxx,  109. 
Dragstedt  and  Chase:  Amer.  Jour.  Physiol.,  1918,  xlvi,  365. 
Smith  and  Hardt:  Arch.  Int.  Med.,  1918,  xxi,  307. 


CHAPTER  XXI 

TYPES  OF  INJURY— OBSTRUCTION   (Continued).— OBSTRUCTION 
OF  RESPIRATORY  TRACT 

Nose  (coryza,  adenoids,  etc.}.  Larynx  (oedema,  diphtheria,  foreign  bodies,  compression, 
stenosis);  bronchi  (foreign  bodies,  stenosis).  Atelectasis:  its  causes.  Mechanism  of  bron- 
chial dilatation.  Bronchiectasis.  Emphysema. 

NASAL  OBSTRUCTION 

IN  the  upper  air-passages,  especially  in  the  nose,  there  are  several  common 
forms  of  occlusion  which  impede  respiration,  with  peculiar  results.  Swell- 
ing of  the  Schneiderian  membrane  in  ordinary  coryza  may  make  it  impos- 
sible to  breathe  through  the  nose,  so  that  the  throat  becomes  dried  from  the 
prolonged  breathing  through  the  mouth.  More  serious,  because  more 
prolonged,  is  the  blocking  of  the  nares  by  certain  polypoid  oedematous  fibro- 
mata, which  hang  down  from  the  septum,  or  by  the  growths  of  adenoid 
tissue  which  project  from  the  roof  of  the  pharynx.  In  young  persons  the 
latter,  at  least,  give  rise  to  great  deformity  of  the  face,  with  flattening  of 
the  features,  which,  since  the  mouth  is  constantly  open,  gives  the  person 
a  most  vacant  expression. 

The  difficulty  in  breathing  through  the  nose,  with  the  consequent  violent 
inspiratory  efforts,  brings  about  curious  deformities  of  the  chest.  A 
lateral  caving  in  of  the  soft  ribs  leaves  the  sternum  prominent  (pigeon- 
breast),  while  the  tension  of  the  diaphragm  at  its  insertion  may  cause  a 
furrow-like  retraction  of  the  ribs  along  that  line  (Harrison's  groove). 

OBSTRUCTION  OF  THE  LARYNX 

Spastic  closure  of  the  glottis  in  children,  especially  in  such  conditions  as 
tetany,  causes  a  peculiar  difficulty  in  inspiration,  with  stridor  (laryngismus 
stridulus),  while  paralysis  of  the  vocal  cords  may  produce  a  similar  obstruc- 
tion in  another  way.  Actual  asphyxia  may  occur.  Asphyxia  is  much  more 
commonly  the  result  of  cedema  about  the  larynx  or  of  other  types  of  inflam- 
matory exudate  there. 

(Edema  of  the  Larynx. — This  is,  in  many  instances,  only  a  part  of  a  wide-spread  oedema 
of  the  tissues  such  as  is  seen  in  cases  of  cardiac  failure  or  renal  disease,  or  due  to  some 
local  disturbance  of  the  circulation,  which  may  be  caused  by  posture,  but  at  other  times 
it  is  the  effect  of  an  inflammation  in  or  about  the  larynx  (Fig.  212).  Masser  and  others 
have  pointed  out  the  existence  of  an  erysipelas-like  infection  of  the  larynx  and  pharynx 
in  the  course  of  which  extreme  cedema  may  arise.  So,  too,  abscesses  in  the  neighbor- 
hood of  the  tonsils,  and  more  especially  the  phlegmonous  inflammations  starting  about 
the  submaxillary  glands  (Ludwig's  angina)  or  from  the  mucosa,  or  even  the  skin,  may 
produce  the  most  intense  infiltration  of  the  tissues  of  the  neck,  with  inflammatory  cedema 
of  the  especially  loose  structures  of  the  larynx.  The  epiglottis  swells  into  a  balloon- 
like  mass,  and  each  aryepiglottic  fold  assumes  huge  dimensions,  so  that  the  opening  of 
the  larynx  may  easily  be  closed  and  suffocation  ensue. 

430 


OBSTRUCTION    OF    THE    LARYNX 


431 


Diphtheria,  by  blocking  the  larynx  and  trachea  with  a  tough,  inflam- 
matory pseudomembrane  may  also  asphyxiate  a  child,  and  it  is  to  obviate 
this  that  tracheotomy  is  sometimes  necessary.  Exactly  the  same  sort  of 
asphyxia  arises  when  a  foreign  body,  such  as  a  piece  of  meat,  is  drawn  into 
the  opening  of  the  larynx  (Fig.  213).  Incredible  as  it  may  appear,  it  is  not 
uncommon  to  find,  in  the  autopsy  upon  drunken  persons  who  have  died 


p 


Fig.  212. — (Edema  of  the  glottis. 


Fig.  213. — Meat  impacted  in 
the  glottis.  Sudden  death  from 
asphyxia. 


with  symptoms  of  choking,  such  masses  so  firmly  wedged  into  the  glottis 
as  to  be  removed  with  difficulty. 

From  without,  the  trachea  may  be  compressed  by  the  growth  of  goitres, 
aneurysms,  and  tumors  of  the  neck.  In  the  case  of  goitres,  it  is  not  unusual 
to  find  the  lumen  of  the  tube  flattened  into  a  slit  from  the  pressure  exerted 
on  each  side.  Dyspnoea  increases  in  intensity  with  the  narrowing  of  the 


432  TEXT-BOOK   OF   PATHOLOGY 

passage.  Syphilitic  ulceration  of  the  tracheal  wall,  with  scarring,  is  no 
uncommon  cause  of  stricture.  The  narrowing  is  generally  ring-shaped, 
and  may  occur  just  above  the  bifurcation,  or  sometimes  even  in  one  of  the 
main  bronchi. 

It  will  be  seen  that,  while  some  of  these  conditions  can  last  only  a  short 
time,  others  are  of  long  standing  and  are  gradually  produced.  The  latter 
can  in  time  produce  anatomical  changes  in  the  lung  which  are  perhaps 
less  striking,  though  analogous  with  those  produced  by  similar  narrowing 
of  the  bronchi. 

OBSTRUCTION  OF  THE  BRONCHI 

The  bronchi,  like  the  trachea,  may  be  completely  or  only  partly  occluded 
in  any  part  of  their  course  by  foreign  bodies  of  all  sorts  accidentally  drawn 
into  the  larynx.  Seeds,  fruit-stones,  teeth,  pieces  of  bone,  nails,  buttons, 
pieces  of  tracheotomy  tubes,  etc.,  are  the  common  objects  found  there. 
In  the  case  illustrated  in  Fig.  214  a  fragment  of  bone,  together  with  a 
tangle  of  string,  partially  occluded  the  large  bronchus,  supplying  air  to  the 
middle  and  lower  lobes,  leaving  the  bronchus  to  the  upper  lobe  quite  open. 
Tumors,  caseous  lymph-nodes,  and  aneurysms  may  also  gradually  close 
the  bronchus  by  pressure,  or  by  actually  growing  into  the  lumen  of  the 
tube. 

The  result,  when  the  occlusion  is  complete,  is  the  collapse  of  the  cor- 
responding part  of  the  lung  (atelectasis),  because  the  air  which  remains  in 
the  alveoli  when  the  closure  is  completed  is  soon  absorbed  by  the  circulating 
blood. 

Atelectasis. — The  fcetal  state  of  the  lungs  is  comparable  to  the  condition 
of  collapse  seen  in  later  life,  except  in  that,  until  the  first  breath  is  taken, 
the  alveoli  have  never  been  expanded.  Since,  in  the  adult,  the  thorax 
has  grown  to  a  size  greater  than  could  be  filled  by  the  collapsed  lungs, 
there  is  even  in  the  position  of  forced  expiration  a  disproportion  which 
keeps  the  lungs  partly  distended  with  air.  In  the  infant,  for  a  time, 
so  nearly  does  the  lung  tissue  fill  the  thorax,  that  the  air  which  is  found  in 
the  lung  is  quite  proportional  to  the  respiratory  movements.  Atelectasis 
is,  therefore,  more  easily  produced  or  maintained  in  the  infant  than  in  the 
adult.  Indeed,  areas  of  lung  tissue  often  remain  undistended  with  air, 
and  if  the  condition  persists,  become  obliterated  and  reduced  to  scar 
tissue.  In  the  adult,  when  the  lung  has  been  expanded,  the  condition  of 
collapse  may  be  produced  by:  (1)  Complete  occlusion  of  the  bronchi,  or 
(2)  by  pressure  from  without.  Only  exceptionally  is  collapse  produced  in 
another  way,  as  in  those  cases  in  which,  while  the  bronchus  is  widely  open 
to  the  trachea,  it  communicates  also  through  a  hole  in  the  lung  with  the 
pleural  cavity.  When  air  can  thus  enter  the  pleura  without  the  necessity 
of  expanding  the  lung,  that  tissue  gradually  collapses.  This  requires  some 
time,  so  that  if,  instead,  a  hole  is  made  in  the  chest-wall,  complete  collapse 
of  the  lung  does  not  occur  at  once. 

The  first  mode  of  production  of  atelectasis  by  complete  occlusion  of  a 


OBSTRUCTION    OF   THE   BRONCHI  433 

bronchus  depends  upon  the  fact  that  the  air  in  the  corresponding  alveoli 
after  the  obstruction  is  complete,  is  soon  dissolved  in  the  circulating  blood, 
so  that  the  alveolar  walls  fall  together.  The  area  appears  sunken  and  of  a 
translucent,  bluish-purple  color.  On  section  it  is  pasty  and  often  congested, 
the  congestion  being  due  to  the  kinking  of  the  veins,  which  prevents  the 
blood  from  escaping.  Such  airless  patches  are  found  about  the  regions  of 
consolidation  in  lobular  pneumonia,  where  they  represent  the  parts  of  the 
lung  supplied  with  air  by  branches  of  bronchi  which,  at  a  higher  point,  are 
obstructed  by  the  inflammatory  exudate.  Precisely  the  same  result  is 
found  if  a  foreign  body  completely  closes  the  bronchus. 

Pressure  from  without,  the  second  cause  referred  to,  is  most  effective 
when  applied  gradually  and  slowly,  for  the  most  forcible  attempt  to  press 
air  out  of  the  lungs  rapidly,  fails  unless  the  alveoli  are  ruptured,  because  the 
smaller  bronchioles  bend  sharply  on  themselves  and  prevent  the  escape  of 
the  air.  The  growth  of  a  tumor,  however,  or  the  gradual  accumulation  of 
fluid  in  the  pleural  cavity,  may  render  airless  the  part  of  the  lung  pressed 
upon  (cf.  Fig.  92).  A  whole  lobe  or  part  of  it,  usually  the  lower  and  pos- 
terior part,  may  thus  collapse  into  a  soft,  pasty,  bluish,  airless  tissue,  which 
sinks  in  water  and  gives  no  crepitation  between  the  fingers.  When  cut 
into,  it  may  be  dry  and  inelastic,  thus  differing  from  an  cedematous  lung 
in  which  the  air  has  been  replaced  by  fluid.  By  stretching  a  little  of  the 
tissue,  first  in  one  direction  and  then  in  another,  the  movements  of  the 
alveolar  walls,  can  be  seen  so  plainly  that  the  condition  of  collapse  is  easily 
distinguished  from  that  of  inflammatory  consolidation.  Adhesions  be- 
tween the  alveolar  walls  and  the  growth  of  fibrous  tissue  through  them 
sometimes  indurate  and  solidify  the  lung  permanently,  so  that  it  cannot 
expand  again. 

Bronchiectasis. — When  the  obstruction  is  incomplete,  the  bronchi  distal 
to  it  become  dilated  (Fig.  214).  This  is  because  both  inspiration  and  expira- 
tion become  difficult  in  that  portion  of  the  lung  on  account  of  the  partial 
blocking  of  the  bronchus,  although  they  go  on  easily  enough  in  the  rest 
of  the  lung.  Quiet  expiration  is  a  more  or  less  passive  process,  due  to  the 
elastic  recoil  of  the  distended  lung,  the  sinking  of  the  ribs  from  their 
actively  elevated  position,  and  the  relaxation  of  the  diaphragm  and  of  the 
distended  abdomen,  although,  of  course,  violent  muscular  contraction  of 
the  chest  is  available  in  forced  expiration. 

Thus  the  force  available  to  carry  air  into  the  lung  when  the  chest  is 
expanded  is  the  whole  atmospheric  pressure,  part  of  which  is  used  in 
stretching  the  elastic  lung.*  The  force  which  drives  the  air  out  in  quiet 
respiration  is  only  the  elastic  contraction  of  the  lung,  aided  by  gravity 
and  a  relatively  slight  muscular  action. 

Consequently,  if  there  arises  a  partial  obstruction  of  a  bronchus,  offering 

*  Just  what  pressure  relations  will  exist  on  each  side  of  a  complete  obstruction  of  the 
main  bronchus  within  the  chest  in  inspiration  will  depend  upon  the  amount  of  air  already 
in  the  lung. 
29 


434 


TEXT-BOOK   OF   PATHOLOGY 


a  constant  resistance  to  the  passage  of  air,  inspiration  will  fairly  readily 
overcome  the  resistance,  drawing  air  into  the  distal  part,  while  expiration 
will  prove  too  feeble  to  drive  it  out.  Air  in  such  a  case  accumulates  behind 
the  obstruction  until  it  is  under  a  pressure  equal  to  that  which  overcame 


Fig.  214.— Partial  obstruction  of  a  bronchus  by  foreign  bodies.     Bronchiectasis  involving- 
the  corresponding  branches. 

the  resistance  of  the  obstruction,  and  at  this  pressure  it  will  remain  as  long 

reathmg  continues,  while  other  air  passes  in  and  out,  just  as  tide-water 

passes  in  and  out  over  a  dyke,  leaving  a  great  depth  imprisoned  behind,  up 

the  level  of  the  top.     It  is  this  continuous  distension  of  the  obstructed 


OBSTRUCTION    OF   THE    BRONCHI  435 

bronchus  which  finally  widens  it  and  is  a  prominent  cause  of  the  condition 
known  as  bronchiectasis,  although  Dr.  Crowe  tells  me  that  in  dogs  in  which 
he  has  produced  stricture  of  a  bronchus,  easily  seen  through  the  broncho- 
scope  as  an  extreme  narrowing  of  the  lumen,  there  is  no  dilatation  of  the 
distal  part  as  long  as  the  bronchus  remains  uninfected. 

There  are  several  different  types  of  dilatation  of  the  bronchi,  which  are 
best  separated  from  one  another  according  to  their  causes,  rather  than 
their  anatomical  form,  although  we  are  not  well  informed  as  to  those 
causes. 

Quite  distinct  is  the  group  described  by  H.  Meyer,  Grawitz,  Stoerk,  and 
others  as  occurring  in  infants,  and  sometimes  found  persisting  in  adults. 
In  this  form  the  lung,  or  part  of  it,  is  found  to  be  converted  into  a  mass  of 
cysts  lined  with  high  epithelium  and  full  of  fluid.  Since  they  are  generally 
not  connected  with  bronchi,  it  seems  hardly  proper  to  speak  of  them  as 
bronchiectasis.  They  represent  rather  a  congenital  malformation  of  the 
lung.  Atelectatic  bronchiectasis  is  that  widening  of  the  bronchi  described 
by  Heller,  Buchmann,  and  others  as  occurring  in  portions  of  the  lung  which 
have  become  permanently  collapsed  in  early  life.  Such  a  lobe  or  lobule 
of  the  lung  remains  unpigmented,  and  consists  of  a  sponge  of  wide  bronchi 
embedded  in  a  firm  tissue  in  which  alveoli  can  no  longer  be  easily  dis- 
tinguished. Such  widening  may  well  be  the  result  of  the  tendency  of 
a  portion  of  the  lung  which  is  not  taking  its  normal  part  in  filling  the 
thorax,  to  dilate  during  inspiration. 

Other  forms  of  bronchiectasis  are  acquired  in  later  life,  and  are  in  all 
cases  associated  with  infection  and  inflammation  of  the  bronchi.  This  in 
itself  is  not  sufficient  cause  for  the  widening  of  the  bronchi  until  there  is 
added  to  it  a  mechanical  distension.  By  bronchiectasis  is  meant  the  forma- 
tion of  abnormally  wide  channels  in  the  lung  from  the  dilatation  of  bronchi. 
Since  these  cavities  are  surrounded  by  the  stretched  bronchial  wall,  the 
term  does  not  include  caverns  excavated  in  the  substance  of  the  lung  itself, 
although  these  may  secondarily  be  formed  in  connection  with  true  bron- 
chiectasis by  gangrene  or  tuberculosis.  The  bronchi  may  be  widened  dur- 
ing an  acute  inflammatory  disease,  but  the  larger  dilatations  are  produced 
more  slowly  by  chronic  processes,  and  are  often  accompanied  by  the  most 
profound  changes  in  the  surrounding  lung  tissue.  When  such  cavities  are 
formed,  they  may  be  recognized  by  auscultation  and  by  the  sudden  dis- 
charge of  great  quantities  of  characteristic  sputum,  which  have  collected 
in  them  during  the  night  when  the  patient  does  not  cough. 

Anatomically,  they  vary  greatly  in  appearance.  In  those  acutely  pro- 
duced, the  bronchi  are  deeply  congested,  thin  walled,  and  soft,  and  filled 
with  a  purulent  secretion.  They  are  usually  associated  with  lobular 
pneumonic  patches  of  consolidation.  In  the  more  chronic  cases  the  same 
cylindrical  dilatation  may  appear,  but  it  is  perhaps  more  common  to  find 
the  widening  excessive  at  the  ends  of  the  bronchi,  so  that  they  become  club- 
shaped.  Occasionally  they  are  beaded  with  separate  dilatations,  or  they 


436  TEXT-BOOK   OF   PATHOLOGY 

may  be  blown  out  into  wide  sacs  which  can  rupture  into  one  another  or 
into  the  pleura.  In  all  these  cases  the  bronchial  wall  is  intensely  inflamed 
and  thickened  by  the  accumulation  of  inflammatory  exudate  in  its  sub- 
stance. The  mucosa  is  thick  and  ragged,  the  musculature  and  elastic  tissue 
spread  apart,  torn,  and  weakened,  and  the  connective  tissue  as  well,  infil- 
trated with  fluid  and  wandering  cells.  The  cartilaginous  plates  tend  to 
disappear,  and  a  newly  formed  connective  tissue  occupies  the  bulk  of  the 
wall.  All  this  tends  to  diminish  greatly  the  strength  and  elasticity  of  the 
wall. 

The  lung  tissue  in  these  protracted  cases  is  sometimes  very  emphysema- 
tous,  but  in  others  it  is  converted  into  a  dense  fibroid  substance  partly  by 
the  organization  of  inflammatory  exudate  within  the  alveoli,  partly  by  the 
growth  of  fibrous  scar  tissue  in  the  walls  of  the  alveoli  and  the  other  tissues 
of  the  lung. 

It  is  not  well  known  what  changes  occur  in  the  channels  of  communica- 
tion between  these  widened  bronchi  and  their  alveolar  tissue,  but  it  is 
probable  that,  according  as  there  is  narrowing  or  complete  obstruction  of 
the  tiny  bronchioles  at  their  entrance  into  the  dilated  bronchus,  there  will 
be  emphysema  or  atelectasis  in  the  corresponding  alveoli. 

Many  theories  have  been  formulated  to  explain  the  distension  of  the 
bronchi,  but  in  these  all  are  agreed  upon  one  point  only,  that  the  infection 
and  inflammation  which  weakens  the  bronchial  wall  and  destroys  its 
elasticity  is  a  necessary  factor.  Not  all  cases  of  bronchitis  are  followed  by 
bronchiectasis,  and  it  may  be  that  special  bacteria,  such  as  the  influenza 
bacillus,  which  has  often  been  found  in  bronchiectasis,  are  particularly  able 
to  cause  the  weakening  of  the  wall.  In  the  course  of  the  recent  epidemic, 
in  which  the  bacillus  of  Pfeiffer  was  frequently  found,  bronchiectatic  dila- 
tation was  described  by  many  writers. 

Pleural  adhesions  generally  accompany  chronic  bronchiectasis,  and 
Corrigan  and  Biermer  express  the  idea  that  in  indurated  and  adherent 
lungs  the  contraction  of  the  scar  tissue  between  the  bronchi  pulls  upon 
them  from  all  sides  and  thus  dilates  them.  Possibly  this  is  true  in  some 
cases,  but  it  cannot  be  a  general  explanation. 

Others  declare  that  the  accumulation  of  secretion  in  the  bronchi  is  suffi- 
cient to  distend  them  to  the  degree  found,  but  it  seems  that  this  can  at 
best  be  only  an  accessory  influence,  because  by  itself  the  secretion  can 
never  exert  any  great  pressure.  Most  writers,  too,  lay  stress  upon  the 
effects  of  the  violent  expiratory  effort  with  closure  of  the  glottis  in  coughing, 
as  capable  of  distending  the  bronchi.  Reflection  will  show,  however,  that 
although  under  those  circumstances  the  trachea  might  be  distended,  the 
pressure  on  the  walls  of  the  bronchi  within  the  chest  is  from  outside,  so 
that  it  cannot  distend  them,  as  a  rubber  and  glass  model  of  the  respiratory 
organs  will  demonstrate  to  perfection.  Indeed,  bronchiectasis  may  be 
experimentally  produced  in  animals  in  the  complete  absence  of  cough. 
On  the  other  hand/the  violent  inspiratory  distension  of  the  lung  preparatory 


OBSTRUCTION   OF   THE    BRONCHI  437 

to  coughing  may  be  able  to  widen  the  bronchi  if  they  are  weak  and  it  is 
constantly  repeated. 

This  leaves  the  idea  of  the  inspiratory  dilatation,  whether  exerted  directly 
or  through  the  imprisonment  of  inspired  air  behind  some  obstruction,  as 
the  most  plausible  explanation.  It  was,  indeed,  the  explanation  given  by 
Laennec  in  his  first  work  on  bronchiectasis  in  1819,  and  it  has  been  recalled 
by  Aron,  and  by  Thornton  and  Pratt  in  their  experimental  work.  When  we 
attempt  to  apply  this  explanation  to  the  cases  of  bronchiectasis  as  they 
occur,  we  find  that  it  is  completely  satisfactory  in  those  in  which  there  is 
an  obvious  partial  obstruction.  But  there  are  many  others  where  obstruc- 
tion is  not  so  obvious,  and  these  offer  difficulties.  It  is  true  that  we  may 
say  that  thick,  sticky,  mucoid  secretion  may  exert  a  valvular  action  in 
the  bronchi,  preventing  the  easy  exit  of  air;  or  we  may  assume,  with  Hoff- 
mann, that  the  weakened  bronchus  may  kink  during  expiration  like  an 
old  rubber  tube,  while  stretching  open  on  inspiration,  in  this  way  fulfill- 
ing the  theoretical  conditions. 

But  these  things  are  hardly  definitely  demonstrated  as  yet,  and  the 
question  needs  further  study. 

LITERATURE 

(Edema  of  Larynx:  Peltesohn:   Berl.  klin.  Woch.,  1889,  xxvi,  931. 
Congenital  and  Atelectatic  Bronchiectasis:    Grawitz:    Virchow's  Archiv,  1880,  Ixxxii, 
217. 

• Stoerk:   Wien.  klin.  Woch.,  1897,  x,  25. 

Edens:   Deut.  Arch.  f.  klin.  Med.,  1904,  Ixxxi,  334. 

Buchmann:    Frankf.  Ztsch.  f.  Path.,  1911,  viii,  263. 

Bronchiectasis:   v.  Criegern:    Akute  Bronchiektasie,  Leipzig,  1903. 

Posselt:    Med.  Klinik,  1909,  vi,  1845. 

Thornton  and  Pratt:  Johns  Hopkins  Hosp.  Bull.,  1908,  xix,  230. 

Open  Pneumothorax :  Graham  and  Bell:  Amer.  Jour.  Med.  Sci.,  1918,  clvi,  839. 

The  effect  of  partial  or  intermittent  obstruction  of  the  air-passages  upon 
the  alveolar  structure  of  the  lungs  may  next  be  examined.  It  has  been 
said  that  complete  obstruction  of  a  bronchus  quickly  results  in  atelectasis 
or  collapse  of  the  corresponding  part  of  the  lung,  but  it  is  also  true  that 
partial  or  intermittent  obstruction  causes  an  overdistension  of  the  alveoli 
with  air.  There  are  many  other  causes  assigned  for  the  overdistension, 
but  the  importance  of  this  one  will  become  evident  in  studying  the  type 
condition,  emphysema. 

Emphysema. — Excessive  distension  of  the  alveoli  may  be  produced 
rapidly  in  the  lung,  when  the  tissue  of  the  alveolar  walls  is  quite  nor- 
mal, so  that  if  the  air  be  allowed  to  escape,  the  alveoli  at  once  return 
to  their  normal  size,  and  their  stretched  walls  to  their  normal  thick- 
ness. If  this  overdistension  be  maintained  at  not  too  great  a  degree,  the 
capillaries  are,  as  Tendeloo  has  shown,  widened  so  that  nutrition  of  the 
alveolar  wall  may  be  well  kept  up.  A  still  greater  distension  narrows  and 


438  TEXT-BOOK    OF    PATHOLOGY 

compresses  the  capillaries,  so  that  the  blood  passes  with  difficulty  or  not  at 
all.  Nutritive  changes  possibly  dependent  on  this  great  stretching  and 
the  impaired  blood  supply  weaken  the  elastic  alveolar  wall  after  a  time, 
so  that  it  may  remain  permanently  stretched,  or,  after  the  breaking  of  its 
elastic  fibres,  give  way  at  one  or  more  points.  Then  the  margins  about  the 
hole  retract,  and  two  alveoli  are  thrown  into  one.*  At  times  great  sacs 
are  formed  on  the  surface  and  along  the  edges  of  the  lung  by  this  process, 
while  the  remainder  of  the  organ  is  softened  and  assumes  a  very  coarse 
texture,  from  the  wide-spread  loss  of  alveolar  walls.  Such  a  lung  is  very 
voluminous,  but  feels  peculiarly  soft  and  non-resilient.  The  characteristic 
crepitation  or  crackling  felt  on  pinching  the  lung  tissue  is  altered,  and  one 
has  the  sensation  of  bursting  large  bubbles  under  the  finger  instead  of  the 
fine  crackling  produced  in  the  normal  tissue.  There  is  also  a  peculiar  pallor, 
which  is  due  to  the  obliteration  of  so  much  of  the  capillary  bed  and  to  the 
absence  of  coal-pigment. 

Microscopically,  the  most  striking  feature  is  the  large  size  of  the  alveolar 
spaces  and  the  extreme  thinness  of  the  alveolar  walls.  With  suitable 
stains  one  may  observe  the  fracture  of  the  strands  of  elastic  tissue  and  the 
formation  of  holes  in  the  walls,  as  well  as  the  narrowing,  obliteration,  and 
rupture  of  the  capillaries. 

This  is  the  chronic  substantive  emphysema  in  which  one  may  some- 
times discern  evidences  of  attempts  at  repair  in  the  new  formation  of  elastic 
tissue  and  the  growth  of  new  blood-vessels  and  connective  tissue.  Atrophy 
of  the  lung  tissue  is  perhaps  the  most  characteristic  feature  of  a  subtype, 
the  so-called  senile  emphysema.  In  old  people  the  lungs  are  sometimes 
found  to  collapse  into  a  very  small  bulk  on  opening  the  chest.  They  may 
contain  much  coal-pigment,  but  the  tissue  is  extremely  soft  and  wide 
meshed.  In  such  cases  it  is  customary  to  ascribe  much  of  the  thinning 
out  and  disappearance  of  the  alveolar  walls  to  senile  atrophy,  but  it  may  be 
questioned  whether  it  is  not  sometimes  the  end  result  of  a  very  protracted 
process  of  the  kind  described  above. 

The  causes  of  emphysema  are  somewhat  different  in  the  various  forms, 
although  only  a  few  principles  can  be  concerned.  When,  through  lobar 
pneumonia,  tuberculosis,  tumor  formation,  etc.,  a  large  portion  of  the  lung 
is  rendered  solid,  so  that  it  cannot  expand  with  the  enlargement  of  the 
thorax,  the  whole  inspiratory  effort  is  expended  upon  the  remaining  open 
hing  tissue,  which  thus  becomes  overdistended  (vicarious  emphysema). 
So,  too,  in  drowning,  water  is  drawn  in  to  fill  part  of  the  lung,  while  further 
violent  inspiratory  efforts  above  water  overdilate  the  rest  of  the  alveoli 
with  air. 


*  The  alveolar  walls  contain  a  rich  network  of  capillaries,  abundant  elastic  tissue, 
and  some  wavy  fibrils  of  connective  tissue,  and  are  covered  on  each  side  by  the  respira- 
tory epithelium.  The  elastic  tissue  stretches  across  in  coarse  bands,  frayed  out  here  and 
there  into  fibres  which  join  again  in  other  directions  to  form  new  bands.  Another  set 
of  fine  fibrils  arises  from  the  elastica  of  the  vessels  and  accompanies  the  capillaries 
(Orsos).  Pores  in  the  alveolar  walls  (pores  of  Kohn)  are  frequently  seen,  but  there  is 
much  evidence  that  they  are  present  only  in  diseased  lungs. 


OBSTRUCTION    OF   THE    BRONCHI  439 

In  many  conditions  in  which  the  trachea  or  bronchi  are  partly  obstructed, 
continued  distension  of  the  alveoli  occurs  by  the  imprisonment  of  air 
introduced  in  inspiration  over  the  obstacle  in  the  way  described  in  connec- 
tion with  the  formation  of  bronchiectasis.  This  is  especially  clear  in  the 
case  of  valvular  obstructions  which  allow  inspiration  only,  as  in  the  case 
of  a  stalked  polyp  in  one  of  these  air-passages,  or  a  flapping  film  of  diph- 
therial  false  membrane.  It  is  true  also  of  the  thick,  sticky,  mucous  exudate 
which  may  collect  in  the  inflamed  bronchioles  in  chronic  bronchitis,  and  is 
particularly  shown  in  the  areas  of  emphysema  which  occur  side  by  side 
with  areas  of  atelectasis  in  the  neighborhood  of  patches  of  broncho- 
pneumonic  consolidation.  Asthma,  in  which  the  bronchioles  are  narrowed 
partly  by  muscular  contraction,  partly  by  swelling  of  their  mucosa  and 
by  exudate,  presents  the  conditions  mentioned.  Inspiration  is  violent, 
and  expiration  prolonged  and  labored,  and  emphysema  is  the  regular 
accompaniment. '  In  all  these  cases  it  seems  to  be  the  inspiratory  effort 
which  is  active  in  dilating  the  alveoli.  Generally  this  is  effective  in  pro- 
ducing a  permanent  anatomical  change  only  when  aided  by  a  partial 
obstruction,  and  when  kept  up  through  a  long  time.  Whether  it  itself 
can  thus  produce  the  nutritive  disturbances  which  lead  to  rupture  of  the 
alveolar  wall  is  not  perfectly  certain.  Doubtless  other  injurious  agencies 
may  also  play  a  part,  because  it  is  known  that  the  lungs  of  certain  people 
exposed  to  mechanical  conditions  of  this  sort  develop  emphysema,  while 
others  do  not. 

Nearly  every  writer  on  the  subject  ascribes  the  widening  of  the  alveoli 
to  the  increased  intrathoracic  pressure  produced  by  cough,  which  is  a 
forced  expiration  during  closure  of  the  glottis,  suddenly  relieved  by  its 
opening.  It  must,  however,  be  clear  that,  as  in  the  case  of  bronchiectasis, 
the  increased  intra-alveolar  pressure  is  produced  only  by  their  compression, 
with  decrease  in  their  size.  Only  in  such  an  unprotected  place  as  the 
suprathoracic  apex  of  the  lung  could  one  imagine  this  pressure  capable  of 
blowing  out  the  alveoli.  In  the  sternal  margins  it  is  still  more  doubtful. 
But  cough  is  preceded  each  time  by  an  extreme  inspiratory  distension  of 
the  lung,  which,  incessantly  repeated,  might  lead  to  changes  in  the  size  of 
the  alveoli.  Tendeloo  presents  some  interesting  arguments  with  regard 
to  the  predominantly  marginal  and  apical  distribution  of  emphysema, 
based  on  his  ideas  as  to  the  unequal  expansion  of  the  alveoli  in  different 
parts  of  the  thorax.  His  laws  seem,  however,  to  depend  upon  doubtful 
evidence,  and  must  be  read  in  the  original.  When  there  are  no  adhesions 
in  the  pleural  cavity,  nor  consolidated  areas  in  the  lung,  the  expansion  of 
all  alveoli  would  appear  to  us  to  be  uniform. 

In  wide-spread  emphysema  of  long  standing,  such  as  often  accompanies 
chronic  bronchitis  or  asthma,  the  capillary  bed  in  the  lungs  is  so  much 
narrowed  by  the  obliteration  of  many  channels  that  the  blood  passes  with 
difficulty,  and  hypertrophy  of  the  right  side  of  the  heart  is  a  consequence. 

Such  persons  usually  present  a  peculiar  thoracic  deformity — the  chest  is 


440  TEXT-BOOK   OF   PATHOLOGY 

enlarged,  with  the  ribs  constantly  in  the  position  of  inspiration,  so  that 
further  respiratory  movements  are  shallow.  The  costal  cartilages  often 
become  calcified  and  rigid,  and  Freund  has  suggested  that  this  condition 
may  be  primary  and  constitute  the  real  cause  of  the  emphysematous 
enlargement  of  the  lungs.  The  evidence  is  not  clear,  however,  in  favor  of 
this  idea. 

LITERATURE 

Eppinger:  Ergeb.  d.  allg.  Path.,  1904,  viii,  267. 

Tendeloo:  Ursachen  d.  Lungenkrankheiten,  1902.     Ergebn.  d.  inn.  Med.,  1910,  vi,  1. 

Freund:  Lungenkrankheiten  u.  Rippenknorpel-Anomalien,  Erlangen,  1859. 

Marchand:  Asthma,  Ziegler's  Beitrage,  1915,  Ixi,  251. 

Orth:  Berl.  klin.  Woch.,  1905,  xlii,  1. 

Ors6s:  Ziegler's  Beitrage,  1907,  xli,  95. 


CHAPTER  XXII 

TYPES    OF    INJURY— OBSTRUCTION    (Continued).— OBSTRUC- 
TION OF  THE  URINARY  TRACT 

Urethral  stricture;  prostatic  obstruction.  Hypertrophy  of  prostate.  Cystitis.  Urinary 
calculi.  Hydronephrosis.  Renal  calculi.  Ascending  renal  infection;  pyelonephritis. 

THE  course  of  the  urinary  tract  in  the  male  is  beset  with  so  many  more 
difficulties  in  the  form  of  narrow  places  than  in  the  female  that  the  greater 
proportion  of  obstructions  may  naturally  be  expected  in  that  sex. 

URETHRAL  STRICTURE 

In  the  female  the  bladder  opens  by  a  canal  so  short  and  wide  that  obstruc- 
tion to  the  flow  of  urine  is  seldom  observed  below  the  ureters.  In  the  male 
it  may  occur  at  the  prepuce,  at  the  meatus,  in  the  urethra,  and  especially 
in  its  prostatic  portion,  and  at  the  vesical  orifice.  Phimosis,  which  is  a 
congenital  or  acquired  narrowing  of  the  prepuce,  may  sometimes  be  suffi- 
cient to  offer  a  considerable  obstacle,  and  even  give  rise  to  fatal  complica- 
tions. A  similar  effect  is  produced  by  those  constrictions  of  the  meatus 
by  scar  tissue  which  occasionally  follow  the  healing  of  an  ulcer  of  the  glans 
or  a  syphilitic  chancre.  It  is,  however,  much  more  common  to  find  the 
narrowing  of  the  urethral  canal  higher  up,  and  there  it  is  due  sometimes  to 
mechanical  trauma,  but  far  more  often  to  gonorrhoea.  When  the  urethra  is 
torn  across,  as  in  those  cases  in  which  a  man  falls  from  a  height  astride  a 
beam,  it  is  difficult  even  for  the  surgeon  to  secure  such  perfect  healing  that 
there  is  not  some  narrowing  at  the  place.  Nevertheless,  such  cases  are 
very  amenable  to  treatment.  Far  different  are  those  in  which,  in  the  course 
of  a  protracted  gonorrhoeal  infection,  the  wall  of  the  urethra  becomes  ulcer- 
ated and  infiltrated  with  inflammatory  exudate.  This  usually  produces  its 
most  profound  effects  in  the  bulbous  portion,  although  other  places  may  be 
involved  instead.  The  organisms  penetrate  deep  into  the  mucosa,  and 
lodge  in  the  lacunse  and  crypts,  where  they  keep  up  the  injury  in  the  most 
persistent  way.  Healing  with  scarring  of  the  ulcerated  tissue  results  in  the 
narrowing  of  the  canal,  and  such  strictures  (Fig.  215)  frequently  make  it 
impossible  for  the  bladder  to  empty  itself.  To  this  are  often  added  the 
injuries  caused  by  forcible  attempts  to  pass  catheters  which,  in  inexper- 
ienced hands,  pierce  the  urethral  wall  and  wound  the  surrounding  tissue. 
The  healing  of  these  false  passages,  added  to  the  mass  of  scar  tissue  around 
the  urethra  which  constricts  and  deforms  it,  is  the  cause  of  ever-impending 
occlusion. 

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PROSTATIC  OBSTRUCTION 

Complex  conditions  exist  about  the  region  of  the  prostate,  so  that  a  variety 
of  alterations  take  part  in  producing  obstructions  there.  Among  these 
abscess  of  the  prostate  and  cancerous  tumors  springing  from  the  gland 
are  important,  but  by  far  the  most  common  is  the  so-called  hypertrophy  of 


Fig.  215. — Gonorrhceal  stricture  of  the  urethra.    At  A  the  urethral  canal  is  surrounded 
by  scar  tissue  and  greatly  narrowed.     There  is  hypertrophy  of  the  bladder. 

the  prostate  of  old  men.  The  obstruction  caused  by  an  abscess  is  transient, 
and  depends  upon  the  bulging  of  the  prostate  until  the  urethra  is  pressed 
flat,  while  that  caused  by  the  cancer  is  quite  irregular,  because  the  tumor 
may  encroach  on  the  urethra  in  any  way.  But  the  hypertrophy  of  the 


PROSTATIC    OBSTRUCTION  443 

prostate  follows  roughly  certain  general  rules,  and  the  type  of  obstruction 
is  for  that  reason  fairly  constant. 

Hypertrophy  of  the  Prostate. — Despite  the  most  lengthy  discussions,  our  ideas  are 
still  quite  hazy  as  to  the  reasons  for  the  enlargement  of  the  prostate  which  is  so  frequent 
in  men  over  sixty  years  of  age,  and  even  as  to  its  anatomical  characters  the  most  diverse 
statements  are  made.  It  is  evidently  desirable  that  more  accurate  observations  in  this 
regard  should  be  made  and  analyzed. 

The  prostate  is  a  sexual  gland  derived  from  the  Wolffian  body,  just  as  are  the  seminal 
vesicles,  and  its  function  is  not  to  control  the  flow  of  urine,  but  to  furnish  its  secretion 
in  jets  at  the  moment  of  ejaculation,  in  such  a  way  as  to  mix  it  with  the  sperm  in  the 
urethra.  In  accord  with  this  requirement  we  find  that  its  abundant  smooth  muscle 
is  arranged  around  the  glands,  so  that  it  can  suddenly  exert  pressure  upon  them.  The 
internal  sphincter  of  the  bladder  controls  the  discharge  of  urine,  and  is  practically  inde- 
pendent of  the  musculature  of  the  prostate.  So,  too,  the  external  sphincter  of  Henle, 
which  consists  largely  of  voluntary  muscle,  is  independent,  although  its  fibres  extend 
in  some  cases  into  the  prostate. 

The  bulk  of  the  gland  tissue  in  the  prostate  is  collected  in  the  lateral  lobes,  where  it 
forms  pyramidal  radiating  masses  opening  through  40  or  50  ducts  into  the  urethra.  The 
glands  are  acinar,  lined  with  cubical  or  cylindrical  epithelium,  and  often  contain  yellow, 
horn-like,  concentrically  laminated  concretions  (corpora  amylacea).  The  posterior 
commissure  is  chiefly  muscular,  and  contains  few  glands.  There  are  a  few,  however, 
which  extend  upward  toward  the  bladder  inside  the  sphincter.  There  are  also  urethral 
glands  there,  such  as  are  to  be  found  throughout  the  course  of  the  urethra.  The  anterior 
commissure  is  tightly  connected  with  the  symphysis  pubis. 

Enlargement  of  the  prostate  is  due,  in  the  great  majority  of  cases,  to  the  develop- 
ment of  more  or  less  distinct  nodules  of  a  granular,  opaque,  and  rather  spongy  appear- 
ance, embedded  in  the  substance  of  the  original  gland,  which  itself  may  be  much 
compressed  by  their  presence.  They  are  surrounded  by  the  dense  stroma  with  some 
muscle,  but,  on  the  whole,  the  muscle  seems  to  be  rather  atrophied  than  increased. 
Taken  together,  these  nodules  may  often  be  shelled  out  in  one  large,  irregular  mass, 
leaving  the  remnants  of  the  old  prostate  tissue. 

Microscopically,  they  are  composed  of  newly  formed  glands,  which  ramify  abundantly 
and  are  lined  with  cylindrical  epithelium.  Often  these  are  partly  filled  with  papillary 
growths  of  epithelium.  At  other  times  they  are  more  nearly  tubular  than  acinar  in 
form.  From  the  cylindrical  form  of  the  epithelium  and  the  extraordinary  ramification 
and  papillary  ingrowth,  it  seems  clear  that  these  are  newly  formed  glands,  and  that 
there  is  an  enormous  multiplication  of  these  elements. 

Without,  such  hyperplasia  of  the  glands  the  increase  of  the  stroma  and  of  the  smooth 
muscle  may  sometimes  cause  enlargement  of  the  prostate,  but  such  cases  are  not  com- 
mon, and  those  in  which  there  is  a  distinct  myoma  or  muscular  tumor  growth  are  rare. 
In  the  glandular  nodules  one  occasionally  finds  cystic  dilatations  which  may  contain 
epithelial  debris  and  sometimes  concretions,  although  the  latter  are  not  so  frequent  as 
in  the  original  glands. 

Inflammatory  infiltrations  of  wandering  cells  are  common,  especially  about  the  ducts. 
The  enlargement  may  affect  one  or  both  of  the  lateral  lobes,  and  is  sometimes  rather 
diffuse,  sometimes  irregular,  inasmuch  as  it  is  produced  by  only  a  few  nodules.  In  these 
cases  the  prostatic  urethra,  being  fixed  to  the  symphysis  pubis,  is  stretched  backward 
so  as  to  assume  the  form  of  a  narrow  slit,  which  is  bowed  backward  and  may  even  be 
enlarged  instead  of  being  constricted  (Fig.  218).  This  need  not  produce  any  obstruc- 
tion, and  urination  is  often  normal.  But  such  increase  in  the  bulk  of  the  lateral  lobes 
tends  to  displace  the  posterior  half  of  the  ring  of  the  sphincter  upward,  so  as  to  form 
a  transverse  muscular  fold  (Mercier's  barrier)  behind  the  vesical  orifice  of  the  urethra, 


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which  may  act  as  a  valve.  In  another  set  of  cases  there  appears,  often  in  association 
with  hypertrophy  of  the  lateral  lobes,  a  pear-shaped  mass  of  glandular  tissue  which  springs 
up  inside  the  sphincter  and  lifts  up  the  floor  of  the  trigonum,  projecting  upward  into 


Fig.  216. — Hypertrophy  of  lateral  lobes  of  prostate.     Cross-section  showing  lateral 
compression  of  urethra.     Prostatic  concretions. 


Fig.  217.— Hypertrophy  of  lateral  and  middle  lobes  of  prostate.     Great  hypertrophy 

of  the  bladder. 


PROSTATIC    OBSTRUCTION  445 

the  bladder.  This  is  the  hypertrophied  midlobe,  which  seems  to  arise  from  hyperplasia 
of  that  insignificant  group  of  glands  which  lies  in  the  midline  and  extends  in  front  of  the 
posterior  half  of  the  sphincter.*  It  may  attain  a  great  size,  and  in  one  of  our  specimens 
must  weight  at  least  50  grams.  Obstruction  to  the  outflow  of  urine  is  almost  sure  to 
result,  because  with  the  contraction  of  the  bladder  the  midlobe,  extending  as  it  does 
through  the  sphincter,  acts  as  a  conical  plug  to  close  the  urethral  orifice.  Besides,  the 
stretching  of  the  sphincter  from  its  presence  is  often  sufficient  to  produce  incontinence 
of  urine. 

As  to  the  nature  and  cause  of  this  enlargement  of  the  prostate,  numerous  ideas  have 
been  expressed,  most  lasting  among  which  are — (1)  that  of  Ciechanowski  and  many 
others  that  it  is  the  result  of  a  chronic  inflammation,  due  probably  to  gonococcal  infec- 
tion of  long  standing,  with  the  formation  of  scar  tissue  about  the  ducts,  constricting  them 
and  producing  dilatation  of  the  glands,  and  (2)  that  maintained  by  Chiari  and  others, 

. 


Pig.  218. — Hypertrophy  of  lateral  and  midlobes  of  prostate,  showing  anteroposterior 

widening  of  the  urethra. 

that  it  is  a  definite  new-growth  of  adenomatous  or  tumor-like  character,  the  direct  cause 
of  which  is  unknown.  Chiari  distinguishes  the  nodules  as  papillary  intracanalicular 
adenomata,  nbro-adenomata,  and  tubular  adenomata. 

With  regard  to  these  theories,  it  may  be  said  that  it  seems  impossible  to  explain  the 
enormous  solid  growths,  as  Ciechanowski  does,  on  the  basis  of  mere  obstruction  of  the 
ducts,  especially  hi  the  case  of  the  midlobe,  which  must  arise  from  such  a  rudimentary 
group  of  glands.  At  any  rate,  many  authors  fail  to  find  inflammatory  processes  in  all 
cases,  and  regard  them,  when  found,  as  secondary  infections.  Still  we  are  familiar  with 

*  It  must  be  said  here  that  Marion  and  Lendorf  have  recently  declared  that  the 
enlarged  midlobe,  and,  indeed,  most,  if  not  all,  of  the  enlargements  of  the  prostate, 
develop  inside  the  sphincter  from  the  urethral  glands  and  not  from  the  prostate  at  all. 
They  support  this  view  by  the  statement  that  the  prostate  is  seen  compressed  and  flat- 
tened outside  of  the  stretched  layer  of  muscle  which  represents  the  sphincter. 


446  TEXT-BOOK   OF   PATHOLOGY 

certain  infections,  such  as  the  coccidiosis  of  the  rabbit's  liver,  which  produces  colossal 
overgrowths  of  epithelium,  so  that  it  is  not  inconceivable  that  infection  might  be  at  the 
origin  of  the  process,  although  not  in  so  mechanical  a  way.  The  condition  arises  most 
commonly,  if  not  exclusively,  in  married  men,  and  has  been  ascribed  to  sexual  excesses. 
It  begins  usually  long  years  after  gonococcal  infection  has  subsided,  even  if  it  ever  were 
present,  and  the  nodules  tend  to  recur  when  removed.  Thus  it  is  that  some  authors 
unhesitatingly  refer  them  to  the  effects  of  inflammation,  while  others  just  as  firmly  rele- 
gate them  to  the  category  of  tumors.  Ribbert  feels  no  doubt  as  to  their  tumor  nature, 
and  shows  that  as  adenomatous  nodules  they  are  derived  from  a  group  of  glands  on  each 
side  of  the  urethra  near  the  colliculus  and  belonging  to  the  great  lateral  lobe,  which  he 
calls  the  lower  urethral  prostatic  glands.  The  growth  of  such  nodules  is  accompanied  by 
some  enlargement  of  the  adjacent  gland  tissue.  The  adenomata  of  the  sphincter  region 
below  the  urethra  (midlobe)  usually  develop  only  in  association  with  those  of  the 
urethral  prostatic  glands. 

LITERATURE 

Ciechanowski:  Mitth.  a.  d.  Grenzg.  d.  Med.  u.  Chir.,  1900,  vii,  183. 
v.  Frisch:   Nothnagel,  Spez.  Path.  u.  Therap.,  1899,  xix. 
Wichmann:    Virchow's  Archiv,  1904,  clxxviii,  279. 
Chiari:   Strassb.  med.  Zeitung,  1912,  ix,  1. 
Ribbert:  Ziegler's  Beitrage,  1915,  Ixi,  149. 


OTHER  FORMS  OF  OBSTRUCTION 

It  is  not  only  in  the  urethra  that  obstructions  to  the  emptying  of  the 
bladder  appear,  for  plugs  may  be  formed  in  the  bladder  itself.  These  are 
often  loose  in  the  cavity  of  the  bladder,  in  the  form  of  urinary  stones  or 
foreign  bodies,  which  have  been  pushed  into  the  bladder  through  the  ure- 
thra. Then  there  are  the  stalked,  papillary,  tassel-like  tumors,  which  very 
commonly  reveal  themselves  later  as  carcinomata,  and  which  can  drift 
into  the  urethral  orifice  and  cause  a  temporary  obstruction.  Tumors  invad- 
ing from  the  uterus  or  rectum  through  the  bladder-wall  may  block  the 
urethra,  just  as  the  tumors  of  the  bladder-wall  itself,  but  their  usual  fate  is 
to  break  down  into  a  canal  into  the  rectum  or  vagina,  which  allows  the 
escape  of  urine  but  renders  infection  of  the  bladder  inevitable. 

Very  important  in  connection  with  the  mechanical  obstruction  of  the 
flow  of  urine  is  the  presence  of  solid  calculi  composed  of  materials  derived 
from  the  urine.  These  are  found  not  only  in  the  bladder,  but  in  the  pelvis 
of  the  kidney,  and,  indeed,  it  seems  that  the  renal  pelvis  is  the  seat  of  orig- 
inal formation  of  many  of  them.  It  is  not  clear  that  obstruction  has  any- 
thing to  do  with  their  primary  formation,  although  the  growth  of  some  of 
them  at  least  seems  to  be  greatly  favored  by  such  changes  in  the  urine  as 
follow  obstruction.  But  they  themselves  are  effective,  just  as  in  the  case 
of  gall-stones,  in  acting  as  plugs  which  retard  the  flow  of  urine  either  inter- 
mittently or  continuously. 

Urinary  Calculi. — Concretions  of  crystalline  material,  mixed  usually  with  some 
organic  substance,  and  found  at  any  point  from  the  renal  papillae  and  renal  pelvis  to 
the  urethra,  constitute  the  group  of  urinary  calculi.  According  to  their  position,  they 
have  the  opportunity  to  assume  one  form  or  other,  and  an  irregular  mass  from  the  pelvis 


OTHER   FORMS   OF   OBSTRUCTION 


447 


of  the  kidney,  if  it  be  swept  into  the  bladder,  is  likely  to  become  round  by  the  con- 
tinuous application  of  new  layers  of  crystals.  These  calculi  vary  in  their  chemical  com- 
position, and  accordingly  in  their  appearance,  depending  partly  upon  the  position  in 
which  they  are  formed,  but  chiefly  and  almost  entirely  upon  the  chemical  character  of 
the  urine  in  which  they  form.  Since  the  urine  may  frequently  change  its  character 
during  the  months  or  years  which  go  by  in  the  growth  of  the  stone,  the  end  result  is 
apt  to  be  made  up  of  layers  or  lamina  of  quite  different  color,  consistence,  and  chem- 
ical composition  (Fig.  219). 

Ebstein  thought  that  the  organic  or  albuminous  supporting  framework  which  one 
can  find  in  every  calculus  was  the  necessary  skeleton  upon  which  the  deposit  of  crystals 
took  place,  and  that  without  such  a  nucleus  of  organic  material  no  crystallization  in 
this  form  would  occur.  Aschoff,  Moritz,  Kleinschmidt,  and  others  dispute  this,  and 
think  this  organic  mesh  work  which  is  present  in  crystals,  even  when  they  are  made  to 
form  in  urine  in  vitro,  is  an  accidental  accompaniment  of  the  crystals,  probably  formed 
through  their  own  power  of  absorption.  Still,  they  admit  that  it  is  of  some  help  in  hold- 


Fig.  219. — Laminated  vesical  calculus.  Central 
mass  of  uric  acid  with  peripheral  zones  of  carbon- 
ates and  phosphates. 


Fig.  220. — Urinary  calcu- 
lus of  uric  acid  in  laminae 
about  a  central  quartz  pebble. 


ing  the  forming  stone  together.  The  application  of  new  layers  of  crystals  to  a  concre- 
tion already  formed  is  thought  to  occur,  just  as  rock  candy  crystallizes  on  the  string. 
But  it  involves  the  idea  of  an  oversaturation  of  the  urine  with  crystallizable  substances, 
or  else  such  changes  in  the  urine  that  it  becomes  less  able  to  hold  those  substances  in 
solution.  Thus  if  the  urine  is  acid,  uric  acid  may  crystallize  out,  while  if  it  is  alkaline, 
phosphates,  ammonio-magnesium  phosphates,  and  ammonium  urates  may  appear. 
Or  something  may  cause  the  precipitation  of  those  colloid  materials  in  the  urine  which 
tend  to  hold  the  uric  acid  in  solution,  after  which  it  quickly  appears  in  crystalline  form. 
Bacterial  infection,  especially  when  it  produces  ammoniacal  decomposition  of  the  urine, 
is  favorable  to  the  formation  of  phosphatic  concretions. 

Thus  there  is  no  insurmountable  difficulty  in  explaining  the  growth  of  such  stones 
once  started,  but  it  is  more  difficult  to  explain  their  origin.  Of  course,  some  are  formed 
around  foreign  bodies — hair-pins,  pieces  of  catheters,  etc.,  which  have  been  introduced 
into  the  bladder,  but  these  incrustations  are  relatively  rare  (Fig.  220).  Ebstein  and 
others,  including  Kleinschmidt,  are  reduced  to  the  explanation  that  most  calculi,  whether 


448 


TEXT-BOOK   OF   PATHOLOGY 


found  in  the  renal  pelvis  or  in  the  bladder,  are  formed  originally  in  the  tubules  of  the 
kidney.  This  idea  has  been  elaborated  especially  for  the  uric-acid  stones,  because  they 
are  the  commonest  and  because  the  conditions  found  in  the  so-called  uric-acid  infarcts 
of  the  kidney  do  explain  their  origin  fairly  well.  These  are  frequent,  especially  in  the 
kidneys  of  children  and  infants,  and  produce  a  curious  yellow  streaking  of  the  papilla 
of  the  pyramid,  sometimes  with  actual  stony  concretions  embedded  in  ragged  cavities 
near  its  tip.  Microscopically,  it  is  found  that  this  is  due  to  the  abundant  excretion  of 
uric  acid  by  the  cells  of  the  tubules.  Sometimes  (Aschoff)  these  are  uninjured  and 
secrete  the  uric  acid  in  minute  crystals  on  their  surface.  Other  cells  may  be  destroyed 
in  the  process.  The  uric  acid  appears  in  minute,  round  "sphseroliths,"  which  become 
massed  together  with  an  albuminous  material,  secondarily  gluing  them  together.  This 

forms  the  primary  concretion,  which  may 
pass  quite  out  through  the  urethra,  or  may 
form  the  nucleus  for  a  urinary  calculus. 

Calculi  may  form  in  normal  non-albu- 
minous urine,  and  may  grow  to  a  consid- 
erable size  without  causing  any  symptoms 
— usually  from  their  angular  form  they 


Fig.  221. — Uric-acid  calculi  with  fine  lamination. 

wound  the  wall  of  the  renal  pelvis  or  of  the  bladder,  and  then  cause  bleeding  and  in- 
flammation, which  in  turn  are  likely  to  change  the  reaction  of  the  urine  and  initiate 
the  deposition  of  layers  of  material  of  a  different  character  from  that  which  composed 
the  stone.  When  the  stone  causes  obstruction  and  bacteria  are  introduced,  this  change 
in  reaction  and  the  deposit  of  phosphates  are  inevitable. 

Kleinschmidt  classifies  all  these  calculi  as  non-inflammatory  and  inflammatory,  in 
each  of  which  groups  there  are  primary  and  secondary  formations  which  represent  stages 
in  the  history  of  the  stone,  just  as  do  successive  strata  in  a  geological  formation.  Several 
of  the  crystalline  substances  in  the  urine  may  form  concretions  without  any  appreciable 
admixture  of  other  things,  so  that  in  these  calculi  the  chemical  composition  is  the  same 
from  the  centre  to  the  surface.  Such  practically  pure  concretions  are  those  composed 
of  unc  acid,  calcium  oxalate,  xanthin,  cystin,  or  calcium  phosphate.  Some  of  them 


OTHER   FORMS   OF   OBSTRUCTION 


449 


grow  in  the  same  way  as  mixed  stones  to  a  large  size.  In  other  cases  they  form  the  nu- 
cleus upon  which,  with  a  change  in  the  character  of  the  urine,  layer  after  layer  of  other 
substances  are  deposited.  When  there  is  no  inflammatory  process,  such  secondary 
stones  may  be  formed  upon  a  uric-acid  concretion  as  nucleus  with  layers  of  uric  acid  and 
urates,  or  layers  of  oxalates  and  calcium  phosphate.  So,  too,  a  calcium  oxalate  nucleus 
may  be  turned  into  a  secondary  calculus  by  being  enveloped  in  layers  of  uric  acid  or  cal- 
cium phosphate. 

When  bacterial  infection  and  an  inflammatory  process  supervene,  phosphates, 
especially  the  ammonio-magnesium  phosphate,  sometimes  with  calcium  carbonate,  etc., 
make  their  appearance  as  strata  of  white,  rather  crumbly  crystals,  on  the  surface  of  one 
of  these  nuclei,  just  as  they  form  an  incrustation  over  any  foreign  body  in  the  bladder. 
Indeed,  they  may  form  the  whole  calculus  by  themselves,  without  any  obvious  non- 
inflammatory stone  or  foreign  body  as  a  nucleus. 

Uric-acid  calculi  (Fig.  221)  are  hard,  smooth,  oval  or  rounded  stones  when  formed 
in  the  bladder,  or  moulded  to  the  cavity  when  in  the  renal 
pelvis.  There  is  often  a  central  granule  of  ammonium 
urate  about  which  fine,  delicate  yellow  or  yellow-brown 
laminae  of  very  compact  appearance  and  great  regularity 
are  laid  down.  In  other  cases  the  consistence  is  more 
like  that  of  pumice-stone,  especially  when  there  is  much 
admixture  of  urates  and  the  lamination  is  correspondingly 
indistinct. 


Fig.  222. — Vesical  calculi  formed  of  calcium  oxalate.     One  in  section  shows  laminae  of 

phosphates  and  carbonates. 


Pure  calcium  oxalate  stones  are  rare,  but  mixed  stones  in  which  it  forms  a  consider- 
able part,  are  common.  They  are  often  formed  about  a  nucleus  of  uric  acid  or  urates, 
and  the  oxalate  covers  this  in  layers  of  varying  thickness,  distinguished  by  their  dark- 
brown  color  and  by  the  extremely  rough,  jagged  external  surface  which  they  present 
(Fig.  222).  The  irritation  caused  by  this  usually  leads  to  the  deposition  of  carbonates 
and  phosphates,  which  fill  up  the  depressions  and  smooth  off  the  surface  (Fig.  223). 
Urates  may  also  alternate  with  layers  of  oxalates.  Such  stones  are  extremely  hard, 
usually  fairly  round,  and  occur  especially  in  the  bladder. 

Phosphatic  Calculi. — In  other  cases,  especially  when  the  bladder  is  inflamed,  ammo- 
nio-magnesium phosphate  and  calcium  phosphates  and  carbonate  predominate,  usually 
on  a  nucleus  of  uric  acid.  These  stones  may  or  may  not  be  laminated  (Fig.  224).  They 
are  nearly  pure  white,  with  occasional  yellow  or  brownish  layers,  and  the  surface  is  rough. 
Rarely,  instead  of  being  chalk-like,  these  phosphate  stones  are  radially  crystalline.  The 
non-laminated  type  are  usually  round  and  rough,  loosely  built,  pumice-like  concretions 
of  a  yellowish-white  color,  but  material  of  this  sort  is  often  deposited  irregularly  on 
30 


450 


TEXT-BOOK   OF   PATHOLOGY 


Fig.  223.— Mixed  oxalate  and  urate  calculus  coated  with  phosphates. 


iVv'.'VHV  **>• 

>V«-vU'>-5', 

:ve.  .',  f  ,»^/<>.^ 


Fig.  224,-Phosphate  calculus  with  a  layer  of  oxalates. 


CYSTITIS  451 

other  stones,  especially  when  they  are  cracked  or  irregular  and  lodged  in  a  bladder  where 
there  is  ammoniacal  decomposition  of  the  urine. 

The  obstruction  produced  by  calculi  is  dependent,  as  long  as  they  are  loose  in  the 
bladder,  upon  the  posture  of  the  patient  and  upon  the  size  and  shape  of  the  stone,  so 
that  unless  it  is  impacted  in  the  urethra,  the  obstruction  is  intermittent. 

LITERATURE 

D.  Kleinschmidt:    Die  Harnsteine,  Berlin,  1911. 
W.  Ebstein:   Natur  u.  Behandlung  der  Harnsteine,  Wiesbaden,  1884. 
H.  A.  Fowler:  Johns  Hopkins  Hosp.  Reports,  1908,  xiii,  507. 

Paralytic  Dilatation  of  the  Bladder.— Normally,  when  the  bladder  is  filled 
to  a  certain  degree  it  tends  to  contract  and  empty  itself,  the  act  of  micturi- 
tion being  under  the  voluntary  control  of  a  sphincter,  and  being  in  itself 
the  effect  of  nervous  reflexes  by  way  of  nerves  which  run  to  and  from  the 
lumbar  and  sacral  cord.  When  injury  of  the  spinal  cord  results  in  complete 
paralysis  of  the  lower  extremities  and  of  the  lower  part  of  the  body,  as  is 
so  frequently  the  case  in  fractures  of  the  spine,  etc.,  neither  afferent  nor 
efferent  impulses  are  effective.  There  is  no  sense  of  overfilling  of  the 
bladder,  no  desire  to  micturate,  and  often  no  power,  even  by  the  aid  of 
the  abdominal  muscles,  to  empty  the  bladder.  Hence  it  gradually  becomes 
distended  to  an  enormous  size,  and  must  be  emptied  by  the  introduction  of 
a  catheter. 

CYSTITIS 

These  various  conditions  offer  a  more  or  less  insuperable  obstacle  to  the 
discharge  of  urine  from  the  bladder,  and  the  immediate  result  is  its  incom- 
plete instead  of  complete  evacuation.  Ordinarily  the  residual  urine  does 
no  harm,  except  in  that  it  occupies  space  in  the  bladder  which  thereupon 
fills  more  quickly,  so  that  micturition  becomes  abnormally  frequent.  That 
is  true  so  long  as  the  urine  remains  sterile,  but  with  increased  difficulty  in 
urination  it  may  become  necessary  to  pass  a  catheter  into  the  bladder,  and 
sometimes  this  operation  falls  to  the  hands  of  the  patient  himself.  Natu- 
rally, in  such  conditions  it  is  not  long  before  bacteria  are  carried  into  the 
residual  urine  and  find  there  an  excellent  culture-medium.  As  soon  as 
this  happens,  the  urine,  which  may  have  been  clear  before,  becomes  turbid 
and  alkaline,  full  of  bacteria,  desquamated  epithelial  cells,  and  leucocytes, 
showing  that  the  response  to  infection  in  the  form  of  an  acute  cystitis  has 
appeared. 

Naturally,  a  great  variety  of  bacteria  may  be  concerned  in  this  process, 
and  in  such  cases  there  is  commonly  a  mixture  of  several  forms,  sometimes 
even  with  yeasts  and  fungi  in  addition.  The  inflammation  (cystitis)  which 
they  set  up  will  vary  in  its  intensity  according  to  the  type  of  infection,  but 
more  especially  according  to  the  degree  of  obstruction  and  the  resistance 
of  the  individual. 

Forms  of  Cystitis. — We  may  distinguish  catarrhal,  purulent,  and  diphtheritic  forms, 
and  there  are  others  that  almost  merit  the  name  gangrenous. 


452  TEXT-BOOK   OF   PATHOLOGY 

In  the  mildest  infections  the  bladder-wall  becomes  swollen  and  reddened,  and  a  few 
leucocytes  pass  through.  The  urine  is  acid  when  Bacillus  coli  is  the  infecting  agent, 
but  otherwise  it  is  often  alkaline,  with  a  small  amount  of  ammonia  and  a  sediment  of 
phosphates,  desquamated  cells,  and  mucus.  The  purulent  form  follows  upon  more 
intense  infections,  and  is  characterized  by  haemorrhages  in  the  mucosa  and  pus-contain- 
ing urine.  These  haemorrhages  may  be  mere  petechiae. 

In  the  diphtheritic  form  much  more  extensive  haemorrhages  appear,  surrounding  the 
patches  of  most  intense  inflammation.  In  these  areas  the  bacteria  are  found  to  have 
caused  a  superficial  necrosis,  with  the  coagulation  of  a  layer  of  yellowish  or  greenish 
fibrin  upon  the  surface  and  into  the  depth  of  the  necrotic  mucosa.  The  loosening  of 
such  a  false  membrane  leaves  an  ulcer  with  haemorrhagic  base,  and  surrounded  by  a  deep- 
red  halo.  Such  ulcers  are  usually  found  at  first  upon  the  more  prominent  parts  of  the 
wall,  where  the  muscular  trabeculae  project,  and  upon  the  smoother  trigonum.  In 
advanced,  long-standing  cases,  though,  the  ulcers  become  deeper  and  may  cover  much 
of  the  bladder-wall,  some  of  them  are  scarred,  while  others  are  newly  formed;  discolora- 
tion occurs;  there  arises  much  blackish-green  staining,  probably  largely  from  sulphides, 
which  blacken  the  haemosiderin  formed  in  the  haemorrhagic  areas,  and  the  bladder-wall 
presents  an  extremely  foul,  ragged,  and  deeply  stained  surface.  In  a  bladder  of  this 
type  the  urine  contains  all  the  materials  which  could  be  shed  from  such  a  wall. 

Usually  a  great  dilatation  of  the  bladder  follows  upon  such  long-continued 
obstruction  to  the  outflow  of  urine.  Its  walls  become  stretched,  and 
particularly  those  portions  which  lie  between  the  main  muscular  trabeculse 
may  be  bulged  out  into  diverticula.  At  the  same  time  there  is  a  distinct 
hypertrophy  of  the  muscle  bundles — a  work  hypertrophy  which  arises  in 
the  oft-repeated  attempt  of  the  bladder  to  discharge  its  contents  (Figs.  215 
217).  Whether  the  dilatation  or  the  hypertrophy  will  predominate  de- 
pends upon  the  age  and  general  condition  of  the  patient.  There  are  old 
men  without  much  obstruction  in  whom  atrophy  of  the  muscle  of  the 
bladder  allows  it  to  become  distended  and  to  retain  residual  urine. 

The  entrance  of  the  ureters  into  the  bladder  is  oblique,  through  the 
muscular  wall,  so  that  the  more  tensely  the  bladder  is  distended,  the 
greater  is  the  pressure  tending  to  flatten  and  close  the  end  of  the  ureter 
as  it  slants  through  the  bladder-wall.  In  addition  to  this  the  actual  ori- 
fice is  guarded  internally  by  valve-like  folds  of  mucosa  which  readily  allow 
the  urine  to  pass  downward  only.  Therefore  the  entrance  of  fluid  from  the 
bladder  into  the  ureter  is  normally  excluded,  and  it  is  impossible,  even  with 
great  force,  to  inject  colored  fluids  into  the  ureter  by  distending  the  bladder 
with  them.  It  requires  some  destructive  change  in  the  intravesical  part 
of  the  ureter  to  make  this  influx  possible — either  the  erosion  of  all  these 
guarding  tissues  or  something  which  will  render  the  ureter  so  rigid  that  it 
will  not  collapse  when  the  bladder  is  distended.  Nevertheless,  it  is  evi- 
dent that  if  it  becomes  difficult  for  the  urine  to  escape  from  the  bladder, 
it  becomes  equally  difficult  for  it  to  leave  the  ureter  and  enter  the  bladder, 
so  that  an  obstruction  which  ends  in  distension  of  the  bladder  is  equally 
an  obstruction  to  the  escape  of  urine  from  the  kidneys  and  ureters. 


EFFECTS   OF   OBSTRUCTION   ON   THE    KIDNEYS 


453 


EFFECTS  OF  OBSTRUCTION  ON  THE  KIDNEYS 

We  have  now  to  consider  the  effects  upon  the  kidney  with  its  pelvis  and 
ureter  of— (a)  Obstruction  without  infection;  (6)  obstruction  with  infection; 
and  (c)  the  rare  infection  by  way  of  the  urinary  tract  without  obstruction. 
Hydronephrosis,  by  which  is  meant  a  dilatation  of  the  pelvis  of  the  kid- 
ney, often  accompanied  by  hydro-ureter  and  practically  invariably  by  a 


Fig.   225. — Hydronephrosis   resulting  from  stricture  at  the   uretero-pelvic   junction. 
Extreme  dilatation  of  the  calyces. 

distension  and  thinning  of  the  renal  substance  itself  through  the  accumula- 
tion of  fluid  in  that  cavity,  may  result  from  various  causes.  All  those  types 
of  obstruction  which  lead  to  distension  of  the  bladder  may  be  accompanied 
by  hydro-ureter  and  by  hydronephrosis,  but,  in  addition,  there  are  those  in 
which  the  ureters  are  blocked  in  some  way.  Therefore  in  the  latter  group 
the  hydronephrosis  may  be  unilateral.  The  pressure  of  tumors  from  the 
outside,  such  as  those  which  arise  from  the  uterus  and  ovaries,  even  if 


?454 


TEXT-BOOK   OF   PATHOLOGY 


they  do  not  invade  the  substance  of  the  ureters,  often  sets  up  such  a  block- 
ing of  their  lumen.  The  same  effect  may  be  produced  by  an  inflammatory 
process  in  the  ureteral  wall  which  leads  to  stricture  formation,  and  Samp- 
son has  diagrammatically  figured  the  effect  in  this  direction  of  those  opera- 
tions for  the  removal  of  pelvic  tumors  in  which  the  blood  supply  of  a  por- 
tion of  the  ureter  has  been  disturbed.  Necrosis  with  scarring,  and  even 
rupture  of  the  ureteral  wall  after  the  distension  has  begun,  may  follow. 

Renal  calculi  formed  in  the  pelvis  of  the  kidney,  when  small  enough, 
pass  through  the  ureter,  causing  intense  pain,  but,  as  is  well  known,  there 
are  normally  several  constrictions  in  the  course  of  this  tube,  and  the 
calculus  may  stick  at  one  of  these  so  as  to  cause  complete  or  partial  plugging. 


Fig.  226. — Renal  calculus  in  pelvis  forming  a  complete  mould  of  all  the  calyces,  and  ex- 
tending into  the  ureter. 

Higher  in  the  neck  of  the  ureter  or  in  the  pelvis  itself  the  same  thing  may 
happen. 

Renal  calculi,  formed  as  has  been  described  above,  present  themselves  in  various  forms 
and  sizes,  the  larger  ones  being  moulded  into  the  calyces  and  about  the  papillae  so  as  to 
present  a  complete  cast  of  the.  pelvis  of  the  kidney,  branching  irjto  each  recess  and  ex- 
tending in  a  pointed,  curved  projection  down  into  the  ureter  (Fig.  226).  Sometimes 
they  are  in  several  pieces, 'and  the  fragments  may  be  fitted  to  one  another  as  though 
articulated.  At  the  other  extreme  we  find  small,  loose,  irregular  calculi,  sometimes  no 
more  bulky  than  coarse  sand.  It  seems  that  unless  they  become  impacted  in  the  ureter 
these  calculi  cause  no  great  distension  of  the  pelvis.  In  children  the  common  uric- 
acid  infarcts  already  mentioned  are  often  associated  with  concretions  which  may 
be  partly  embedded  in  the  renal  substance  itself. 

Finally  there  are  some  deformities  of  the  pelvis,  especially  with  relation 
to  the  insertion  of  the  ureter,  which  can  give  rise  to  hydronephrosis,  and 


EFFECTS   OF   OBSTRUCTION   ON   THE    KIDNEYS  455 

which  in  turn  are  emphasized  by  it.  These  are  especially  the  instances  in 
which  the  ureter  springs  from  a  point  high  up  in  the  pelvis  and  leaves  it  at 
an  acute  angle.  There  is  then  a  valve-like  arrangement,  which  is  brought 
into  play  by  any  disarrangement  of  the  kidney  and  completed  by  the  dis- 
tension of  the  pelvis.  Sometimes  the  ureter  divides  before  it  reaches  the 
hilum  of  the  kidney,  so  that  the  pelvis  is  in  several  compartments  with 
their  corresponding  calyces  and  papillae.  Then  it  is  possible  to  have  a 
partial  hydronephrosis  if  only  one  of  these  branches  is  obstructed. 

Geraghty  and  Frontz  mention  also  a  form  of  hydronephrosis  which  de- 
pends on  the  constriction  of  the  ureter  by  an  inflammatory  process  with 
scarring,  which  is  likely  to  occur  near  the  transition  of  the  pelvis  into  the 
ureter.  Hunner  has  also  made  a  careful  study  of  the  various  types  of  ureter- 
itis  with  stricture  and  hydronephrosis,  and  finds  them  far  commoner  than 
was  formerly  suspected.  We  have  recently  met  with  such  a  case  at  autopsy 
which  is  illustrated  in  Fig.  225. 

The  fluid  which  accumulates  is  generally  clear,  and  contains  urea  and 
other  urinary  constituents,  although  in  unusual  proportions.  It  has 
generally  been  looked  upon  as  urine,  but  except  perhaps  in  those  cases  in 
which  the  obstruction  is  intermittent,  it  will  be  seen,  from  the  mode  of 
development,  that  it  must  differ  a  good  deal  from  normal  urine.  It  often 
contains  casts  of  the  renal  tubules  and  desquamated  epithelium. 

Cohnheim  made  the  statement  that  only  partial  or  intermittent  obstruc- 
tion is  followed  by  great  distension  of  the  pelvis,  while  complete  obstruc- 
tion results  in  cessation  of  the  flow  of  urine  and  atrophy  of  the  kidney. 
In  human  beings  this  has  the  appearance  of  being  true,  for  in  cases 
of  complete  obstruction  of  the  ureter  one  finds  the  kidney  reduced  to  an 
insignificant,  flattened,  fibrous  mass,  in  which  hardly  any  well-ordered 
renal  substance  can  be  found  (cf.  Fig.  70).  On  the  other  hand,  an  inter- 
mittent or  partial  obstruction  can  cause  the  distension  of  the  ureter  and 
pelvis  until  a  sac  is  formed  which  may  occupy  a  great  portion  of  the 
abdominal  cavity.  But  it  has  been  shown  recently  by  Ponfick  and  others 
that  the  absolute  closure  of  the  ureter  is  followed  by  such  distension  of  the 
pelvis  and  the  kidney  as  to  reduce  the  kidney  to  a  thin  layer  of  firm  fibroid 
tissue.  In  the  earlier  stages  the  bulk  and  weight  of  the  kidney  substance, 
exclusive  of  the  accumulated  fluid,  actually  increase  up  to  about  thirty- 
six  days  after  the  ureteral  ligation,  after  which  they  decrease  steadily. 
In  view  of  this  we  may  easily  conclude  that  the  atrophic  remnants  which 
we  find  in  human  beings  after  the  ureter  has  been  plugged  by  a  stone  are 
the  final  results  of  a  much  longer  period  of  obstruction  than  even  the  seven 
months  through  which  Ponfick  watched  his  experiments. 

With  the  distension  of  the  pelvis  the  calyces  become  widened  and  the 
1  apillse  flattened  until  in  time  they  come  to  form  only  circular  portions  of 
the  wall  of  the  hemispherical  calyces,  the  orifice  being  located  only  as  a 
slight  central  elevation  with  radiating  blood-vessels  and  tubular  markings. 
Even  more  complete  distortion  occurs,  and  hardly  any  trace  of  the  papilla 


456  TEXT-BOOK    OF    PATHOLOGY 

is  left — the  whole  kidney  is  reduced  to  a  multilocular  sac  in  which 
the  partitions,  as  Ponfick  points  out,  are  held  in  place  by  the  blood- 
vessels, whose  course  they  indicate.  The  section  shows  that  the  pyra- 
mids lose  their  radiate  appearance  because  the  tubules  come  to  lie  parallel 
with  the  surface  of  the  kidney  (Fig.  227).  The  cortex  becomes  very  thin, 
and  loses  its  striations,  which  are  obscured  in  the  gray,  scar-like  tissue 
which  takes  their  place.  It  is  strange  that  sometimes  this  effect  is  very 
irregular,  so  that  one  finds  patches  of  relatively  thick  renal  cortex  scattered 
in  the  otherwise  thin  wall  of  the  sac.  Possibly  this  is  due  to  the  unequal 
diminution  in  the  blood  supply  of  various  areas  of  the  cortex,  which  comes 
through  vessels  which  run  in  the  partitions  of  the  sac  and  may  be  exposed 
to  different  degrees  of  pressure. 

It  is  a  remarkable  secretory  process  which  produces  a  fluid  which  may 
attain  a  pressure  higher  than  that  of  blood.  Ponfick  describes  the  appear- 
ance of  hyaline  casts,  of  leucocytes,  and  especially  of  red  blood-corpuscles, 


Fig.  227. — Hydronephrosis.  Section  shows  the  thinning  and  flattening  of  cortex 
and  pyramid,  with  great  distension  of  the  pelvis  and  calyces.  The  flattened  papilla 
is  at  a;  the  margins  of  the  calyx,  at  b,  b. 

together  with  a  coagulable  fluid  in  the  tubules  and  glomerular  capsules. 
The  epithelial  cells,  at  first  swollen,  later  become  flattened,  and  even  the 
glomerular  tufts  may  disappear,  leaving  spaces  that  look  like  tubules. 
There  is  apparently  the  formation  of  an  actual  exudate  of  inflammatory 
character  in  response  to  the  destructive  effect  upon  the  cells.  Associated 
with  it  comes  a  diffuse  formation  of  abundant  new  connective  tissue  every- 
where between  the  tubules  and  about  the  glomeruli.  The  end-result  is 
that  we  have  in  an  advanced  case  an  extraordinary  thinning-out  of  the 
renal  substance,  which  assumes  a  gray,  uniform,  translucent  appearance, 
and  an  almost  leathery  consistence.  In  this  the  tubules  are  found  lined 
by  a  uniform  flattened  epithelium,  and  often  interrupted  by  the  collapse 
of  their  walls,  so  that  spindle-shaped  or  even  rounded  portions  remain, 
filled  with  hyaline  casts.  The  glomeruli  are  obliterated  and  converted 
into  fibrous  nodules,  or  else  surrounded  by  a  thickened  fibrous  capsule,  and 
everywhere  the  interstitial  connective  tissue  is  prominent,  not  only  through 
its  actual  increase,  but  because  of  the  disappearance  of  many  tubules.  It 


EFFECTS    OF    OBSTRUCTION    ON    THE    KIDNEYS  457 

will  be  seen  that  this  process  is,  in  nearly  every  respect,  analogous  to  that 
which  follows  the  ligation  of  the  duct  of  such  a  gland  as  the  pancreas. 

Ascending  Renal  Infection. — In  all  forms  of  obstruction  to  the  outflow 
of  a  secretion  we  have  traced  the  liability  of  the  tissues  to  infection,  and  the 
kidney  is  no  exception  to  this  rule.  With  the  advent  of  virulent  bacteria 
in  an  already  formed  hydronephrotic  sac  there  arises  an  inflammation 
which  is  of  a  far  more  intense  character  than  any  which  may  have  been 
associated  with  the  mere  mechanical  obstruction,  and  when  the  sac  is  filled 
with  a  purulent  fluid,  we  speak  of  the  condition  as  pyonephrosis.  A 
similar  condition,  naturally  with  somewhat  different  course  and  clinical 
symptoms,  may  arise  when  the  distending  fluid  is  from  the  first  infected 
and  the  inflammatory  process  is  intense  throughout.  Thus,  when  there 
appears  an  infection  about  impacted  renal  calculi  which  may  not  in  them- 
selves have  caused  an  effective  obstruction,  or  when  an  obstruction  lower  in 
the  ureter  or  in  the  bladder  or  urethra  causes  the  damming-up  of  urine  which 
quickly  becomes  infected,  we  have  a  distension  which  is  by  no  means  so 
great,  but  in  which  the  pelvic  walls  are  injured  by  the  bacteria  and 
present  a  hsemorrhagic,  ulcerated,  and  purulent  surface. 

It  is  hard  to  draw  a  line  between  the  cases  in  which  the  distension  is  pre- 
dominant and  those  in  which  the  inflammatory  processes  are  more  impos- 
ing. These  latter,  which  are  known  under  the  name  pyelitis,  or  more 
usually  pyelonephritis,  constitute  a  form  of  ascending  suppurative  nephritis 
which  is  most  commonly  associated  with  obstruction  and  stagnation  of 
urine.  But  it  must  be  borne  in  mind  that,  with  very  slight  differences,  an 
inflammatory  process  in  the  kidney  with  suppuration  and  secondary  inflam- 
mation of  the  pelvis  may  be  caused  by  bacteria  brought  to  the  kidney 
through  the  blood-stream  when  there  is  no  disease  of  the  lower  urinary 
tract  at  all.  This  can  often  be  easily  distinguished,  and  we  shall  speak 
of  it  elsewhere. 

In  all  these  cases  in  which  infection  of  the  kidney  is  associated  with 
obstruction  and  infection  of  the  urinary  passages,  there  appear  abscesses 
in  the  substance  of  the  kidney  itself,  in  addition  to  the  acute,  oftentimes 
very  intense,  inflammation  of  the  mucosa  of  the  pelvis.  These  are  usually 
situated  chiefly  in  the  cortex,  and  are  sometimes  very  small,  but  generally 
conglomerated,  so  that  they  reach  the  size  of  a  pea  and  bulge  on  the  surface. 
If  one  tears  off  the  capsule  of  the  kidney,  many  of  them  are  broken  open  and 
exude  a  greenish-yellow  pus.  On  section,  the  tissue  around  them  is  gray- 
ish red  and  swollen,  and  has  lost  the  distinctness  of  its  markings.  Often, 
but  not  always,  there  are  grayish-yellow,  opaque  streaks  running  down 
through  the  pyramid  toward  the  papilla,  which  are  produced  by  extensions 
of  the  abscesses  along  the  conducting  tubules  (Figs.  228,  229,  230). 

Active  discussion  has  raged  for  a  long  time  as  to  the  paths  followed  by 
bacteria,  which,  from  an  infected  bladder,  arrive  at  the  production  of  more 
or  less  isolated  abscesses  in  the  cortex  of  the  kidney,  and  many  views  have 
been  proposed.  It  has  been  stated  that  the  organisms  get  into  the  blood- 
stream from  the  bladder,  and  lodge  finally  in  the  kidney,  which  is  rendered 


458 


TEXT-BOOK    OF    PATHOLOGY 


Fig.  228. 


Fig.  229 


Figs.  228  and  229.— Pyelonephritis— case  of  prostatic  obstruction  with  cystitis 


EFFECTS   OF   OBSTRUCTION   ON   THE    KIDNEYS 


459 


susceptible  by  the  obstruction.  Others  think  they  pass  along  the  lymph- 
atics of  the  ureter  or  by  the  venous  anastomoses  between  the  vessels  of  the 
pelvic  organs,  ureter,  and  kidney.  Neither  of  these  last  views  seems  to 
me  based  on  probability,  because  they  involve  retrograde  embolism,  which 
is  not  to  be  lightly  called  to  our  aid. 

The  more  common  view  is  that  the  bacteria  pass  up  the  lumen  of  the 
ureter  to  the  pelvis,  and  thence  into  the  kidney.     They  cannot  easily  ascend 


•  i'  ••. 


•8       18 


Fig.  230. — Pyelonephritis.  There  are  beginning  abscesses  in  the  cortex,  shown  as 
areas  of  necrotic  tubules  with  purulent  exudate  about  them.  Many  of  the  tubules  con- 
tained bacteria. 

the  ureter  when  it  is  open  and  flushed  by  the  normal  stream  of  urine,  but 
if  it  is  obstructed  and  occupied  by  a  nearly  stagnant  column  of  urine,  it  is 
easy  to  believe  that  bacteria  may  spread  to  the  kidney.  This  is  especially 
true  if  any  inflammation  of  the  ureteral  wall  in  its  intravesical  part  has 
rendered  it  rigid,  and  thus  rendered  useless  the  guard  at  the  ureteral  opening. 
Having  attained  the  pelvis  and  produced  a  pyelitis,  it  remains  to  explain 


460  TEXT-BOOK   OF   PATHOLOGY 

their  entrance  into  the  kidney.  Orth  looks  askance  at  the  glibly  expressed 
belief  that  they  wander  up  the  tubules,  but  Schmidt  and  Aschoff  have  found 
bacteria  in  the  tubules  in  animals  in  which  they  have  experimentally 
obstructed  and  infected  the  ureters,  and  adopt  this  idea.  Without  it  we 
must  have  recourse  to  the  blood-vessels,  of  which,  of  course,  only  the  ar- 
teries are  available,  or  to  the  lymphatics.  Muller  thinks  he  can  prove  the 
lymphatic  transmission  by  finding  the  tubules  attacked  and  perforated  on 
one  side  by  exudate,  which  also  fills  the  lymphatics.  It  is  difficult,  how- 
ever, when  the  inflammation  has  proceeded  to  such  a  degree,  to  say  which 
way  it  is  working,  and  the  findings  of  Schmidt  and  Aschoff,  which  show  that 
the  bacteria  can  enter  the  tubules,  seem,  after  all,  most  convincing. 

LITERATURE 

Ponfick:  Ziegler's  Beitrage,  1910,  xlix,  127;  1911,1, 1. 
Orth:  Lehrb.  d.  spez.  Path.,  1893,  ii,  59. 
Schmidt  and  Aschoff:    Pyelonephritis,  Jena,  1893. 
Jores:  Ergeb   d.  allg.  Path.,  1907,  xi2,  146. 
Geraghty  and  Frontz:  Jour.  Urology,  1918,  ii,  161. 
Vernon  David:  Surg.,  Gyn.,  and  Obst.,  1918,  xxvi,  159. 
Hunner:  Johns  Hopkins  Hosp.  Bull.,  1918,  xxix,  1. 
Sampson:  Ibid.,  1903,  xiv,  334. 


CHAPTER  XXIII 

TYPES  OF  INJURY— OBSTRUCTION  (Continued).— GENERAL 
DISTURBANCES  OF  CIRCULATION 

Mechanism  of  circulatory  organs.  Pericardial  and  pleural  effusions.  Emphysema. 
Chemical  influences.  Effects  of  arterial  and  myocardial  disease.  Myocarditis.  Valvular 
disease.  General  mechanism  of  the  obstruction  thus  produced.  Various  valvular  lesions 
and  their  special  effects.  Cardiac  hypertrophy  and  dilatation.  Decompensation;  chronic 
passive  congestion.  Disturbances  of  conduction  system  in  heart. 

Mechanism  of  Circulatory  Organs. — Reflection  upon  the  general  mechan- 
ism of  the  circulation  of  the  blood  will  give  one  an  idea  of  the  extraor- 
dinary number  of  things  that  can  fail  in  playing  their  proper  part  and 
upset  the  smooth  working  of  the  whole.  Incidentally,  it  gives,  too,  a  sense 
of  wonder  that  a  machine  of  such  marvelous  complexity  should  work  at 
all,  and  not  be  constantly  interrupted  or  overtaxed  by  the  variable  tasks 
laid  upon  it  and  the  difficulties  thrown  in  its  way.  It  is  found,  however, 
that  not  only  does  it  keep  up  a  definite  standard  output  of  work  day  and 
night,  but  it  will  do  this  in  spite  of  the  most  unreasonable  obstacles. 

The  Heart. — The  heart,  as  a  bulbous  muscular  pump,  must  keep  the  blood 
moving  in  two  circles,  one  through  the  lungs,  the  other  through  the  rest 
of  the  body,  for  which  reason  it  is  in  two  halves;  and  it  must  do  this 
promptly,  having  a  new  supply  of  blood  ready  when  it  has  discharged 
one,  wherefore  it  has  its  auricles.  There  are  wonderfully  perfect  valves 
to  maintain  the  direction,  and  the  left  side  of  the  heart  is  more  powerful 
than  the  right,  because  it  drives  the  blood  into  a  larger  field  and  against 
greater  resistance.  Still,  with  these  unequal  tasks,  which  may  vary 
between  two  beats,  one  side  of  the  heart  may  not  eject  more  or  less  blood 
than  the  other.  If  the  right  ventricle  throws  out  so  much  as  one  drop  more 
than  the  left  in  each  beat,  the  lungs  would  be  overdistended  and  burst 
within  a  few  minutes.  This  perfect  coordination  between  the  two  sides 
is  even  more  remarkable  when  we  think  that  the  ventricles  are  formed 
essentially  from  two  coils  of  one  long  muscle  band,  the  tendinous  ends  of 
which  are  attached  to  the  valves  as  the  chordae  tendinese,  and  that  the 
tasks  of  the  two  sides  are  not  only  different,  but  vary  differently.  To  be 
effective,  the  auricle  must  empty  itself  into  the  ventricle  at  the  precise 
moment  required,  and  the  ventricle  must  be  ready  for  its  new  load;  to 
expel  the  blood  with  adequate  force,  the  walls  of  these  chambers  must  con- 
tract not  only  rhythmically,  but  uniformly,  and  to  insure  this  rhythmic 
and  perfect  contraction  there  are  special  telegraphic  connections  with 
central  stations  at  at  least  two  places,  from  which  controlling  impulses  are 
sent  out — one  sets  the  pace,  the  other  relays  the  message. 

461 


462  TEXT-BOOK   OF   PATHOLOGY 

The  Blood-vessels.— The  heart  is  aided  in  its  work  by  the  arteries,  and 
to  a  less  extent  by  the  veins.  They  are  not  merely  elastic  tubes,  in  places, 
in  the  veins  at  least,  furnished  with  valves,  but  active  contractile  organs, 
which  not  only  drive  on  the  blood  by  a  sort  of  peristaltic  contraction,  but 
control  the  head  of  pressure  with  which  the  heart  works,  by  narrowing  or 
widening  their  own  calibre.  Were  it  not  for  this  healthy  opposition  to  the 
push  of  the  heart,  there  would  arise  one  of  the  vicious  circles  that  may 
prove  disastrous  to  the  whole  circulation;  not  only  would  the  arterial 
blood  escape  into  the  distensible  veins  through  the  capillaries,  but  the 
back  pressure  into  the  coronaries,  upon  which  the  nutrition  of  the  heart 
depends,  being  gone,  the  heart  would  fail  at  once.  The  fact  that  this  con- 
trolling contraction  and  relaxation  of  the  arterioles  occurs  locally  in  differ- 
ent regions  of  very  different  extent  explains  the  possibility  of  rapid  varia- 
tions in  pressure,  which  must  be  compensated  either  by  extra  effort  of  the 
heart  or  by  other  changes  in  calibre  in  the  vessels. 

Control  of  Blood-vessels. — The  heart  and  blood-vessels  then,  work  in 
cooperation  almost  as  intimate  as  that  of  the  two  sides  of  the  heart.  This 
must  be  managed  by  the  nervous  system.  There  are  nerves  important  in 
this  respect,  the  accelerator  and  augmentor  nerves,  which  form  part 
of  the  sympathetic  system,  and  to  which  the  inhibitory  vagus  nerves  act 
antagonistically.  The  blood-vessels  are  made  to  contract  by  vasocon- 
strictor fibres,  which,  starting  from  the  ganglion-cells  of  a  centre  in  the  floor 
of  the  fourth  ventricle,  reach  the  blood-vessel  walls  by  relays  of  cells 
through  the  sympathetic  ganglia.  They  are  made  to  dilate  by  inhibitory 
vasodilator  fibres,  which  seem  to  have  no  definite  centre  in  the  brain  and 
do  not  act  rhythmically,  like  the  vasoconstrictors,  which  maintain  a  tone 
in  the  vessels.  These  mechanisms  which  govern  the  vessels  may  be  set 
in  action  reflexly  by  impulses  conducted  along  sensory  nerves,  but  prob- 
ably by  special  fibres,  some  of  which  act  to  stimulate  the  release  of  vaso- 
constrictor impulses  (pressor  fibres),  while  others  set  in  action  vasodilator 
impulses  (depressor  fibres).  From  the  aorta  and  heart  there  even  runs  a 
nerve  whose  sole  function  is  of  an  afferent  depressor  character.  Psychical 
stimuli,  as  well  as  those  from  various  organs,  may  affect  the  vascular  con- 
trol, and  in  a  reflex  way  cause  the  blanching  or  flushing  of  different  parts 
of  the  body.  Indeed,  violent  painful  stimuli  may  produce  sometimes 
such  extreme  relaxation  of  the  vessels  that  the  blood-pressure  falls  to  a 
degree  which  proves  fatal  (shock).  Certain  chemical  stimuli,  such  as 
extracts  of  the  adrenal  and  pituitary  glands,  are  known  to  have  a  powerful 
influence  upon  blood-pressure  through  causing  changes  in  the  calibre  of  the 
blood-vessels,  and  it  is  often  suggested,  though  not  quite  proved,  that  the 
control  of  the  balance  is  largely  dependent  on  the  activities  of  these  organs 
of  internal  secretion. 

Other  Influences. — There  are  other  factors  of  a  more  mechanical  nature 
which  have  a  very  great  influence  upon  the  circulation,  namely,  respiration, 
the  condition  of  the  abdominal  contents,  posture  and  muscular  activity, 
and  many  others.  Respiration  aids  the  flow  of  venous  blood  to  the  heart 


PATHOLOGICAL  OBSTRUCTIONS  463 

by  producing  a  partial  vacuum  in  the  thorax  during  inspiration,  and  at  the 
same  moment  increasing  the  intra-abdominal  pressure.  Most  of  this  is 
done  by  the  diaphragm,  which  both  sucks  and  presses  the  blood  out  of  the 
abdominal  veins.  Enteroptosis  or  sagging  of  the  abdominal  viscera,  which 
pulls  down  the  diaphragm  and  diminishes  its  excursion,  annuls  to  a  great 
extent  this  beneficial  action.  Great  accumulations  of  fluid  or  large  tumors 
in  the  abdomen  bring  about  the  same  result  in  a  different  way,  by  pressing 
the  diaphragm  up  and  immobilizing  it.  The  circulation  is  made  easier 
by  the  recumbent  posture — more  difficult  by  the  erect,  but,  of  course,  this 
is  not  felt  much  by  the  normal  heart.  Violent  muscular  exercise  elicits 
greater  activity  of  the  heart,  both  to  aerate  the  blood  more  rapidly  and  to 
bring  it  in  increased  quantity  to  the  active  muscles.  The  heart  may  be 
overtaxed  by  too  great  and  prolonged  effort,  so  that  it  dilates  and  the  man 
falls  in  a  faint  or  dies.  This  is  really  an  example  of  the  response  of  the 
heart  to  demands  which  arise  from  an  enormously  accelerated  metabolism. 
From  all  this  it  is  seen  that  in  the  circle  through  which  the  blood  is 
forced  the  conditions  in  each  part  are  influenced  by  those  in  the  preceding 
and  succeeding  parts.  Each  portion  of  the  circle  is  governed  by  regulating 
mechanisms,  and  instantly  adapts  itself  to  new  conditions,  whether  these 
are  produced  by  changes  within  the  stream-bed  or  by  influences  from  out- 
side, and  this  very  adaptation,  like  the  original  change,  is  felt  not  only 
just  in  front  of  or  just  behind  that  point,  but  all  around  the  circle.  All 
these  regulatory  mechanisms  act  together  to  maintain  the  arterial  blood- 
pressure  at  a  fairly  definite  standard,  which  reaches  110  to  150  mm.  of 
mercury  during  systole  in  the  larger  arteries,  falling  with  each  pulsation  to 
60  to  80  mm.  in  diastole.  As  the  blood  advances  into  the  arterioles  and 
capillaries,  the  pressure  sinks  and  the  differences  between  systolic  and 
diastolic  pressure  disappear,  so  that  in  the  veins  the  stream  is  constant, 
and  at  a  pressure  which  still  decreases  toward  the  heart.  In  the  pulmonary 
circulation  its  pressure  is  very  much  lower  and  the  pulsatory  variations 
less,  but  it  passes  with  greater  velocity  through  those  capillaries  than 
through  the  capillaries  of  the  systemic  organs.  The  importance  of  the 
maintenance  of  this  pressure  and  the  corresponding  rapid  exchange  of 
blood  are  most  evident  in  the  coronary  circulation  of  the  heart  and  in  the 
brain.  The  nice  balance  of  this  mechanism  is  maintained  with  great 
tenacity,  and  the  effects  of  disturbing  influences  may  often  be  found  not  in 
changes  in  the  blood-flow  itself,  but  only  in  the  differences  in  the  machine 
developed  to  compensate  for  the  interference. 

PATHOLOGICAL  OBSTRUCTIONS 

Pericardial  Effusion. — Mechanical  influences  quite  outside  the  circulation 
itself  can  have  such  effects.  The  accumulation  of  fluid  in  the  pericardial 
cavity  may  go  on  gradually  until  the  sac  is  enormously  distended,  but  if  it 
comes  suddenly,  as  in  the  case  of  a  haemorrhage  from  the  heart,  or  when  one 
injects  it  experimentally  in  an  animal,  the  pericardium  has  no  time  to 
stretch.  Then  the  heart  is  greatly  embarrassed  because  it  cannot  expand 


464  TEXT-BOOK   OF   PATHOLOGY 

to  allow  the  entrance  of  blood  from  the  veins.  Great  distension  of  the 
veins  occurs,  with  heightening  of  the  blood-pressure  there,  while  the  amount 
of  blood  thrown  into  the  aorta  becomes  so  small  that  even  the  action  of  the 
vasoconstrictors  fails  to  keep  up  the  blood-pressure,  little  blood  goes  into 
the  coronary  arteries  and  the  heart  gives  up  its  beating.  Quick  removal  of 
the  fluid  from  the  pericardium  may  restore  the  normal  conditions  in  time 
to  start  the  heart  once  more.  Moderate  collections  of  fluid  (hydroperi- 
cardium  or  pericarditis)  may  cause  only  a  tolerable  overfilling  of  the  veins 
and  decrease  in  the  arterial  blood-flow. 

Intrapleural  and  Pulmonary  Obstruction. — Effusions  of  fluid  into  the 
pleura  compressing  the  lung  (cf.  Fig.  92),  tumors  in  the  pleura,  narrowing 
and  distortion  of  the  thorax  by  deformities,  such  as  curvature  of  the  spine 
(skoliosis,  kyphosis,  etc.),  and  destructive  changes  in  the  lungs  themselves 
have  a  similar  effect  in  obstructing  the  circulation,  but  act  at  a  different 
point.  Now  the  difficulty  which  still  affects  the  whole  blood-stream  lies 
in  forcing  the  blood  through  the  compressed  or  reduced  pulmonary  stream- 
bed,  and  the  burden  is  put  upon  the  right  ventricle.  It  rises  at  once  to  its 
increased  task,  and  may  be  able  to  perform  it  by  drawing  on  its  reserve 
power.  Often  it  can  go  on  like  this,  forcing  the  obstacle  and  maintaining 
the  normal  circulation,  in  time  growing  in  thickness  and  strength  of  wall 
through  the  increased  exercise.  But  if  it  fails  only  partially,  the  blood 
accumulates  in  the  veins  and  in  the  auricle,  and  reaches  the  aorta  in 
diminished  amount. 

Emphysema. — One  of  the  common  obstructions  acting  at  this  point  is 
emphysema  of  the  lungs  (see  p.  437),  in  which  the  rarefaction  of  the  lung 
tissue  obliterates  much  of  the  stream-bed  in  the  lung.  Other  changes, 
which,  by  cramping  the  thoracic  organs  or  obstructing  the  pulmonary 
blood-flow,  produce  the  same  effect,  will  be  referred  to  later  and  easily 
understood.  This  is  the  narrow  pass  for  the  whole  circulation.  After- 
ward in  the  systemic  circle  nothing  can  so  readily  obstruct  the  whole  blood- 
flow,  since  there  are  always  roundabout  ways,  and  the  closure  even  of  large 
arterial  trunks  has  practically  no  effect  upon  the  blood-pressure.  Even 
the  whole  aorta  below  the  renal  arteries  may  be  ligated,  with  only  a  trifling 
rise  in  blood-pressure.  Ligation  of  the  renal  arteries  adds  little  to  this; 
that  of  the  splanchnic  arteries  has  much  more  effect,  but  even  this  (Long- 
cope  and  McClintock)  is  a  matter  of  only  a  few  millimetres  of  mercury. 
Such  extreme  obstructions  are,  of  course,  rare  and  of  little  importance,  as 
far  as  the  circulatory  apparatus  goes;  their  importance  relates  rather  to  the 
nutrition  of  the  tissues  which  those  vessels  should  supply. 

Toxic  Influences. — Chemical  influences  have  great  importance  also,  in 
so  far  as  they  affect  the  nervous  control  of  the  heart  or  arteries  (atropine, 
adrenaline,  etc.),  or  the  muscular  walls  of  these  structures  (barium,  ergot, 
etc.),  but  their  effects  are  transient  and  need  not  be  considered  further  here. 
The  poisons  at  work  in  many  infections  act  upon  the  heart  to  injure  its 
muscle  and  weaken  its  power,  or,  as  in  the  case  of  diphtheria,  affect  also 
the  vasomotors,  paralyzing  their  control  over  the  vessels  and  thus  allowing 


THE    EFFECT   OF  MYOCARDIAL  DISEASE  465 

a  fall  in  blood-pressure  which  may  be  fatal  in  withdrawing  blood  from  the 
coronary  circulation.  This  constitutes  the  underlying  principle  of  the 
shock  in  which  patients  die  in  such  intoxications. 

Anatomical  Changes  in  the  Blood-vascular  Apparatus. — Changes  in  the 
circulatory  apparatus  itself  are  productive  of  great  changes  in  the  blood- 
flow,  nearly  always  in  the  sense  of  an  obstruction,  or  diminution  in  the 
efficiency  of  its  propulsive  power.  These  commonly  affect  the  elasticity 
and  contractility  of  the  arterial  walls,  the  muscular  power  of  the  heart- 
walls,  the  efficiency  of  the  valves,  and  the  mechanism  which  maintains  the 
rhythm  of  the  heart,  and  may  be  considered  in  this  order. 


THE  EFFECT  OF  ARTERIAL  DISEASE 

Disease  of  the  arterial  walls  (cf.  p.  335)  results  commonly  in  their  partial 
rigidity.  At  least  the  elastic  tissue  which  gives  them  their  resiliency  is 
broken  and  degenerated  and  greatly  decreased  in  amount.  What  remains 
is  rendered  useless  by  the  formation  of  stiff  fibrous  tissue,  or  even  calcified 
patches  which  will  not  stretch.  In  the  same  way  the  smooth  muscle,  so 
important  in  changing  the  calibre  of  the  vessel,  and  in  propelling  the  blood 
by  its  contractions,  is  partly  destroyed,  partly  splinted  by  the  new  tissue, 
which  thickens  the  once  delicate  inner  layer  of  the  vessel,  and  thus 
changes  it  to  a  rigid  tube,  perfectly  incapable  of  aiding  the  heart.  Beside 
this,  the  lumen  of  these  tubes  is  often  narrowed  by  this  process,  and  some- 
times to  an  extreme  degree. 

The  general  effect  is  to  withdraw  from  the  heart  whatever  aid  the  vessels 
previously  afforded  in  the  propulsion  of  the  blood.  While  this  is  important, 
it  is  not  so  great  that  an  extreme  burden  is  put  upon  the  heart  by  its  loss. 
Nor,  except  in  the  case  of  the  splanchnic  vessels,  is  the  narrowing  of  the 
channels  likely  to  cause  a  noteworthy  rise  in  blood-pressure.  Extra  work 
is,  of  course,  put  upon  the  heart  by  both  these  factors,  and  the  wall  of  the 
left  ventricle  thickens  and  becomes  stronger  in  response  to  it,  but  there  is 
still  uncertainty  as  to  the  degree  to  which  the  arterial  changes  alone  are 
responsible  for  this;  probably  their  effect  has  been  frequently  overestimated 
in  cases  in  which  several  factors  are  available  in  explaining  high  blood- 
pressure  and  the  enlargement  of  the  heart.  The  opinion  has  been  expressed 
by  many  (Hasenfeld,  Longcope)  that  rigidity  and  narrowing  of  the  splanch- 
nic vessels  are  by  far  the  most  important  in  this  respect. 

Of  special  interest  are  the  changes  in  the  coronary  arteries  of  the  heart, 
for  any  interference  with  the  abundant  blood  supply  necessary  to  that 
muscle  must  bring  with  it  injuries  of  the  heart-wall,  to  the  detriment 
of  the  general  circulation. 

THE  EFFECT  OF  MYOCARDIAL  DISEASE 

The  arrangement  of  the  musculature  of  the  heart-walls  (J.  B.  MacCallum, 
Mall)  is  such  as  to  control  with  the  greatest  completeness  the  propulsion  of 


466  TEXT-BOOK   OF   PATHOLOGY 

the  blood — not  only  does  it  obliterate  the  cavity  of  the  ventricles,  but  by 
the  contraction  of  the  papillary  muscles  it  insures  the  proper  tension 
and  perfect  closure  of  the  auriculoventricular  valves.  Further,  special  sub- 
divisions of  the  muscle  support  the  semi  lunar  valves,  and  maintain 
their  closure  in  such  a  way  that  even  with  slight  imperfections  of 
the  valves  leakage  is  much  diminished  by  this  muscular  action.  The 
heart  muscle  has  always  been  regarded  as  a  network  of  cells  attached 
to  one  another  along  transverse  cement  lines,  but  in  recent  years 
there  has  been  a  tendency  to  look  upon  it  as  a  sort  of  syncytium  with- 
out cellular  limits,  the  cement  lines  being  thought  to  be  the  product  of 
physical  influences  which  act  more  intensely  with  the  advance  of  age 
(Cohn,  Aschoff,  and  Tawara).  The  muscle  fibrils,  with  their  sarcoplasmic 
discs,  are  arranged  in  each  fibre  around  a  central  space,  in  which  lies 
the  nucleus  surrounded  by  undifferentiated  protoplasm.  It  is  in  this 
space  at  the  poles  of  the  nucleus  that  a  yellowish  pigment  begins  to  accumu- 
late in  early  years  of  life,  and  increases  with  the  advance  of  age.  With 
great  wasting  of  the  heart  muscle  this  pigment  may  become  so  abundant 
as  to  give  a  chestnut-brown  color  to  the  whole  heart  (brown  atrophy). 
As  indicated  elsewhere,  it  is  one  of  the  lipochrome  pigments  and  takes  a 
reddish  stain  with  Sudan.  The  specific  stimulus-conducting  system  of 
fibres  will  be  described  later. 

Myocardial  Injuries. — Myocarditis. — Degenerative  and  destructive 
changes  occur  in  the  heart  muscle  in  the  course  of  various  infections,  in- 
toxications, and  nutritive  disturbances,  but  are  not  specially  characteristic 
of  any.  Fat  accumulates  in  the  form  of  fine  droplets  arranged  in  the  sarco- 
plasmic discs,  and  therefore  often  in  longitudinal  lines.  This  fat  is,  as  a 
rule,  not  uniformly  distributed,  but  is  very  abundant  in  certain  little 
groups  of  fibres,  while  almost  absent  in  the  neighboring  ones.  On  the 
whole,  it  is  far  more  abundant  in  the  inner  layers  of  the  heart-wall  than  the 
outer.  This  results  in  the  peculiar  mottling  with  minute,  opaque,  yellow 
patches,  most  commonly  seen  in  the  wall  of  the  right  ventricle  below  the 
orifice  of  the  pulmonary  artery,  and  in  the  papillary  muscles  of  the  left 
ventricle,  although  it  may  be  spread  all  over  the  interior  and  deep  in  the 
substance  of  both  ventricles.  This  is  the  so-called  tigering  or  faded-leaf 
appearance  (cf.  Figs.  32  and  33).  Ribbert  thinks  that  this  peculiar  dis- 
tribution is  due  to  unequal  nutrition  in  the  regions  of  different  minute 
branches  of  the  coronary  arteries.  It  is  found  most  often  in  extreme  and 
long-standing  anaemias,  protracted  febrile  states,  and  in  chronic  diseases, 
such  as  nephritis,  associated  with  anaemia.  The  presence  of  the  fat  seems 
to  have  very  little  detrimental  effect  upon  the  function  of  the  heart,  or  per- 
haps it  should  be  said  that  the  diseased  condition  of  the  muscle  which  leads 
to  the  retention  of  the  fat  does  not  greatly  impair  its  activity.  Dr.  Welch, 
in  studying  animals  kept  for  a  long  time  at  a  fever  heat,  found  abundant 
deposition  of  fat  in  their  hearts,  but  no  special  functional  alteration.  In 
the  same  way  we  find  a  certain  cloudiness  of  the  heart  muscle  in  such  infec- 


THE    EFFECT   OF   MYOCARDIAL   DISEASE  467 

tions  as  typhoid,  but  although  we  may  name  this  parenchymatous  degenera- 
tion, we  cannot  find  that  it  indicates  much  harm  to  the  heart. 

On  the  other  hand,  in  a  few  very  acute  and  intense  infections  or  toxic 
processes,  such  as  diphtheria  and  scarlet  fever,  there  may  be  actual  necrosis 
or  hyaline  degeneration  of  fibres  here  and  there,  much  like  that  seen  in  the 
rectus  abdominis  in  typhoid  fever,  and  these  or  even  slighter  lesions,  not 
easily  seen  as  changes  in  the  muscle,  may  in  these  diseases  give  rise  to  a 
wide-spread  acute  inflammatory  reaction  with  focal  accumulations  of  leuco- 
cytes, oedema,  and  fibrinous  coagula.  It  is  impossible  that  these  things, 
involving  as  they  do  the  loss  of  many  of  the  muscle-fibres,  should  not 
weaken  the  heart.  Such  is  its  reserve  power,  however,  that  it  generally 
continues  to  beat  well  enough  in  spite  of  them.  They  have  been  regarded 
by  many  authors  (Stejskal  and  others)  as  the  cause  of  the  sudden  collapse 
and  death  at  the  height  of  diphtheria  (and  also  in  peritonitis  and  other 
septic  infections),  but  Passler  and  Romberg,  MacCallum,  and  others 
have  shown  that  deaths  of  this  sort  are  due  rather  to  failure  of  the  vaso- 
motor  control  of  the  arteries  (or  possibly  to  the  effect  of  Dale's  capillary 
poisons),  which  allows  the  blood-pressure  to  fall  and  the  whole  heart  to 
suffer  acutely  from  lack  of  nutrition.  Abscesses  in  the  myocardium  in 
the  course  of  general  septic  infections  or  resulting  from  embolism  of  the 
coronary  branches  by  infected  fragments  of  endocardial  vegetations  (septic 
infarcts),  and  extensions  into  the  myocardium  from  endocardial  vegetations, 
produce  similar  effects,  but  they  will  be  considered  elsewhere. 

Calcified  foci  are  sometimes  found  which  may  be  the  outcome  of  the 
healing  of  such  necroses.  So,  too,  it  must  be  admitted  that  scar  tissue  of 
no  specific  character  may  remain  as  the  result  of  their  healing,  and  that, 
therefore,  these  lesions  may  give  one  explanation  of  the  origin  of  the  so- 
called  fibrous  myocarditis.  That  there  are  other  changes  potent  in  bring- 
ing about  this  scarring  of  the  heart  muscle  we  shall  see. 

Tubercles  and  syphilitic  gummata  are  rare  in  the  heart,  but  after  acute 
articular  rheumatism,  the  aetiology  of  which  is  still  uncertain,  there  appear, 
as  Aschoff,  Bracht  and  Wachter,  and  many  more  have  shown,  minute 
elongated  nodules  of  peculiar  structure,  scattered  especially  in  the  poste- 
rior wall  of  the  left  ventricle  near  its  base,  and  much  more  rarely  situated 
elsewhere.  These  are  often  periarterial,  and  are  composed  of  large  pale 
epithelioid  cells  with  large  vesicular  nuclei  (Fig.  231).  Some  of  the  cells 
become  very  conspicuous  from  the  size  of  their  nucleus,  and  others  stand 
out  as  actual  giant-cells.  Eosinophiles  and  polynuclears  accompany  them 
sparsely.  Aschoff  is  probably  correct  in  contending  that  these  cells  are 
derived  from  mononuclear  wandering  cells,  and  not  from  the  muscle  or 
connective  tissue.  There  is  no  definite  evidence  of  their  influencing  the 
muscular  activity  to  a  recognizable  degree. 

Affections  of  the  coronary  arteries  are  particularly  important  in  pro- 
ducing changes  in  the  heart  muscle.  In  some  cases  fragments  of  the 
thrombotic  vegetations  upon  the  heart  valves  may  be  thrown  as  emboli 
into  these  vessels,  suddenly  obstructing  a  branch  or  the  whole  artery. 


468 


TEXT-BOOK   OF   PATHOLOGY 


In  others  arteriosclerotic  thickening  of  the  vessel-walls  gradually  leads 
to  narrowing  of  the  lumen,  which  may  be  extreme,  or  which  may  be 
quickly  completed  by  the  formation  of  a  thrombus  upon  the  degenerated 
plaque,  obstructing  the  flow  of  blood  altogether.  Any  of  these  modes  of 
obstruction  is  effective  in  shutting  off  the  blood  supply  from  a  certain 
part  of  the  heart-wall  because,  although  Spalteholz  has  shown  clearly 
by  injections  that  there  are  rather  numerous  anastomoses  between  the 
coronary  arteries,  these  are  insufficient  to  maintain  the  enormous  supply 
of  rapidly  moving  blood  which  the  heart  muscle  needs.  A  less  active 
organ  might  find  it  sufficient,  but  in  the  case  of  the  heart-wall  a  part  rather 


Fig.  231. — Aschoff  body  in  the  heart  in  acute  rheumatism,  showing  the  rather  charac- 
teristic relation  to  the  blood-vessel. 


less  in  extent  than  the  region  supplied  by  the  obstructed  artery  dies.  The 
dead  area  promptly  assumes  the  character  of  an  anaemic  infarction,  and 
may  at  times  occupy  large  parts  of  the  walls  of  both  ventricles,  together 
with  part  of  the  interventricular  septum.  Experimental  occlusion  of 
various  branches  of  the  coronary  arteries  shows  a  variable  result;  often 
the  heart  stops  beating  at  once,  especially  in  the  case  of  the  anterior 
descending  branch  of  the  left  artery,  but  in  other  cases,  or  in  an  animal  of 
another  kind,  it  may  not.  That  human  beings  can  often  withstand 
extensive  occlusion  of  the  coronary  arteries  is  familiar  to  every  one  from 
autopsy  experience,  for  it  is  not  uncommon  to  find  large  infarctions,  re- 
vealed only  by  death  from  their  rupture  or  from  some  other  cause.  Indeed, 


THE    EFFECT   OF   MYOCARDIAL   DISEASE  469 

many  of  these  heal  completely  into  a  rather  thin  fibrous  scar,  which  re- 
places the  heart-wall,  becomes  bulged  out  into  an  aneurysmal  sac,  and 
lined  with  thrombi  (Fig.  232).  Pericardial  adhesions  are  generally  found 
on  their  surface. 

The  effect  of  such  obstructions  when  they  concern  the  smaller  branches 
is  to  produce  little  infarcts,  which  can  be  seen  and  felt  upon  the  surface  or 
in  the  interior  of  the  heart  as  inelastic,  hard,  yellow,  opaque  masses  with 


Fig.  232. — Hypertrophied  heart  with  apical  myocardial  scar,  aneurysmal  dilatation, 
and  extensive  thrombus  formation.  The  thrombi  show  central  softening  and  excava- 
tion. 


a  halo  of  deep  red.  More  common  still  is  the  discovery  of  various  stages 
in  the  healing  and  scarring  of  such  infarcts.  But  from  finding  scars  in  the 
heart-wall  one  cannot  be  sure  that  infarcts  preexisted — indeed,  many  of 
these  scars  seem  to  have  been  gradually  formed  by  the  wasting  away  of 
undernourished  heart-muscle  fibres  and  their  replacement  by  fibrous  tissue, 
especially  in  cases  where  no  obvious  obstruction  or  extreme  narrowing  of 
the  vessels  can  be  found.  And,  after  all,  in  that  stage  one  cannot  feel  sure 


470  TEXT-BOOK    OF    PATHOLOGY 

that  they  have  not  arisen  through  the  healing  of  focal  areas  of  toxic  or 
infectious  injury,  which,  after  passing  through  a  stage  of  inflammatory 
reaction,  have  ended  in  scars.  Indeed,  it  has  been  suggested  by  R.  Keith 
that  the  extensive  scars  and  aneurysmal  dilatations  of  the  ventricular  walls 
are  the  end-results  of  a  tertiary  syphilitic  process  with  gumma  formation, 
and  he  was  able  to  collect  a  very  complete  series  of  hearts  showing  the  most 
gradual  transitions  from  fresh  gummata  through  all  stages  of  healing  to 


Fig.  233. — Vascular  soft  scar  in  the  heart-wall.     This  is  an  early  stage  in  the  replace- 
ment of  dead  heart  muscle  by  scar  tissue. 

the  well-developed  aneurysmal  sac.  While  this  is  not  proof,  the  lack  of 
marked  sclerotic  changes  in  the  coronaries  in  some  of  these  cases  and  the 
frequency  of  syphilitic  lesions  in  other  parts  of  the  circulatory  apparatus 
make  the  idea  seem  very  plausible. 

Thus,  although  from  the  presence  of  fresher  stages  in  the  form  of  infarcts 
it  is  sometimes  possible  to  feel  certain  that  the  scars  are  due  to  embolic  or 
arteriosclerotic  and  thrombotic  occlusion  of  the  coronary  vessels,  it  is  by 


THE    EFFECT   OF  MYOCARDIAL  DISEASE 


471 


no  means  always  so:  The  fresher  of  these  scars  can  often  be  felt  on  the 
surface  of  the  heart  as  soft,  depressed  areas,  which  on  section  look  gel- 
atinous or  spongy,  and  are  grayish  red  and  semi-translucent  (Fig.  233). 
They  are  composed  of  a  loose,  soft  granulation  tissue,  very  rich  in  small 
blood-vessels,  which  have  doubtless  grown  in  from  neighboring  vascular 
areas.  The  older  ones  are  dense,  shining,  tendon-like,  pearly-white 
patches,  sometimes  very  small  and  finely  distributed,  sometimes  so  large 


Fig.  234. — Old  scars  in  the  heart-wall  (chronic  fibrous  myocarditis). 


as  to  occupy  much  of  the  thickness  of  the  wall  (Fig.  234).  They  are  often 
indefinite  in  outline,  and  radiate  into  the  neighboring  tissue  (Fig.  235). 
Under  the  microscope  they  are  formed  of  compact  fibrous  tissue  poor  in 
blood-vessels,  but  sometimes  pigmented.  Around  their  margins  the  muscle- 
fibres  are  frayed  out,  often  reduced  to  pigmented  strands  (J.  B.  Mao- 
Callum),  or  swollen,  with  very  much  enlarged  and  deeply  staining  nuclei. 
Whenever  any  of  these  scars  reaches  the  endocardial  lining  of  the  heart, 
it  is  covered  by  thrombi  which  doubtless  began  to  be  formed  in  earlier 


472 


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stages,  when  injured  heart  tissue  was  exposed  to  the  passing  blood.  One 
may  not  say  that  all  thrombi  formed  on  the  lining  of  the  heart  overlie  such 
definite  areas  of  destruction  of  the  heart-wall,  but  nearly  always,  on  cut- 
ting through  the  base  of  a  globular  intertrabecular  thrombus,  there  is 
found  a  superficial  scar.  As  mentioned  above,  it  is  at  the  apex  of  the  heart 
that  the  conversion  of  the  whole  wall  into  scar  tissue,  thickly  lined  with 
thrombus  material,  is  most  common. 

There  is  much  dispute  as  to  the  effect  of  these  scars,  or  rather  of  the 
injuries  which  give  them  origin,  upon  the  muscular  power  of  the  heart. 
Unquestionably  the  destruction  of  heart  muscle  and  its  replacement  by 
rigid  scar  tissue  must  deprive  the  heart  of  some  of  its  strength,  but  such 
is  the  phenomenal  reserve  power  of  this  organ 
that  a  great  deal  may  be  destroyed  before  the 
circulation  is  impaired.  In  a  dog  one  may  inject 
strong  alcohol  with  a  hypodermic  syringe  into 
the  muscle  of  the  heart-wall,  so  as  to  coagulate 
instantly  a  patch  of  the  muscle;  the  slight  fall 
of  pressure  is  almost  instantly  made  up,  and  this 
may  be  repeated  a  dozen  times,  until  almost  all 
the  wall  of  the  ventricle  is  turned  into  a  hard, 
dead  white  mass  before  the  circulation  finally 
begins  to  fail.  Aschoff  and  Tawara  lay  little 
stress  on  such  scarring  of  the  heart  as  a  cause  of 
the  final  breakdown  of  the  circulation,  and  most 
clinical  writers  also  agree  that  even  extreme  de- 
grees of  fibrous  alteration  may  exist  for  a  long 
time  without  giving  rise  to  any  symptoms.  Ir- 
regular, feeble,  slow  pulse  and  dyspnoea  are  gen- 
erally given  as  the  symptoms,  but  these  are  not 
particularly  distinctive.  Whether  the  conversion 
of  a  part  of  the  heart  muscle  into  scar  tissue  is 
followed  by  hypertrophy  of  the  rest  of  the  mus- 
cle, so  as  to  enlarge  the  whole  heart,  is  a  question 
difficult  to  answer,  because  the  condition  seldom 

occurs  without  other  changes  within  or  outside  of  the  heart,  which  could 
also  be  concerned  in  causing  cardiac  hypertrophy.  Exact  experimental 
study  seems  not  to  have  been  carried  out  with  reference  to  this  point, 
except  that  Stewart  has  found  that  when  myocarditis  is  produced  by  injec- 
tions of  adrenaline,  the  scarred  hearts  are  distinctly  hypertrophied  and  weigh 
more  than  the  normal  in  proportion  to  the  body  weight.  He  thinks  the 
action  of  the  adrenaline,  which  causes  the  formation  of  scar  tissue  and  en- 
largement of  the  muscle-fibres,  results  in  an  enlarged  organ  whose  func- 
tional capacity  is  below  normal.  Naturally,  although  the  scars  probably 
occupy  less  space  than  the  muscle  which  they  replace,  the  increase  of  the 


Fig.  235. — Tangential 
section  of  heart-wall  show- 
ing old  scars. 


THE    EFFECT   OF   MYOCARDIAL   DISEASE 


473 


remaining  muscle,  in  its  attempt  to  carry  on  the  work  of  the  heart,  might 
more  than  compensate  for  this,  and  result  in  an  enlargement  of  the  whole 
heart. 

Fragmentation  of  the  Heart  Muscle. — In  many  hearts,  especially  those  of  old  people, 
and  perhaps  also  those  of  persons  who  have  long  suffered  from  chronic  infections  or  from 
advanced  circulatory  decompensation,  there  is  found  wide-spread  disintegration  of  the 
heart  muscle,  nearly  every  fibre  being  fractured  transversely  once  or  twice.  These 


Fig.  236. — Fragmentation  of  the  myocardium,  showing  simple  transverse  fractures. 


uneven  or  step-like  breaks  seem  to  cross  the  muscle-fibre  at  any  point,  and  are  not  essen- 
tially separations  of  the  fibres  at  the  so-called  cement  line.  J.  B.  MacCallum  dis- 
tinguished simple  fragmentation  (Fig.  236)  from  a  degenerative  form  (Fig.  237),  in  which 
the  fibre  breaks  across  a  place  where  it  was  evidently  in  extreme  extension,  and  where 
the  fibrils  break  at  different  levels,  so  as  to  produce  an  area  made  up  of  many  short 
lengths  of  individual  fibrils.  It  seems  possible  to  recognize  the  existence  of  this  con- 
dition in  many  cases  from  the  softness  and  flabbiness  of  the  heart.  There  has  been  much 
dispute  as  to  its  significance,  and  since  it  seems  incompatible  with  the  continued  activity 
of  the  heart,  and  yet  is  surrounded  by  no  evidence  of  any  reaction  on  the  part  of  the 


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tissues  it  is  generally  thought  to  occur  during  the  death  agony,  and  to  be  produced  by 
thTfinal irregular  contractions.  Such  evidence  is  not  conclusive,  however,  and  we  must 
await  further  information. 


Fig.  237.— Fragmentation  of  the  myocardium  with  disintegration  of  the  fibrils  (degenera- 
tive fragmentation). 


LITERATURE 

Hasenfeld:  Dtsch.  Arch.  f.  klin.  Med.,  1897,  lix,  193. 
Longcope  and  McClintock:  Johns  Hopkins  Hosp.  Bull.,  1910,  xxi,  270. 
J.  B.  MacCallum:  Johns  Hopkins  Hosp.  Rep.,  1900,  ix,  307.  Jour.  Exp.  Med.,  1899,  iv, 

409. 

F.  P.  Mall:  Amer.  Jour.  Anat.,  1911,  xi,  211. 
A.  Cohn:  Verh.  Dtsch.  path.  Gesellsch.,  1909,  xiii,  182. 

Aschoff  and  Tawara:   Path.  Anat.,  Grundlagen  der  Herzschwache,  Jena,  1906. 
Passler  and  Romberg:  Dtsch.  Arch.  f.  klin.  Med.,  1899,  Ixiv. 
Stejskal:    Ztschr.  f.  klin.  Med.,  1902,  xliv,  367. 
MacCallum:    Amer.  Jour.  Med.  Sci.,  1914,  cxlvii,  37. 
Aschoff:  Verh.  Dtsch.  Path.  Gesellsch.,  1904,  viii,  46. 
Geipel:    Munch,  med.  Woch.,  1907,  liv,  1057,  and  1909,  Ivi2,  2469. 
Bracht  and  Wachter:  Dtsch.  Arch.  f.  klin.  Med.,  1907,  xcvi,  493. 

H.  A.  Stewart:  Jour.  Exp.  Med.,  1911,  xiii,  187;  Jour.  Path,  and  Bact.,  1912,  xvii,  64. 
Fleischer  and  Loeb:  Arch.  Inter.  Med.,  1909,  iii,  78;  1910,  vi,  427. 


CARDIAC    VALVULAR   DISEASE   AND    ITS    CONSEQUENCES         475 

CARDIAC  VALVULAR  DISEASE  AND  ITS  CONSEQUENCES 
Mechanism  of  the  Obstruction. — In  another  place  (page  245)  the  nature 
of  infectious  endocarditis  was  discussed,  and  it  was  found  that  thrombotic 
vegetations  on  the  valves  might  impair  the  accuracy  of  their  closure; 
further,  that  the  erosion  and  destruction  of  the  valves  would  produce  ex- 
treme incompetency  to  close  the  orifice.  On  kthe  other  hand,  even  if  heal- 
ing ensued,  the  valves  became  so  stiff,  distorted,  and  contracted  by  the  for- 
mation of  the  scar  tissue  that  they  no  longer  reached  one  another,  or  met 
so  imperfectly  that  leaks  occurred.  In  some  cases  they  fused  into  a  rigid 
ring  that  greatly  narrowed  the  orifice.  This  may  result  not  only  from 
bacterial  infection,  but  from  traumatism,  arteriosclerotic  changes,  and  as 
congenital  malformations.  Since  the  circulation  depends  so  largely  upon 
the  perfect  action  of  the  valvular  mechanism,  it  is  important  to  study,  in 
cases  where  it  is  defective,  the  changes  in  the  rate  and  volume  of  the  moving 
blood  and  the  consequent  changes  in  blood-pressure.  In  a  mechanical 
model,  such  as  that  of  v.  Basch,  these  relations  are  complicated,  but  they 
become  much  more  so  in  the  living  circulatory  apparatus,  where  many 
compensatory  mechanisms  are  at  work.  Every  valvular  lesion  produces 
an  obstruction  to  the  circulation,  either  by  opposing  a  barrier  to  the  flow  or 
by  failing  to  maintain  the  advance  effected  by  the  contraction  of  the 
heart.  Accumulation  of  blood,  therefore,  occurs  behind  each  diseased 
valve,  and  unless  exceptional  compensation  is  available,  the  amount  of 
blood  actually  propelled  into  the  circulation  beyond  it,  is  reduced  by  the 
amount  of  that  accumulation.  It  is  not  meant  that  any  particular  cor- 
puscles or  cubic  centimetres  of  the  blood  remain  stagnant  behind  the 
injured  valve,  but  that,  while  there  may  be  constant  mixing  in  this  region, 
it  is  as  though  a  stream  ran  in  and  out  of  a  lake.  The  vessels  in  that 
area  are  overfilled  and  distended,  and  the  exchange  of  blood  is  slow — not 
like  the  torrent  which  normally  sweeps  the  stream-bed  clean  at  each  beat. 
When  an  obstruction  or  regurgitation  occurs  at  any  valve,  say  the  aortic, 
the  amount  of  blood  thrown  into  the  aorta  must  be  constantly  less  than 
normal  as  long  as  the  cavity  of  the  ventricle  retains  its  normal  dimensions, 
and  the  wall  its  normal  force  of  contraction.  This  may  be  modified  by  the 
power  which  the  ventricle  possesses  of  dilating  to  receive  more  blood,  and 
expelling  it  with  greater  force,  but  in  order  to  throw  the  normal  quantity 
of  blood  into  the  arteries  the  left  ventricle  must  receive  that  amount  plus 
the  amount  regurgitated.  This  is  possible  only  if  there  is  an  actual  addi- 
tion to  the  amount  of  the  blood,  although  constriction  of  the  arterioles 
may  keep  up  the  normal  blood-pressure.  If  for  a  time  a  diminished 
amount,  less  than  the  normal  by  the  quantity  held  back  or  regurgitated, 
circulates  in  narrowed  vessels,  there  would  be  a  rapid  addition  of  fluid  from 
the  tissues  and  water  taken  into  the  stomach  until  the  circulating  amount 
was  again  normal.  Indeed,  one  receives  the  impression  from  observing 
the  amount  of  blood  in  the  vessels  at  autopsy  in  cases  of  long-standing 


476  TEXT-BOOK   OF   PATHOLOGY 

chronic  passive  congestion  from  cardiac  lesions,  that  there  is  a  great  in- 
crease in  its  quantity. 

The  changes  in  the  distribution  of  the  blood  may  be  thought  of  perhaps  in  terms  of 
numbers,  quite  arbitrarily  selected,  to  represent  the  amounts  of  blood  concerned.  This 
is,  of  course,  entirely  schematic,  but  it  serves  as  a  concise  way  of  describing  the  probable 
changes. 

Thus  if  the  amount  handled  by  any  one  part  of  the  heart  in  one  systole,  say  the  right 
ventricle,  be  represented  by  10,  the  left  auricle  will  receive  10  and  the  left  ventricle  also 
10.  If,  now,  insufficiency  of  the  mitral  valve  arises,  a  portion,  say  4,  is  driven  back  from 
the  left  ventricle  into  the  left  auricle,  and  6  goes  on  into  the  aorta.  With  the  same 
systole  10  again  reaches  the  left  auricle  and  meets  the  4  regurgitated  from  the  ventricle, 
so  that  the  left  auricle  now  contains  14.  That  which  follows  will  depend  upon  the 
activity  of  the  left  ventricle.  If  it  will  not  receive  more  than  the  usual  10,  4  remains 
stagnant  in  the  auricle,  6  is  thrown  into  the  aorta,  and  4  more  regurgitates.  By  this 
time  6  is  thrown  into  the  auricle  from  the  right  ventricle  instead  of  10,  and  meets  with 
8  of  regurgitated  blood,  making  up  14,  of  which  10  goes  again  into  the  ventricle.  Thus 
the  circulating  blood  amounts  to  6,  while  the  stagnant  blood  in  the  pulmonary  circula- 
tion amounts  to  4.  The  right  ventricle  forces  6  into  the  pulmonary  circulation,  already 
containing  4,  and  into  which  the  left  ventricle  simultaneously  forces  4. 

It  is  usual,  however,  for  the  left  ventricle  under  such  circumstances  to  dilate  and  to 
exert  greater  force  in  the  expulsion  of  the  greater  amount  of  blood  received.  This  may 
be  represented  as  follows: 

When  the  left  ventricle  has  thrown  6  into  the  aorta  and  there  is  14  in  the  left  auricle, 
the  ventricle  dilates  at  the  next  diastole — perhaps  not  enough  to  receive  the  whole  14, 
but  enough  to  receive  12.  Of  this,  it  expels  8  into  the  aorta,  while  4  is  again  regurgi- 
tated. The  regurgitated  4  meets  now  with  6  driven  in  by  the  right  ventricle,  and  2  left 
behind  from  the  14,  making  in  all  12.  With  the  next  diastole  the  ventricle  receives  the 
whole  12,  regurgitates  4,  and  throws  8  into  the  aorta.  By  this  time  the  amount  8 
thrown  out  by  the  ventricle  into  the  aorta  reaches  the  auricle  and  meets  the  4  regurgi- 
tated. The  whole  12  passes  into  the  ventricle,  and  thus  a  circulation  is  established  in 
which  8  circulates  while  4  is  regurgitated  with  each  systole. 

These  examples  assume  the  ability  of  the  ventricle  to  empty  itself  completely,  but  if, 
finally,  it  does  not,  a  new  set  of  conditions  arises  in  which  the  ventricle  itself  forms  part 
of  the  reservoir  for  stagnant  blood.  Many  other  conditions  which  commonly  occur  may 
be  represented  and  discussed  in  this  numerical  way. 

What  has  been  said  shows  clearly  enough  that  an  increased  strain  is  put 
upon  the  chamber  of  the  heart  behind  the  defect,  because  it  is  made  to 
handle  an  increased  amount  of  blood,  and  often,  though  not  always,  to 
propel  it  against  an  increased  resistance. 

As  explained,  the  heart  is  particularly  remarkable  in  being  able  to  rise 
instantly  to  the  emergency  if  an  excess  of  work  is  suddenly  demanded  of  it, 
and  this  adaptation  takes  place  so  smoothly  that  not  a  single  beat  is  lost 
or  disturbed.  This  is  an  evidence  of  its  great  reserve  power,  which  is 
ordinarily  not  drawn  upon,  but  which  permits  it  to  perform  greatly  in- 
creased work  for  a  limited  time,  as  one  sees  in  the  case  of  any  violent  mus- 
cular exertion  during  which  the  heart  pumps  with  increased  force  and 
rapidity.  But  if  the  excessive  work  must  be  kept  up  for  a  long  time, 
the  heart-wall  thickens  like  the  muscle  of  a  blacksmith's  arm,  to  enable 
the  more  easily  to  bear  its  burden.  Such  hypertrophied  hearts  and 


CARDIAC    VALVULAR   DISEASE   AND    ITS    CONSEQUENCES         477 

even  normal  hearts,  when  the  muscle  is  injured  or  badly  nourished  or 
finally  exposed  to  entirely  excessive  strain,  may  give  way  and  dilate  to 
a  degree  which  makes  their  proper  pumping  impossible. 

While  these  are,  in  outline,  some  of  the  principles  concerned  in  the 
effects  of  valvular  lesions,  they  come  into  play  differently  with  lesions  of 
different  valves. 

Aortic  Insufficiency. — Regurgitation  through  the  aortic  valves  may 
follow  destruction  of  the  valves  by  fresh  or  repeated  bacterial  infection, 


Fig.  238. — Aortic  insufficiency.  There  is  great  thickening  with  shortening  of  the 
aortic  valves  v  which  are  thereby  rendered  incompetent.  Hypertrophy  of  left  ventricle. 
Endocardial  thickening  beneath  aortic  valve.  Network  of  soft  white  bands  extending 
from  the  septum  to  the  papillary  muscle. 

but  it  is  most  commonly  the  result  of  syphilitic  infection  which  produces 
a  specific  type  of  arteriosclerosis  of  the  aorta,  and  analogous  scarring  and 
retraction  of  the  aortic  valves  (Fig.  238).  Very  often  they  are  fused 
together  at  their  base,  or  in  other  cases  merely  thickened  into  a  cord-like 
roll  at  the  edge,  so  that  they  are  shortened,  and  the  filmy  edge  which 
normally  completes  their  closure  is  lost.  At  times  the  diseased  valves 
rupture  or  tear,  the  fragments  flapping  in  the  stream.  Experimentally 
one  may  imitate  this  disease  by  cutting  through  a  valve  with  a  hook,  which 
can  be  pushed  down  the  carotid  artery,  after  which  the  effects  are  quite 


478  TEXT-BOOK   OF   PATHOLOGY 

like  those  observed  clinically.  There  need  be  no  great  disturbance  of  the 
circulation  nor  of  the  blood-pressure.  The  pulse  is  changed  to  a  bounding, 
collapsing  type,  with  a  dicrotic  wave  low  on  the  descending  limb.  This 
character  is  due  to  the  lowering  of  the  diastolic  pressure  after  each  beat 
by  the  rapid  regurgitation  of  the  blood,  so  that  the  aortic  wall  is  not  kept 
at  its  usual  high  tension.  The  pulse  pressure  is  high,  because  the  systolic 
pressure  remains  nearly  normal,  while  the  diastolic  pressure  cannot  be  kept 
up.  With  such  a  condition  the  pulse  is  felt  in  the  most  distal  vessels  like 
a  water-hammer,  and  can  be  seen  as  alternate  flushing  and  paling  in  the 
capillaries  of  the  fingers  and  toes. 

During  diastole  the  regurgitant  blood  returns  to  the  ventricle,  making 
a  loud  diastolic  murmur,  and  the  ventricle  dilates  to  receive  it  as  well  as 
the  auricular  blood.  So  perfect  is  the  left  ventricle  in  its  power  of  response 
to  the  increased  demand  that  ordinarily  it  succeeds  in  ejecting  an  amount 
into  the  aorta  sufficient  to  allow  of  regurgitation  and  still  maintain  the 
normal  filling  of  the  vessels.  This  requires  the  ability  to  dilate  and  to 
handle  the  excess  of  blood,  and  generally  the  left  ventricle  is  found  enlarged 
and  its  wall  thickened,  but  without  necessarily  producing  any  change  in  the 
pulmonary  circulation  or  the  right  heart.  Extreme  defects  of  the  valves, 
especially  when  the  ring  of  muscle  in  the  conus  arteriosus  which  supports 
them  fails,  may  be  followed  by  failure  on  the  part  of  the  left  ventricle  to 
carry  on  the  great  excess  of  work  without  leaving  a  great  deal  of  residual 
blood  in  its  cavity.  Then  it  becomes  difficult  for  the  auricle  to  empty 
itself,  the  pulmonary  vessels  remain  partly  filled,  and  the  right  ventricle 
hypertrophies  in  the  attempt  to  drive  its  blood  through  them.  Compensa- 
tion is,  however,  maintained  in  aortic  insufficiency  much  better  than  in 
other  lesions,  and  death  often  comes  unexpectedly  from  a  final  sudden 
failure. 

Stewart  has  claimed  that  the  collapsing  character  of  the  pulse  is  due  to  the  rapid 
escape  of  blood,  not  by  regurgitation,  but  through  widened  peripheral  capillaries,  and 
that  in  view  of  the  very  slight  regurgitation  the  hypertrophy  of  the  left  ventricle  is  due 
to  its  exposure  to  the  diastolic  pressure  of  the  aorta.  These  results  I  have  not  been 
able  to  accept,  although  the  last  statement  implies  a  regurgitation  during  diastole. 

Aortic  Stenosis. — Aortic  stenosis  (Fig.  239),  produced  by  thickening  and 
fusion  of  the  aortic  valves,  narrows  the  aortic  orifice  so  as  to  offer  a  mechan- 
ical obstruction  to  the  expulsion  of  blood;  usually  since  the  valves  are 
incapable  of  closing  accurately  there  is  some  regurgitation  too.  The  blood 
is  forced  out  slowly  with  a  rasping  systolic  murmur,  producing  a  pulse 
which,  in  contrast  to  that  of  aortic  regurgitation,  is  small  and  rather  slow. 
Again,  the  increase  in  effort  is  felt  and  assumed  by  the  left  ventricle,  which 
hypertrophies  in  response  but  does  not  dilate.  It  is  not  until  it  finally 
fails  to  accomplish  its  momentary  task  of  expelling  the  blood  that  residual 
blood  plus  that  from  the  auricle  overdistends  it,  and  it  becomes  difficult  for 
the  auricle  to  empty  itself.  In  both  aortic  insufficiency  and  stenosis  it 


CARDIAC    VALVULAR   DISEASE   AND   ITS   CONSEQUENCES         479 

seems  inevitable  that  the  coronary  circulation  should  be  impaired  in  the 
extreme  degrees  of  the  disease,  thereby  weakening  the  heart  itself. 

Mitral  insufficiency  (Fig.  240)  gives  rise  to  rather  complicated  and 
extensive  disturbances  of  the  circulation,  because  the  ventricles,  the  effec- 
tive compensating  mechanisms,  are  put  at  a  disadvantage.  Part  of  the 
blood  received  by  the  left  ventricle  rushes  back  into  the  auricle  during 
systole,  producing,  as  usual,  an  audible  murmur.  This  diminishes  the 
amount  available  for  the  aorta  and  distends  the  auricle  and  pulmonary 
veins.  The  right  ventricle  drives  its  blood  into  this  partly  filled  pul- 


Fig.  239. — Aortic  stenosis  with  hypertrophy  of  the  left  ventricle. 

monary  circulation  with  increased  effort,  and  in  time  hypertrophies.  The 
pulmonary  circulation  remains  overdistended,  and  the  left  auricle,  laboring 
with  blood  under  higher  pressure  and  in  increased  amount,  dilates  and 
hypertrophies. 

The  left  ventricle,  too,  takes  part  in  the  compensatory  process,  and 
dilates  to  receive  an  excess  of  blood  until  it  can,  in  addition  to  the  regurgi- 
tant  amount,  throw  out  a  nearly  normal  quantity  into  the  aorta.  Conse- 
quently the  left  ventricle  dilates  and  hypertrophies.  The  pulsation  pro- 
duced by  the  systolic  regurgitation  is  felt  through  the  pulmonary  circuit, 
and  the  wave  impinges  upon  the  wall  of  the  right  ventricle  before  its  valves 


480 


TEXT-BOOK   OF   PATHOLOGY 


are  closed.  In  a  sense  the  right  ventricle  is  working  against  the  left, 
which  doubtless  contributes  to  the  need  for  hypertrophy.  Compensa- 
tion begins  to  fail  through  the  final  inability  of  the  left  ventricle  to  expel 
all  the  blood  brought  to  it,  and  the  emptying  of  the  left  auricle  and  the 
pulmonary  veins  is  embarrassed.  The  same  obstruction  is  felt  by  the 
right  side  of  the  heart,  and  with  the  dilatation  of  the  right  ventricle  which 
may  follow,  a  relative  insufficiency  of  the  tricuspid  valves  can  arise — that 
is,  the  tricuspid  ring  becomes  so  wide  that  the  normal  valves  are  too  small 
to  close  it.  Doubtless,  however,  here,  as  in  the  case  of  the  mitral  valve, 
the  failure  of  the  usual  muscular  support  of  the  valves  which  helps  to  close 
the  orifice  contributes  largely  to  the  insufficiency.  Such  relative  insuffi- 


Fig.  240.— Mitral  insufficiency.     The  valves  are  thickened  and  shortened,  and  the 
chordae  tendineae  are  heavier  than  normal,  but  there  was  no  actual  stenosis. 

ciency  or  even  the  difficulty  which  the  right  ventricle  finds  in  expelling  all 
its  contents  into  the  overdistended  pulmonary  circulation  will  impede  the 
outflow  of  the  systemic  venous  blood,  and  a  general  chronic  passive  con- 
gestion ensues.  The  patient  becomes  cyanotic  and  very  short  of  breath, 
with  a  cough  which  expels  sputum  tinged  brown  by  the  presence  of  pig- 
mented  cells.  (Edema  of  the  extremities  and  the  body  and  effusion  into 
the  serous  sacs  follow.  The  end  is  usually  brought  about  by  continued 
lilatation  of  the  heart  and  final  failure,  although  temporary  recovery  with 
partial  disappearance  of  the  symptoms  may  take  place  over  and  over. 
Such  decompensation  or  break  in  compensation  is  also  a  feature  of  other 
forms  of  valvular  disease. 


CARDIAC    VALVULAR   DISEASE   AND    ITS    CONSEQUENCES         481 

Mitral  Stenosis. — The  narrowing  and  rigidity  of  the  mitral  valves 
(Fig.  241)  present  an  obstacle  to  the  outflow  of  blood  from  the  auricle 
into  the  left  ventricle.  Usually  the  change  in  the  valves  is  such  that  the 
orifice  is  bounded  by  thick,  precipitous  edges,  which  may  fit  together  fairly 
well  if  they  can  move  into  approximation — otherwise  if  they  are  rigidly 
held  apart  there  is  necessarily  mitral  insufficiency  combined  with  the 
stenosis.  This  is  the  usual  condition,  and  is  really  avoided  only  in  those 
rare  cases  in  which  a  delicate  film  persists  past  the  line  of  rigidity  and  calci- 
fication, capable  of  completing  the  closure.  The  narrowing  of  the  actual 


Fig.  241. — Mitral  stenosis  with  great  hypertrophy  of  the  left  auricle,  which  has  been  cut 
across.      Stenosis  of  the  tricuspid. 

orifice  through  which  all  the  blood  must  pass  may  be  extreme,  so  that  a 
mere  crescentic  slit  is  left  with  rigid  margins  only  a  few  millimetres  apart, 
and  it  is  wonderful  that  life  can  be  maintained  until  this  is  developed. 
Globular  thrombi  formed  in  the  auricle  may  sometimes  add  to  the  obstruc- 
tion, or  even  suddenly  complete  it  by  plugging  the  mitral  orifice. 

With  such  difficulty  in  expelling  its  blood  the  left  auricle  dilates  and 

becomes  hypertrophied.     The  blood  is  driven  through  the  narrow  hole  and 

produces  a  thrill  and  a  simultaneous  presystolic  rough  murmur.     But 

much  of  it  fails  to  get  through  and  accumulates  in  the  pulmonary  vessels, 

32 


482  TEXT-BOOK    OF   PATHOLOGY 

where  the  circulation  is  accordingly  very  slow  and  under  a  high  pressure 
because  of  the  compensatory  activity  of  the  right  ventricle. 

The  effects  of  this  upon  the  lung  are  described  below,  but  the  right 
ventricle  must  obviously  hypertrophy.  If  it  does  so  adequately,  it  may 
prevent  the  appearance  of  any  symptoms  except  those  from  the  lung  if  the 
stenosis  is  not  extreme,  and  enough  blood  may  be  forced  through  to  allow 
the  left  ventricle  to  propel  a  satisfactory  quantity  into  the  aorta.  If  the 
orifice  is  so  narrowed  that  the  left  ventricle  receives  much  less  than  it 
should  handle,  its  wall  atrophies  and  it  shrinks  to  a  relatively  small  size 
as  compared  with  the  enlarged  and  thickened  left  auricle  and  right  ventricle 
in  the  same  case.  As  in  mitral  insufficiency,  a  final  break  in  compensation 
produces  cyanosis,  serous  effusions,  cough,  dyspnoea,  and  often  the  cough- 
ing-up  of  blood  from  the  lungs  (haemoptysis). 

Pulmonary  stenosis  is  nearly  always  a  congenital  anomaly,  and  is  one 
of  the  commonest  and  most  important  of  those  found  in  the  heart.  It 
is  generally  associated  with  other  imperfections,  such  as  an  open  foramen 
in  the  septum  ventriculorum.  Pulmonary  insufficiency  is  rare  and  some- 
times due  to  malignant  endocarditis. 

Tricuspid  regurgitation,  generally  due  to  a  relative  insufficiency  (though 
sometimes  caused  by  endocarditis),  is  often  secondary  to  lesions  on  the 
left  side  or  to  obstruction  in  the  pulmonary  circulation — it  causes  a  mur- 
mur and  pulsation  as  well  as  great  distension  of  the  systemic  veins. 
Tricuspid  stenosis  also  occurs,  and  is  accompanied  by  symptoms  generally 
resembling  those  of  mitral  stenosis,  i.  e.,  presystolic  murmur,  cyanosis, 
etc.,  but  this  is  less  significant,  as  it  is  usually  associated  with  valvular 
lesions  on  the  left  side. 

Indeed,  valvular  lesions  affecting  several  valves  at  once,  either  to  pro- 
duce insufficiency  or  stenosis  or  both,  are  the  rule  rather  than  the  exception, 
and  hence  in  the  calculation  of  the  effects,  complexities  arise.  It  is  possible 
that  one  lesion  may  partly  compensate  for  another,  although  such  com- 
pensation is  seldom  an  unmixed  good.  Mitral  stenosis  may  diminish 
the  regurgitation  if  added  to  mitral  insufficiency.  In  all  cases  the  outcome 
depends  largely  upon  the  extent  of  the  defect,  and  persons  with  definite 
valvular  lesions  go  on  leading  an  active  life  for  years  without  any  symp- 
toms because  the  strength  of  the  compensating  ventricles  is  not  too  greatly 
overtaxed. 

Compensation,  Cardiac  Hypertrophy,  Dilatation,  Decompensation. — It  is 
clear,  from  the  description  of  all  these  valvular  lesions,  that  in  each  case 
extra  work  is  demanded  of  the  heart,  and  that  while  this  task  is  some- 
times assumed  by  the  chamber  directly  behind  the  obstruction,  the  burden 
is  in  the  end  usually  felt  by  the  whole  heart.  When  blood  regurgitates  into 
a  chamber  so  that  it  must  dilate  to  accept  more  than  its  usual  quantity, 
it  does  so,  and  emptying  itself  with  the  next  systole,  it  rises  to  the  emergency 
by  the  use  of  its  reserve  power.  When  the  systolic  discharge  is  opposed 
by  a  stenosis,  the  chamber  again  uses  its  reserve  power  to  drive  out  the 


CARDIAC    VALVULAR   DISEASE   AND    ITS    CONSEQUENCES         483 

blood,  but  does  not  necessarily  dilate.  Such  work  at  high  tension  is  possible 
for  a  time  for  the  normal  heart,  as  we  see  every  day  in  people  who  make 
violent  muscular  efforts.  When  they  are  again  at  rest  the  heart  subsides 
to  its  normal  work  and  is  itself  unchanged.  In  its  growth  it  probably 
merely  maintains  its  proportion  to  the  body  musculature. 

It  is  different  with  such  an  effort  as  is  required  of  the  heart  by  a  valvular 
defect,  because  that  is  a  constant,  never-lifting  burden  which  weighs  on  the 
ventricle  wall  with  every  beat  night  and  day.  After  a  time  the  heart- 
wall  thickens  and  strengthens  itself,  probably  chiefly  by  an  enlargement 
of  the  muscle-fibres  rather  than  an  increase  in  their  numbers.  Its  reserve 
force  increases  in  proportion,  and  now  what  was  an  extreme  effort  near  to 
the  maximum  limit  for  the  normal  heart  is  a  moderate  achievement  for 
the  hypertrophied  one,  to  which  still  greater  putting  forth  of  strength  is 
possible  through  its  newly  advanced  reserve  power. 

This  has  not  been  agreed  upon  by  all  writers.  Martius  stated  that  while  the  abso- 
lute power  of  the  hypertrophied  heart  was  greater  than  that  of  the  normal,  neverthe- 
less, in  carrying  on  the  increased  work,  it  was  nearer  to  its  limit  of  endurance  than  the 
normal  heart  was  with  the  lesser  burden — in  other  words,  its  reserve  power  made  up  a 
relatively  small  part  of  the  new  strength.  But  Romberg  and  Hasenfeld  think  that  the 
hypertrophied  heart  is  just  as  alert  and  capable  as  the  normal  in  response  to  increased 
demands,  although  it  must  be  remembered  that  the  hypertrophied  heart  is  commonly 
working  at  an  increasing  disadvantage. 

Hypertrophy  is  usually  thought  of  as  the  response  to  increased  work,  and 
it  is  often  called  a  work  hypertrophy.  Although  this  does  not  explain  it, 
unless  perhaps  we  think  that  excessive  work  demands  an  increase  in  the 
metabolism  of  the  cell  and  thus  promotes  growth,  it  is  no  better  explained 
by  Horvath's  idea  that  growth  depends  on  stretching,  or  by  E.  Albrecht's, 
that  it  is  a  sort  of  inflammatory  process,  or  even  by  Loeb's  theory  of  the 
imbibition  of  water  with  subsequent  addition  of  new  material.  Stewart 
thought  it  due  to  injury  of  the  heart  muscle,  followed  by  enlargement  and 
scarring,  in  the  hypertrophy  produced  by  adrenaline  injections. 

The  attempts  at  explanation  of  cardiac  hypertrophy  on  other  grounds 
than  the  response  to  increased  work  have  been  made  chiefly  because  of  the 
cases  of  so-called  idiopathic  hypertrophy,  in  which  enormous  enlargement 
of  the  heart  appears  without  any  valvular  lesions  or  other  evident  obstruc- 
tion to  its  work.  Difficult  as  it  is  to  explain  these  cases,  the  suggestion  that 
they  are  of  toxic  or  inflammatory  origin  seems  quite  unsatisfactory  unless 
abundant  scars  are  found  in  the  heart  muscle.  Then,  perhaps,  the  hyper- 
trophy of  the  remaining  muscle  might  effect  a  compensation  for  that  which 
was  lost.  But  still,  and  even  in  this  case,  the  only  acceptable  explanation 
seems  to  be  the  increased  demand  upon  the  muscle. 

Stewart  has  pointed  out  that  even  in  experimental  aortic  insufficiency,  where  the  left 
ventricle  encompasses  its  new  task  without  any  increase  in  pressure  in  the  auricles,  the 
walls  of  the  auricles  hypertrophy.  Whether  this  co-hypertrophy  is  quite  independent 


484  TEXT-BOOK   OF   PATHOLOGY 

of  obstruction  of  the  flow  of  blood  or  not  in  this  particular  case,  the  usual  cause  of  the 
hypertrophy  seems  to  be  the  extension  of  the  influence  of  the  obstruction  from  one  cham- 
ber to  another.  It  may  be  possible  for  the  ventricle,  in  the  case  of  aortic  insufficiency  of 
moderate  degree,  to  assume  all  the  new  work,  quickly  expanding  in  each  diastole  to  re- 
ceive the  original  normal  amount  of  blood  from  the  auricle,  as  well  as  the  amount 
regurgitated,  and  expelling  it  into  the  aorta,  but  even  here,  with  an  increase  in  the  extent 
of  the  insufficiency  of  the  valve,  as  well  as  the  hypertrophy  and  power  of  dilatation, 
there  might  occur  a  disparity  during  which  the  auricle  would  have  to  make  an  effort, 
perhaps  partly  unsuccessful,  to  force  all  its  blood  into  the  ventricle.  Then  arises  the 
need  for  auricular  hypertrophy.  But  aortic  insufficiency  is  well  known  to  be  the  best 
compensated  of  valvular  lesions.  In  mitral  insufficiency  the  auricle  must  hyper- 
trophy, the  right  ventricle  must  hypertrophy,  and  as  soon  as  it  fails,  in  the  way  just 
described,  the  right  auricle  feels  the  strain.  Combined  insufficiencies  of  the  valves  are 
even  more  certainly  followed  by  a  distribution  of  the  excess  of  work  all  through  the 
heart. 

Thus  no  compensation  restores  the  circulation  to  its  original  condition. 
In  every  case  some  part  of  the  heart  is  working  at  a  disadvantage,  either 
against  abnormal  resistance  or  with  an  excessive  proportion  of  the  blood. 
Slowing  of  the  pulse-rate  may  sometimes  aid  in  compensating  the  first  of 
these,  while  an  addition  to  the  amount  of  the  blood  in  circulation  may 
make  up  for  the  blood  which  [lingers  in  the  heart  or  in  the  pulmonary 
vessels,  so  that  the  aorta  is  once  more  normally  filled.  But  such  defects- 
as  mitral  insufficiency  or  stenosis  can  hardly  be  completely  compensated, 
for  in  all  cases  there  remains  the  overfilling  of  the  vessels  of  the  lungs. 

At  best  all  these  compensations  are  subject  to  the  probable  increase  in 
the  severity  of  the  valvular  lesion  itself,  and  to  the  fact  that  their  defi- 
ciencies, such  as  the  constant  congestion  of  the  lungs  in  mitral  disease, 
may  be  aggravated  to  an  intolerable  degree  by  muscular  effort  or  psychic 
disturbance  which  would  be  scarcely  felt  by  a  normal  person. 

Failure  of  compensation  is,  then,  an  impending  danger  in  all  these  cases, 
and  while,  as  we  have  seen,  the  hypertrophied  heart  is  stronger  both  in  its- 
ordinary  and  its  reserve  power  than  the  normal,  there  are  many  ways  in 
which  it  can  be  overtaxed.  Besides  muscular  exertion  and  psychic  excita- 
tion, which  have  been  mentioned  and  which  in  general  the  patient  with  a 
cardiac  defect  must  sedulously  avoid,  there  must  be  mentioned  all  the 
diseased  conditions  of  the  heart  muscle  which  have  been  described  above, 
and  which  are  particularly  common  in  hypertrophied  hearts.  Those 
which  are  acutely  produced  in  such  hearts  must  weaken  the  walls  through 
destruction  of  muscle-fibres.  Scars  and  old  remains  of  such  injuries  in- 
dicate rather  that  that  danger  has  been  survived,  and  probably  that  part 
of  the  hypertrophy  has  arisen  to  make  up  for  the  fibres  whose  loss  they 
signalize.  Nevertheless,  such  a  scarred  heart  is  weakened  and  subject 
especially  to  the  influences  which  conduce  to  failure.  Sclerosis  of  the 
coronary  arteries  is  particularly  important  in  restricting  the  nutrition  of 
the  heart-wall,  and  sudden  complete  failure  of  its  activity  may  follow  occlu- 
sion of  these  vessels  by  thrombi.  Surprising  degrees  of  sclerosis  are  sur- 
vived, however,  and  even  extensive  infarctions  of  the  wall. 


CARDIAC    VALVULAR   DISEASE   AND    ITS    CONSEQUENCES         485 

Perhaps  more  important  still  in  disturbing  compensation  in  such  a  hyper- 
trophied  heart  with  valvular  defects  is  the  functional  disturbance  of  the 
coronary  circulation,  either  when,  with  extreme  destruction  of  the  aortic 
valves,  the  entrance  of  blood  into  the  coronary  arteries  is  deficient,  or  when 
great  accumulation  of  blood  under  high  pressure  in  the  right  heart  and 
systemic  veins  impedes  the  return  of  the  coronary  blood  into  the  right 
auricle.  The  wall  of  the  heart  suffers  then  a  chronic  passive  congestion 
which  involves  malnutrition,  and  it  fails  through  the  action  of  this  vicious 
circle. 

Extraneous  influences,  such  as  chronic  nephritis,  extreme  arteriosclerosis, 
pericardial  effusions  and  adhesions,  advancing  pulmonary  disease  with 
obliteration  of  vessels,  pleural  adhesions,  etc.,  may  gradually  heap  more 
work  on  the  heart  until,  in  spite  of  its  hypertrophy,  it  is  unable  to  keep  up 
its  activity.  Whether  it  can  stop  from  sheer  weariness  and  exhaustion 
one  can  hardly  say,  but  it  seems  probable. 

The  first  effect  of  failure  of  the  heart-wall  to  meet  the  demand  is  the 
accumulation  of  blood  in  its  cavities  and  its  passive  dilatation.  Unlike  the 
competent  ventricle  which  expands  and  sucks  in  an  excess  of  blood  which  it 
readily  expels,  the  wall  is  overstretched  and  incapable  of  closing  completely 
on  the  blood  in  its  cavity.  For  some  time  it  may  continue  to  drive  out 
part,  dilating  again  to  receive  more,  so  that  thus  a  feeble  circulation  is 
maintained.  Sometimes,  especially  with  the  administration  of  drugs,  it 
may  recover  and  return  to  its  former  competency,  but  often  it  only  grows 
weaker  and  finally  stops  beating,  hugely  distended  with  the  accumulated 
blood.  It  is  in  the  course  of  such  dilatation  that  the  muscle  of  the  auricu- 
loventricular  orifices  fails  to  support  the  valves  by  narrowing  those  orifices, 
and  relative  insufficiencies  with  regurgitation  occur.  Extreme  distension 
of  the  veins  results,  with  cyanosis  and  often  with  dropsy.  Profound  dysp- 
noea attends  the  same  condition  in  the  lungs,  and  the  patient  lies  helpless 
and  gasping,  propped  up  in  bed  until  death  or  one  of  the  temporary  re- 
coveries relieves  him.  Lewis  and  his  colleagues  have  recently  suggested 
that  such  dyspnoea  is  identical  with  renal  dyspnoea,  and  due  to  the  produc- 
tion of  acids  other  than  carbonic  acid.  Peabody,  however,  in  his  important 
discussion  of  cardiac  dyspnoea,  to  which  the  reader  is  referred,  states  that 
acidosis  plays  no  part  in  the  dyspnoea  of  pure  cardiac  disease  except  in 
the  extreme  stages  of  decompensation,  while  in  cases  in  which  the  cardiac 
disability  is  complicated  by  renal  disease  acidosis  becomes  more  significant 
in  that  it  renders  the  patients  unusually  susceptible  to  the  production  of 
dyspnoea  by  exertion.  In  general,  the  tendency  to  dyspnoea  depends  upon 
a  diminution  of  the  patient's  pulmonary  reserve,  that  is,  a  decrease  in  the 
maximum  volume  of  air  which  he  is  capable  of  breathing  in  its  relation  to 
the  volume  of  air  which  he  breathes  while  at  rest.  The  vital  capacity  or 
volume  of  air  which  can  be  expired  after  the  greatest  possible  inspiration 
may  be  decreased  during  cardiac  decompensation  by  many  factors  which 
limit  the  expansion  of  the  lungs  so  that  the  margin  of  safety  is  narrowed. 


486 


TEXT-BOOK   OF   PATHOLOGY 


The  question  of  dyspnoea  in  heart  disease  is  shown  to  be  much  more  compli- 
cated than  we  suspected,  and  our  knowledge  is  still  incomplete. 

Chronic  Passive  Congestion. — From  what  has  been  said  regarding  the 
overdistension  of  the  pulmonary  and  systemic  veins  and  the  consequent 
slowing  of  the  circulation  of  at  least  part  of  that  blood,  one  might  expect 
to  find  changes  in  the  tissues  so  supplied.  With  increasing  failure  of  com- 
pensation the  veins  become  more  and  more  dilated  by  the  increasing  pres- 
sure of  the  blood,  and  less  arterial  blood  is  driven  through  the  tissues  into 
them.  The  capillaries  are  widened  and  pulsation  passes  into  them — the 
tissues  assume  a  deep  bluish  color  and  the  veins  stand  out  tensely.  In 
places,  as  in  the  subcutaneous  tissues  of  the  legs,  they  are  irregularly  dilated 
and  tortuous.  Everywhere  there  is  malnutrition  of  the  tissues,  accom- 
panied by  certain  pressure  effects  from  the  widening  of  the  veins  and 
capillaries.  Neither  nutritive  nor  gaseous  exchange  is  carried  on  as  it 


"  "^Sff^^^i 
f'^:;- ??£$--&£    ^fo^^v?^--^  *  *(.&- " 

\S»»l!v-    ^m^     te-v. 

Fig.  242. — Chronic  passive  congestion  of  the  lung  with  induration  and  muscular  hyper- 
trophy.    Some  alveoli  contain  the  pigmented  "heart  failure  cells." 

should  be,  and  doubtless  excretory  products  accumulate  there.  An  almost 
universal  result  associated  with  the  injurious  effects  upon  the  more  sensi- 
tive tissues  is  the  new  formation  of  connective  tissue  in  the  congested  and 
cyanotic  organs. 

The  Lungs. — The  lungs  are  most  readily  affected  in  mitral  insufficiency 
and  stenosis  when  compensation  fails,  and  in  myocardial  disease,  but  local 
congestion  may  appear  with  the  same  results  in  collapsed  areas  of  a  lung 
on  account  of  the  kinking  of  the  venules  and  obstruction  of  the  return  flow 
of  blood.  The  capillaries  in  the  alveolar  walls  become  greatly  dilated  and 
tortuous,  so  that  they  project  in  loops  into  the  alveolar  cavities.  Gross- 
man and  von  Basch  speak  of  a  sort  of  rigidity  of  the  lung  produced  by  this 
overfilling.  The  alveolar  epithelium  is  ill  nourished,  and  very  many  of  the 


CARDIAC   VALVULAR   DISEASE    AND    ITS    CONSEQUENCES         487 

cells  are  desquamated  into  the  air-cell;  fluid  exudes  from  the  tense  capil- 
laries, often  with  red  blood-corpuscles.  These  quickly  disintegrate,  and 
hsemosiderin  is  formed  from  their  haemoglobin  and  taken  up  by  the  phago- 
cytic  epithelial  cells.  Such  cells,  when  desquamated,  are  large  and  round, 
and  often  fairly  loaded  with  this  brown  pigment  in  clumps  and  granules. 
They  are  coughed  up  in  the  sputum,  and  give  a  clinical  indication  of  the 
existence  of  disease  of  the  heart  with  pulmonary  congestion,  for  which 
reason  they  are  called  heart-failure  cells.  In  the  lungs  they  are  generally 
sufficiently  numerous  to  give  a  distinct  rusty  color  to  the  cut  surface 
(cf.  Fig.  13). 

As  to  the  origin  of  these  cells,  there  is  room  for  discussion  because  it  is  not  perfectly 
clear  that  they  are  epithelial  cells  which  have  become  phagocytic.  Although  this  is  the 
generally  accepted  idea,  one  finds  in  many  cases  that  the  cells  which  can  be  recognized 
with  certainty  as  epithelial  from  their  position  in  a  layer  on  the  alveolar  wall,  are  not  at 
all  pigmented,  although  the  alveolus  is  full  of  the  phagocytic  cells.  Further,  the  fact 
that  the  pigmented  cells  are  found  wandering  in  the  perivascular  tissues  of  the  lung 
suggests  their  closer  relation  to  the  large  wandering  mononuclear  cells  which  are  the 
usual  phagocytes  in  other  tissues. 

The  smooth  muscle  in  the  septa  that  form  the  vestibules  in  each  lobule 
is  greatly  increased  in  bulk,  and  the  alveolar  walls  in  extreme  cases  become 
thickened  and  indurated  by  the  appearance  of  new  connective  tissue  (brown 
induration  of  the  lung — Fig.  242). 

The  sluggishness  of  the  circulation  which  causes  such  general  malnutri- 
tion makes  it  impossible  for  one  arterial  branch  to  supply,  as  in  the  normal, 
nutrition  for  the  territory  of  another  which  may  be  plugged  by  an  embolus. 
Hence  it  is  that  heemorrhagic  infarctions  are  found  in  these  congested 
lungs  and  practically  only  there. 

Great  dyspnoea  usually  accompanies  such  chronic  passive  congestion, 
and  the  explanation  is  not  difficult  in  view  of  the  inadequate  aeration 
which  the  blood  receives  when  it  requires  so  long  to  send  all  of  it  through 
the  lungs. 

Such  lungs  at  autopsy  quickly  lose  any  bluish  color  they  may  have 
had;  instead,  they  are  usually  rather  pale,  sometimes  dry,  sometimes 
cedematous,  and  of  a  distinct  rusty  brown  color,  which,  on  the  applica- 
tion of  ferrocyanide  of  potassium  and  hydrochloric  acid  after  fixation, 
turns  to  an  intense  Prussian  blue  (Perl's  reaction  for  an  iron-containing 
pigment).  The  consistence  is  altered,  too,  and  the  lung  feels  dense  and 
elastic.  In  cases  of  long-standing  congestion,  especially  in  mitral  stenosis, 
where  the  pressure  in  the  pulmonary  vessels  has  been  high,  arterio- 
sclerotic  patches  in  the  pulmonary  artery  and  its  branches  are  common. 

The  Liver. — When  the  systemic  veins  are  overdistended  for  a  long  time, 
the  liver  is  among  the  first  organs  to  exhibit  the  effects.  It  is  enlarged  so 
that  it  may  be  felt  extending  below  the  costal  margin,  and  often  it  pul- 
sates. At  autopsy  it  projects  as  a  tense  bluish  mass  in  which  the  impress 


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of  a  finger  remains  for  a  little  and  is  slowly  filled  up.  On  cutting  the 
great  veins  the  liver  often  visibly  collapses  and  loses  its  uniform  dark 
color,  assuming  a  lobular  mottling.  On  section  this  is  extremely  bright 
and  distinct,  the  alternation  of  deep  red  and  yellow  or  gray  markings 
giving  rise  to  the  name  "nutmeg  liver"  (Fig.  243). 

Close  examination  of  the  cut  surface  with  a  lens,  if  necessary,  or  of  a 
thick  frozen  section  without  staining,  shows  that  the  ordinary  lobular 


Fig.  243.— Chronic  passive  congestion  of  the  liver  (nutmeg  liver). 

markings  are  much  modified  by  the  conversion  of  so  much  of  the  tissue 

into  the  deep  red  zones.    Indeed,  in  places,  quite  extensive  patches  may  be 

homogeneously  red,  spongy,  and  ooze  blood.    The  grayish  yellow  islands 

J  found  to  surround  in  every  case  the  minute  twigs  of  the  portal  vein 

and  hepatic  artery,  a  gray  zone  lying  directly  against  the  vein,  and  then  a 

>nght  yellow  zone  which  passes  sharply  into  the  crimson.     Scattered  in 

ie  anastomosing,  irregular  crimson  bands  there  are  often  sharply  outlined, 

opaque,    orange-yellow    flecks.      Microscopical    study    explains    all    this 


CARDIAC   VALVULAR   DISEASE   AND   ITS    CONSEQUENCES         489 

promptly.  (See  Fig.  145.)  It  is  the  lobule  of  Sabourin  which  is  outlined 
and  preserved  in  part  as  the  pale  islands — that  is,  for  a  certain  distance 
around  the  afferent  portal  vein  and  hepatic  artery  the  liver-cells  are  pre- 
served. Those  nearest  are  well  preserved  and  show  gray;  further  out  they 
are  injured  and  loaded  with  refractive  yellow  fat-globules.  Still  further 
they  are  dead,  and  in  so  far  as  patches  of  dead  cells  sometimes  remain, 
appear  as  opaque,  orange-colored  flecks  (colored  somewhat  by  blood-pig- 


Fig.  244. — Chronic  passive  congestion  of  the  liver.      Necrosis  of  the  cells  about  the 

efferent  vein. 


ment).  But  in  this  region  the  overwhelming  distension  of  the  capillaries 
with  venous  blood  and  the  escape  of  that  blood  into  the  intercapillary 
spaces  formerly  occupied  by  the  liver-cells  converts  the  whole  tissue  into 
a  blood-filled  sponge  in  which  only  the  framework  and  capillary  walls 
remain,  with  some  debris  of  cells. 


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'  Referred  to  the  old  idea  of  the  lobule,  we  must  say  that  the  blood-filled  portion  lies 
about  the  central  or  efferent  vein,  but  that,  owing  to  the  course  of  the  capillaries  (cf. 
p.  297),  it  maintains  a  distribution  equidistant  from  the  portal  vein,  and  hence  extends 
from  lobule  to  lobule. 

Ordinarily  all  this  is  thought  to  be  caused  by  the  increased  pressure  of 
the  venous  blood  in  the  capillaries,  which  is  said  to  be  felt  with  especial 
force  in  the  liver  because  it  is  near  the  heart,  but  I  think  that  these  dying 


*  .v  >  -  ."<"«   **  V «?«  ^   °'  $  »*»*»  **V  •••••*•      -  %' 


Fig.  244A.— Chronic  passive  congestion  of  Uver  with  dilatation  of  capillaries.    Atrophy 
of  liver  cells  without  necrosis.     (Lambert  and  Allison.) 

cells  (Fig.  244)  in  no  way  resemble  compressed  cells,  such  as  one  sees 
about  a  tumor  in  the  liver,  nor  does  this  seem  a  plausible  explanation  from 
a  mechanical  point  of  view,  since  if  the  pressure  in  the  efferent  vein  were 
higher  than  that  in  the  portal  vein  and  hepatic  artery,  the  blood  must  run 
the  other  way.  On  the  contrary,  it  is  easier  to  believe  that  the  sensitive 
liver-cells  are  badly  nourished  by  the  sluggish  venous  stream,  and  that 
oxygenation  is  especially  interfered  with,  so  that  those  which  receive  the 


CARDIAC   VALVULAR   DISEASE   AND   ITS   CONSEQUENCES         491 

blood-stream  last  suffer  most  severely  and  in  time  disappear,  leaving  a 
space  which  is  then  filled  up  with  blood.  On  this  ground  the  gradual 
transition  from  practically  normal  cells  near  the  source  of  nutritive  supply 
through  fatty  to  necrotic  cells  may  be  explained. 


Fig.  244B. — Chronic  passive  congestion  of  the  liver,  Type  4.  Necrosis  and 
haemorrhage  about  the  efferent  vein,  with  a  narrow  zone  of  fatty  cells  surrounding  each 
necrotic  area.  (Lambert  and  Allison.) 


Mallory  regards  the  necrosis  of  the  cells  as  due  to  toxic  influences  usually  of  infectious 
origin  and  minimizes  the  effect  of  changes  in  blood-pressure.  Lambert  and  Allison, 
who  have  gone  over  the  literature  and  have  studied  112  cases  in  which  chronic  passive 
congestion  of  the  liver  was  well  marked,  divide  the  cases  into  five  groups  in  which  the 
lesions  are  as  follows:  (1)  capillary  dilatation  with  atrophy  of  the  cells  toward  the  centre 
of  the  lobule,  (2)  central  degeneration  with  or  without  capillary  dilatation,  (3)  marked 
fat  accumulation  in  the  cells  about  the  hepatic  veins,  with  midzonal  hypersemia, 
(4)  central  necrosis  with  haemorrhage,  and  (5)  collapse  fibrosis.  The  more  extreme  the 
stasis,  the  more  certain  is  the  central  necrosis  and  hemorrhage,  while  the  collapse 


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fibrosis  depends  naturally  upon  a  protracted  course.  They  too  think  the  necrosis  to 
depend  upon  stasis  alone  which  causes  asphyxia  in  the  most  distal  cells.  Infection  plays 
a  minor  part  if  any. 

The  Spleen. — The  most  striking  features  of  the  change  in  the  spleen 
wrought  by  chronic  passive  congestion  are  its  deep  purple  color  and  its 
extreme  hardness  (cyanotic  induration).  Enlargement  is  usually  moder- 
ate, and  the  great  increase  in  the  size  of  the  spleen  in  connection  with 


Fig.  245.— Chronic  passive  congestion  of  the  spleen.     Induration  of  the  tissues  between 
the  venules  renders  them  conspicuous. 

cirrhosis  of  the  liver  is  probably  due  to  other  causes  than  the  mere  con- 
gestion. The  capsule  is  tense  and  smooth,  and  the  cut  surface  stands 
firmly  at  right  angles  to  it,  neither  bulging  nor  sinking  into  a  concavity, 
as  in  so  many  enlargements  from  other  causes.  Malpighian  bodies, 
trabeculae,  and  vessels  stand  out  sharply  in  the  background  of  the  smooth, 
deep  purple,  splenic  pulp.  Microscopically  (Fig.  245)  one  is  impressed 
by  the  great  clearness  with  which  the  splenic  venules  or  sinuses  are  out- 
lined. Their  walls  are  thickened  so  as  to  present  themselves  as  very  defi- 


CARDIAC   VALVULAR   DISEASE   AND   ITS    CONSEQUENCES         493 

nite  membranes  lined  with  endothelium,  and  every  one  is  distended  with 
blood.  In  the  interstices  there  is  a  moderate  increase  in  the  connective- 
tissue  framework,  but  no  great  accumulation  of  the  cells  of  the  pulp. 

The  kidney  in  such  chronic  congestion  is  sometimes  little  altered,  since, 
as  has  been  said,  the  effect  of  circulatory  obstruction  is  often  very  unequally 
distributed.  But  the  characteristic  change  is  a  notable  swelling,  with 
extreme  rubbery  hardness,  such  that  the  kidney  tissue  will  snap  away 


Fig.  246. — Haemorrhoids.     Vertical  section  showing  distended  vein  near  anus,  partly 

occluded  by  a  thrombus. 

from  between  the  fingers  and  almost  rebound  if  dropped.  The  whole 
organ  is  deep  purplish  gray  in  color,  the  surface  smooth,  the  capsule  not 
adherent,  and  on  section,  in  the  thick,  grayish-purple  cortex,  one  sees  the 
striations  with  startling  distinctness,  the  blood-vessels  and  glomeruli 
standing  forth  prominently  in  deep  red,  while  the  tubular  portions  are 
opaque  and  gray.  The  pyramids  are  also  deeply  reddened. 

Microscopically  little  more  is  to  be  seen — the  capillaries,  especially  of  the 


494  TEXT-BOOK   OF   PATHOLOGY 

glomeruli,  are  distended  with  blood,  and  there  may  be  some  coagulated 
fluid  in  Bowman's  capsules  or  hyaline  casts  in  the  tubules.  The  tubular 
epithelium  shows  perhaps  a  moderate  degree  of  cloudy  swelling,  but  even 
this  need  not  be  marked.  Interstitial  connective-tissue  increase  may 
occur  in  extreme  cases,  but  it  is  scarcely  evident,  as  a  rule,  and  it  seems  that 
the  hardness  is  chiefly  due  to  the  distension  with  blood. 

In  contrast  to  this  indefinite  microscopical  picture  the  functional  changes 
are  very  marked.  By  itself  chronic  passive  congestion  can  lead  to  the 
excretion  of  albumin  and  casts  of  various  sorts  in  the  urine,  and  also  to  dis- 
tinct disturbances  in  the  function  of  the  kidney  with  regard  to  the  excre- 
tion of  water,  salt,  and  other  substances,  for  which,  as  is  well  known,  the 
kidney  has  specific  powers  of  secretion. 

It  is  particularly  important  to  estimate  the  part  played  by  such  con- 
gestion in  producing  the  derangements  found  in  cases  of  chronic  nephritis 
complicated  by  heart  disease,  for  they  can  particularly  aggravate  the 
deficiencies  of  an  already  disabled  renal  function.  If,  then,  there  is  hope 
of  relieving  the  factor  of  chronic  passive  congestion,  the  outlook  for  the 
patient  is  greatly  improved. 

Similar  conditions  of  malnutrition  with  overdistension  of  the  vessels 
are  found  in  all  other  organs.  In  the  stomach  and  intestine  they  lead  to 
moderate  digestive  disturbances,  often  with  excessive  secretion  of  mucus 
and  with  desquamation  of  many  epithelial  cells.  In  the  rectum  the 
enlargement  of  the  veins  produces  the  painful  hemorrhoids,  which  often 
bleed  and  in  time  cause  an  extreme  anaemia  (Fig.  246).  They  are,  however, 
perhaps  more  often  due  to  local  conditions  and  especially  to  obstinate  con- 
stipation. In  the  limbs  we  find  the  varicose  veins  mentioned  above,  often 
associated  with  such  derangements  of  the  nutrition  of  the  tissues  that  great 
ulcerations  that  refuse  to  heal  appear  over  the  shins. 

LITERATURE 

v.  Basch:  Allg.  Phys.  u.  Path,  des  Kreislaufes,  Wien,  1892. 

MacCallum:   Johns  Hopkins  Hosp.  Bull.,  1906,  xvii,  251. 

MacCallum  and  McClure:    Ibid.,  260  (mitral  insufficiency). 

Martius:  Erg.  d.  allg.  Path.,  1895,  i2,  38. 

Krehl:  Pathologische  Physiologic,  1912,  Nothnagel's  Spec.  Path.  u.  Therap.,  xv,  Th.  1, 
Abth.  5. 

Hasenfeld  and  Romberg:  Arch.  f.  exp.  Path.,  1897,  xxxix,  333. 

Moritz  and  Tabora:  Krehl  and  Marchand:  Handb.  d.  allg.  Path.,  1913,  ii. 

Thorel:  Ergeb.  d.  allg.  Path.,  1903,  ixx,  559;  1907,  xi2,  694;  1911,  xiv2, 133;  1915,  xvii2, 90. 

MacCallum:   Johns  Hopkins  Hosp.  Bull.,  1911,  xxii,  197  (aortic  insufficiency). 

Stewart:    Arch.  Int.  Med.,  1908,  i,  102  (aortic  insufficiency). 

Stewart:  Jour.  Exp.  Med.,  1911,  xiii,  187;  Jour.  Path,  and  Bact.,  1912,  xvii,  64  (hyper- 
trophy). 

E.  Albrecht:  Die  Herzmuskel,  Berlin,  1903. 

Aschoff  and  Tawara:    Grundlagen  der  Herzschwache,  Jena,  1906. 

Lewis  and  others:  Heart,  1913,  v,  45;  1914,  v,  367. 

Peabody:  Amer.  Jour.  Med.  Sci.,  1918,  civ,  100. 

Lambert  and  Allison:  Johns  Hopkins  Hosp.  Bull.,  1916,  xxvii,  350. 


PATHOLOGY   OF   THE    CONDITION   BUNDLES   OF   THE   HEART     495 

PATHOLOGY  OF  THE  CONDUCTION  BUNDLES  OF  THE  HEART 

Until  quite  recently  the  study  of  the  diseases  of  the  heart  concerned 
chiefly  the  mechanical  results  of  distortion  of  the  valves,  of  weakening  of 
the  muscle,  etc.,  but  the  extraordinary  discovery  of  His,  Keith  and  Flack, 
Tawara,  and  others  of  an  unsuspected  connecting  system  of  specialized 
strands  of  muscle  stretching  from  one  part  of  the  heart  to  another  has 
opened  a  new  field  for  this  study.  It  quickly  became  apparent  that  these 
strands,  like  the  electric  signals  in  an  engine-room,  or  like  nerves,  con- 
trolled from  a  central  station  the  activities  of  other  parts  of  the  heart,  and 
at  once  there  was  hope  of  clearing  up  the  obscure  chapter  of  the  disturb- 
ance of  its  rate  and  rhythm.  This  hope  has  not  been  disappointed,  and 
with  the  aid  of  several  new  technical  methods  it  has  become  possible  to 
study  with  extreme  accuracy  all  these  disturbances  and  to  explain  them 
clearly.  Most  of  these  results  have  been  worked  out  experimentally  in 
animals,  after  which  cases  have  been  found  in  human  beings  which  cor- 
respond so  exactly  to  the  experimental  results  as  to  make  diagnosis  easy 
and  certain. 

The  conduction  system  (Fig.  247)  consists  of:  (1)  An  elongated  node 
(the  sino-auricular  node  of  Keith  and  Flack),  which  lies  in  the  angle 
between  the  superior  vena  cava  and  the  right  auricle,  extending  downward 
for  a  distance  of  one  to  two  centimetres  along  the  sulcus  terminalis;  (2)  a 
second  node  or  mass  of  tissue  lying  at  the  posterior  and  lower  part  of  the 
right  auricle,  just  in  front  of  the  coronary  sinus.  This  gives  rise  to  the 
main  stem  of  the  conduction  bundle  which  extends  along  the  interauricular 
septum  forward  and  to  the  left  until  it  reaches  the  septum  membranaceum 
behind  the  tricuspid  valve.  There  it  follows  the  lower  part  of  this  septum, 
thus  lying  at  the  upper  margin  of  the  muscular  portion  of  the  interventric- 
ular  septum,  and  runs  forward  to  divide  into  two  main  branches,  one  of 
which  continues  under  the  endocardium  of  the  right  ventricle  toward  its 
apex.  The  other  branch  pierces  its  way  into  a  similar  situation  in  the  left 
ventricle.  The  node,  in  which  Aschoff  has  recently  distinguished  two  parts, 
is  the  auriculoventricular  node  of  Tawara,  while  the  continuation  across 
the  septum  membranaceum  into  the  two  branches  is  the  bundle  of  His. 
These  branches  subdivide  to  distribute  themselves  throughout  the  muscle 
of  the  ventricles,  especially  stout  branches  passing  to  the  papillary  muscles. 
In  spite  of  patient  search  no  definite  specialized  connections  have  been 
found  in  the  auricular  walls  between  the  sino-auricular  and  the  auriculo- 
ventricular nodes. 

These  nodes  and  bundles  are  composed  of  muscle-fibers  of  a  peculiar 
kind,  very  narrow,  striated,  with  numerous  nuclei  and  rich  in  glycogen. 
In  the  nodes  they  are  matted  together,  but  in  the  fasciculi  they  lie  parallel. 
They  form  no  direct  connection  with  the  musculature  of  the  heart,  but 
unite  with  the  Purkinje  fibres,  which  are  large,  pale,  faintly  striated  fibres 
lying  just  under  the  endocardium,  and  which  in  turn  unite  with  the  ordinary 
muscle-fibres.  Numerous  nerve-fibres  are  interwoven  with  the  muscle- 


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fibres  of  the  bundle  of  His  and  of  the  nodes,  so  that  it  is  impossible  to  exclude 
the  participation  of  the  nervous   system   in  their  activities.     All  these 


Fig.  247.— Diagrammatic  representation  of  the  conduction  system:    1,  Sino-auricular 
node;  2,  atrio ventricular  node;  3,  bundle  of  His. 

structures  are  enclosed  in  connective  tissue  and  fat   and  are  supplied  by 
special  arteries. 


PATHOLOGY   OF   THE    CONDUCTION   BUNDLES   OF   THE    HEART      497 

In  the  embryo,  when  the  heart  has  the  form  of  a  curved  tube,  and  before 
the  ingrowth  of  any  nerves  has  occurred,  a  sort  of  peristaltic  contraction 
wave  takes  place.  Although  the  ingrowth  of  the  epicardium  to  form  the 
central  lamina  of  the  auriculoventricular  valves  interrupts  in  mammals 
most  of  the  connection  between  auricular  and  ventricular  muscle,  a  por- 
tion of  the  continuous  musculature  remains  and  becomes  specialized  as  the 
specific  conduction  bundle.  The  function  of  this  system  has  been  clearly 
shown  by  numerous  experiments  to  lie  in  the  initiation  and  propagation 
of  the  normal  impulses  which  set  in  motion,  in  an  orderly  way,  the  muscu- 
lature of  the  heart.  The  impulse  begins  normally,  as  shown  by  the  experi- 
ments of  Lewis  and  others,  in  the  sinu-auricular  node  of  Keith,  and  spreads 
thence  to  the  auriculoventricular  node,  whence  it  is  transmitted  to  the 
ventricle  by  the  bundle  of  His.  The  heart  muscle  itself  is  excitable  and 
capable  of  conducting  the  impulse;  its  excitability  is  such  that,  however 


Fig.  248. — Simultaneous  tracings  of  the  jugular  pulse,  the  carotid  pulse,  and  the  apex- 
beat  (Bachmann,  from  Howell). 

great  or  slight  the  impulse  which  is  capable  of  causing  a  contraction,  that 
contraction  is  a  maximal  one.  On  the  other  hand,  having  once  con- 
tracted, the  muscle  enters  on  a  refractory  phase,  during  which  no  stimulus 
will  provoke  a  contraction.  These  peculiarities  account  for  some  of  the 
phenomena  of  disturbance  in  rhythm  to  be  described. 

The  movements  of  the  heart  normally  follow  one  another  in  an  orderly 
succession,  and  at  a  regular  rate  which  can  be  accurately  studied  in  various 
ways.  In  addition  to  the  auscultation  of  the  heart  and  the  palpation  of 
the  pulse,  which  give  only  rough  information,  tracings  are  made  by  means 
of  the  sphygmograph  or  polygraph  to  show  simultaneously  the  pulsations 
of  the  radial  or  of  the  apex  of  the  heart,  and  of  the  jugular  vein.  Such 
33 


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tracings  are  supplemented  by  electrocardiographic  tracings,  which  give 
a  clear  idea  of  the  movements  of  the  heart.  When  we  compare  the  trac- 
ings from  the  jugular  with  those  from  the  carotid  (Fig.  248),  it  is  found  pos- 
sible to  recognize  in  the  jugular  tracings  a  wave  (a)  which  is  due  to  a  contrac- 
tion of  the  auricle,  a  second  or  c  wave  (s),  caused  in  part  by  changes  in 
pressure  in  the  auricle  at  the  closure  and  lifting  up  of  the  tricuspid  valves, 
and  in  man  also  by  the  transmitted  carotid  pulse,  and  a  third  (v)  which 


Fig.  249.* — Electrocardiogram  from  a  normal  person  showing  the  orderly  sequence  of 
waves  which  have  been  distinguished  arbitrarily  by  letters  P,  R,  T,  etc.  In  the  second 
curve,  which  is  spread  over  a  greater  space  by  the  rapid  movement  of  the  paper,  there 
is  also  a  microphonographic  record  of  the  heart-sounds. 


represents  the  rilling  of  the  auricle  and  veins  during  the  latter  part  of  sys- 
tole, with  elevation  of  the  base  of  the  heart,  after  which  the  sudden  drop 
is  due  to  the  opening  of  the  tricuspid  valves. 

The  electrocardiogram  is  a  curve  made  by  photographing,  on  a  moving 
film,  the  shadow  of  a  fine  thread  of  silvered  quartz  stretched  between  the 

*  These  and  the  following  curves  were  kindly  given  me  by  Dr.  Horatio  Williams. 


PATHOLOGY   OF   THE    CONDUCTION   BUNDLES   OF   THE    HEART 

poles  of  a  magnet,  and  connected  by  its  ends  with  wires  leading  to  electrodes 
attached  to  the  two  arms  or  one  arm  and  a  leg  of  the  patient.  The  part 
of  the  heart  muscle  which  is  contracting  at  a  given  instant  becomes  electro- 
negative to  the  rest,  and  the  slight  electrical  current  thus  produced,  passing 
through  the  silvered  thread,  causes  it  to  be  deflected  toward  one  pole  or 
other  of  the  magnet.  In  the  tracing  there  is  recorded,  in  order,  the 
deflection  produced  as  the  wave  of  excitation,  i.  e.,  electronegativity, 
passes  through  the  heart.  The  result,  as  shown  in  Fig.  249,  gives  an 
elevation  (P)  representing  the  spread  of  the  excitation  wave  throughout 
the  auricular  musculature,  followed  immediately  by  auricular  contraction; 
a  high-pointed  elevation  (R),  the  descending  limb  of  which  goes  below  the 
line  (S),  and  later  another  rounded  elevation  (T).  The  latter  three  result 
from  the  spread  of  the  excitation  wave  throughout  the  ventricles.  This 
is  the  normal  curve,  and  any  abnormality  in  the  rhythm  is  at  once  visible 
in  the  curve  taken  from  the  irregularly  beating  heart. 

Irregularities  in  the  rate  and  rhythm  of  the  heart-beat  may  arise  either 
(1)  through  changes  in  the  rate  of  the  impulses  originating  in  the  sino- 
auricular  node,  and  normally  transmitted  through  the  rest  of  the  system 
(homogenetic  impulses) ;  (2)  through  changes  in  the  conducting  power  of  the 
bundle  of  His  or  other  part  of  the  system,  or  (3)  through  the  occurrence  of 
abnormal  impulses  starting  elsewhere  in  the  system  than  in  the  sino- 
auricular  node,  or  even  in  the  musculature  of  the  heart,  quite  outside  the 
conducting  system  (heterogenetic  impulses) . 

1.  Changes  in  Rate  of  Homogenetic  Impulses. — Tachycardia,  in  which 
the  cycle  of  the  heart-beat  is  normal,  but  in  which  the  beats  follow  one 
another  more  rapidly  than  normal,  arises  in  the  sino-auricular  node  after 
an  effort,  or  an  emotion,  or  in  the  course  of  fevers,  tuberculosis,  etc.,  as 
well  as  under  the  influence  of  such  poisons  as  atropine.    Probably  in  most 
cases  this  is  due  to  the  diminution  of  the  activity  of  the  vagus  nerve,  but 
in  some  it  may  be  a  direct  action  on  the  node.    Bradycardia,  in  which  the 
pulse  is  slowed  to  45  to  50  beats  per  minute,  generally  transient,  occurs  in 
uraemia,  icterus,  mitral  disease,  convalescence  from  acute  infections,  etc., 
and  is  probably  due  to  excitation  of  the  pneumogastric,  since  it  can  be; 
made  to  disappear  by  the  administration  of  atropine,  which  paralyzes 
that  nerve:  jugular  tracings  and  electrocardiograms  present  normal  cycles, 
although  widely  separated.    There  are  also  sinus  arrhythmias,  which  show 
normal  electrocardiographic  complexes  irregularly  spaced.     They  usually 
disappear  on  exertion. 

2.  Disturbances  Due  to  Partial  or  Complete  Interruption  of  Conduction. 
— (a)  An  interruption  between  the  sino-auricular  node  and  the  rest  of  the 
system,  which  would  correspond  to  the  first  ligature  of  Stannius,  has  given 
different  results  in  the  hands  of  different  experimenters.    The  heart  may 
stop  entirely  or  assume  a  different  rhythm,  in  which  impulses  arise  else- 
where.   If  the  interruption  is  incomplete,  some  of  the  impulses  may  pass 
through  so  that  whole  cardiac  cycles  are  missed,  while  others  occur. 


500  TEXT-BOOK   OF   PATHOLOGY 

(6)  Interruption  of  conduction  in  the  bundle  of  His  may  occur  in  various 
degrees  of  completeness.  When  it  is  confined  to  a  slight  retardation  of 
conduction,  there  are  no  symptoms,  but  the  jugular  tracings  show  a  length- 
ening of  the  interval,  etc.  Corresponding  with  this,  the  electrocardiogram 
presents  an  elongation  of  the  space  between  P  and  R.  When  the  inter- 
ruption is  more  intense,  some  of  the  impulses  from  the  sino-auricular 
node  fail  to  reach  the  ventricles,  so  that  while  in  the  jugular  tracings  the 
elevations  a  a,  which  represent  the  auricular  contractions,  are  equidistant 
from  one  another,  some  are  not  accompanied  by  the  elevations  c,  v,  that 
is,  they  are  not  followed  by  ventricular  contractions.  Thus  a  3  :  2  rhythm 
or  a  2:1  rhythm  may  be  established.  Complete  interruption  of  the 
conduction  allows  the  auricles  to  proceed  in  their  regular  contraction, 
while  no  impulses  reach  the  ventricles  from  the  sino-auricular  node.  Then 
the  ventricles  beat  about  30  times  per  minute,  but  with  a  rhythm  quite 
independent  of  that  of  the  auricles  (idio ventricular  rhythm),  so  that 
in  the  tracings  one  can  determine  no  relation  between  them.  Under  such 
circumstances  the  elevations  produced  by  auricular  and  ventricular  con- 
tractions are  sometimes  superposed,  sometimes  separate,  or  if  their  rates 
happen  to  be  multiples  they  may  give  the  impression  of  an  incomplete 
dissociation.  Such  dissociation  is  commonly  spoken  of  as  heart-block 
(Fig.  250). 

The  severer  grades  of  disturbed  auriculoventricular  conduction  (Stokes- 
Adams  disease)  are  often  accompanied  by  crises  or  paroxysms  of  syncope 
or  by  epileptiform  convulsions,  due  to  the  insufficient  flooding  of  the  brain 
with  blood.  These  may  pass  off  as  the  heart-rate  improves,  but  occasion- 
ally end  in  death,  when  the  slowing  of  the  ventricular  rhythm  is  extreme. 
Strangely  enough  such  crises  are  rather  less  common  in  the  cases  of  com- 
plete heart-block  than  in  those  in  which  dissociation  is  only  partial. 

All  these  conditions  can  be  produced  experimentally  by  gradually  con- 
stricting the  bundle  of  His,  and  in  human  beings  there  is  generally  found 
at  autopsy  some  destructive  lesion  in  the  bundle.  This  may  be  a  gumma 
or  a  gummatous  infiltration  surrounding  the  tract,  or  a  scar  or  atheromatous 
calcified  mass  may  extend  from  the  neighboring  valves  so  as  to  interrupt 
it.  Cases  have  been  described,  however,  in  which  absolutely  no  lesion 
of  the  bundle  could  be  found  despite  the  existence  of  heart-block.  In 
such  cases  it  seems  possible  that  excitation  of  the  pneumogastric  may  be 
responsible,  for  it  has  been  shown  that  such  excitation  can  greatly  aggravate 
the  effects  of  a  slight  lesion  of  the  bundle,  and  also  that  excessive  doses  of 
digitalis  can  thereby  produce  heart-block  without  any  injury  of  the  bundle. 

3.  Arrhythmias  Due  to  Heterogenetic  Impulses. — Arrhythmias  or  dis- 
turbances of  rhythm  arising  from  the  origination  of  impulses  elsewhere  than 
in  the  sino-auricular  node  may  assume  several  types.  They  depend  on  the 
fact  that,  although  the  normal  source  of  impulses  is  as  described,  the  node  of 
Keith,  nevertheless  the  node  of  Tawara,  or  the  bundle  of  His,  or  any  part  of 
the  wall  of  the  heart  itself,  may  give  rise  to  such  impulses,  which  spread  then 


PATHOLOGY    OF    THE    CONDUCTION    BUNDLES    OF    THE    HEART      501 

either  in  a  normal  or  quite  abnormal  direction.  It  seems  scarcely  possible 
to  say  whether  these  impulses  arise  in  the  ordinary  heart  muscle  itself  or 
in  the  terminal  ramifications  of  the  conducting  bundle,  but  at  least  the 
character  of  the  electrocardiogram  is  sufficient  to  show  that  they  do  not 
originate  in  the  main  trunk  of  the  bundle  of  His. 

When  such  an  impulse  leads  to  a  contraction  interpolated  in  the  ordinary 
rhythm,  it  is  denominated  an  extra-systole  (Fig.  251).  The  simultaneous 
sputtering  of  such  impulses  from  many  points  in  the  heart's  wall  causes 
a  disorganized,  uncoordinated,  waving  contraction  (fibrillation)  which 


Fig.  250. — Electrocardiogram  in  heart-block.     The  auricular  beats  are  not  regularly 
followed  by  ventricular  systoles,  and  apparently  have  no  influence  upon  them. 


Fig.  251. — Pulsus  bigeminus  in  which  premature  beats  arise  in  the  auricles. 

produces  no  impulsion  of  the  blood.    Such  a  condition  may  exist  in  the 
auricles,  but  quickly  leads  to  death  if  it  occurs  in  the  ventricles. 

(a)  Fibrillation  in  the  auricular  wall  leads  to  complete  arrhythmia,  or 
the  pulsus  irregularis  perpetuus.  Such  is  the  tremulous  quivering  of  the 
wall  of  the  auricle  that  no  contraction  of  the  auricles  is  registered  in  the  jug- 
ular curve,  though  minute  oscillations  occur  in  the  electrocardiogram,  and 
at  occasional  and  irregular  intervals  impulses  pass  through  to  the  ventricles, 
so  that  their  contractions  are  in  complete  disorder  and  show  no  constant 
rhythm.  Such  arrhythmia  is  commonest  in  connection  with  disease  of  the 


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TEXT-BOOK   OF   PATHOLOGY 


mitral  valve,  when  the  auricle  is  distended  and  its  wall  scarred  in  places. 
Usually,  but  not  always,  it  is  permanent.  The  cause  of  the  auricular 
fibrillation  is  not  certain,  but  is  apparently  due  to  degenerative  changes 
in  the  myocardium. 

(6)  In  other  cases,  again  often  in  connection  with  mitral  disease,  extra- 
systoles  starting  in  various  points  in  the  auricle  are  transmitted  to  the 
ventricles,  and  give  rise  to  attacks  of  tachycardia  of  auricular  origin.  The 
cycles  are  complete,  but  follow  one  another  so  rapidly  that  in  the  tracings 
the  elevations  a  and  v  may  overlap,  and  in  the  electrocardiograms  P  and 
T,  in  which  case  the  deflection  will  be  the  algebraic  sum  of  the  two. 

(c)  As  in  the  auricles,  impulses  may  arise  in  any  part  of  the  ventricles 
and  give  rise  to  effective  extra-systoles  which  are,  however,  independent 
of  the  normal  impulse.  These  may,  when  the  heart-rate  is  slow,  be  simply 
interpolated  between  the  normal  heart-beats,  but  usually,  owing  to  the 


Fig.  252.— Pulsus  bigeminus  with  premature  beats  or  extra-systoles  arising  in  the 

ventricles. 


refractory  period  which  follows  a  systole,  there  is  a  compensatory  rest. 
The  next  impulse  from  the  auricle  finding  the  ventricle  in  the  refractory 
phase  produces  no  response,  and  the  normal  cycle  is  missed.  Thus  the 
space  between  the  normal  cycle  preceding  and  that  following  the  extra- 
systole  is  that  of  two  normal  cycles.  Occasionally  such  extra-systoles  may 
follow  one  another  in  rapid  succession,  and  even  drive  back  an  impulse 
in  retrograde  direction  so  as  to  affect  the  auricular  contractions  (ventricular 
tachycardia).  Tracings  from  the  jugular,  studied  together  with  those  from 
the  radial  during  the  occurrence  of  ventricular  extra-systoles,  show  first 
the  normal  cycle,  then  the  elevation  c,  followed  by  the  ineffectual  eleva- 
tion a,  of  the  auricular  contraction,  and  later  the  next  normal  cycle.  Occa- 
sionally a  and  c  are  superposed  and  form  one  high  elevation.  In  the 
electrocardiogram  the  extra-systole  is  represented  by  a  diphasic  wave  the 
point  of  which  is  directed  up  when  the  impulse  comes  from  the  base  and 


PATHOLOGY   OF   THE    CONDUCTION   BUNDLES    OF   THE   HEART     503 

the  right  ventricle,  downward  when  it  arises  at  the  apex  or  in  the  left 
ventricle  (cf.  Fig.  252) .  Lewis  has  shown,  by  the  experimental  production 
of  extra-systoles  from  different  points,  that  this  typical  form  of  the  electro- 
cardiogram can  be  actually  used  for  diagnostic  purposes.  Nothing  is 
known  of  the  aetiology  of  such  ventricular  extra-systoles  in  the  human  being. 

LITERATURE 

His:    Arb.  a.  d.  Med.  Klinik,  Leipzig,  1,  1893,  xciii. 
Tawara:    Reizleitungssystem  des  Saugetierherzens,  Jena,  1906. 
Aschoff:    Verhandl.  Dtsch.  Path.  Gesellsch.,  1910,  xiv,  3. 
Hering:    Ibid.,  36. 
Lewis:    Mechanism  of  Heart  Beat,  London,  1911.     Lectures  on  the  Heart,  New  York, 

1915,  2d  ed.,  London,  1919. 
Carter:  Arch.  Int.  Med.,  1918,  xxii,  331. 

Oppenheimer  and  Rothschild:  Jour.  Amer.  Med.  Assoc.,  1917,  Ixix,  429. 
Keith  and  Flack:  Jour,  of  Anat.  and  Physiol.,  1907,  xli,  172. 
Josue:  Localisations  cardiaques,  XVII  Internat.  Congress  of  Medicine,  London,   1913, 

iii,  pt.  1,  1.     (General  Pathology.) 


CHAPTER    XXIV 

TYPES  OF  INJURY   (Continued).— OBSTRUCTION  OF  THE 
CEREBROSPINAL  FLUID:   HYDROCEPHALUS 

THE  term  hydrocephalus  signifies  that  enlargement  of  the  head  which 
arises  through  the  accumulation  of  large  quantities  of  fluid  within  the 
cavities  of  the  brain.  Its  cause  has  never  been  properly  understood  and 
even  the  anatomical  studies  of  such  brains  have  left  much  to  be  desired, 


Cisterna  chiaamatis' 
CJsterna  interpeduncularif 
Descending  horn  of  Lateral  ventricle' 
Cisterna  pontis> 

Aqueduct  of  Sylvius' 
Right  and  left  foramen  of  LuschKa 


Foramerv 
ofMagenciie 


Cisterna  magna 
(cerebello-medullaris) 


^•jai^^ 

Fig.  252 A.— Diagram  of  ventricles  of  brain  and  subarachnoid  cisternae  (Dandy).    Dr, 
Dandy  has  kindly  allowed  me  the  use  of  this  illustration  from  his  forthcoming  paper. 

since  they  failed  to  demonstrate  the  changes  which  led  to  the  retention  of 
the  cerebrospinal  fluid,  and  described  only  those  which  followed  as  second- 
ary effects.  Further,  they  were  based  on  an  imperfect  or  faulty  conception 
of  the  paths  of  circulation  of  the  fluid  in  the  normal  brain. 

Hydrocephalus  may  be  congenital  and  associated  with  malformation 
or  prenatal  inflammation  in  the  brain,  it  may  be  the  effect  of  pressure 

504 


HYDROCEPHALUS 


505 


caused  by  tumor  or  cyst  within  the  skull,  or  it  may  arise  as  the  result  of 
meningitis.  Other  causes  more  rarely  give  rise  to  it. 

Advanced  stages  are  easily  recognized  by  the  ungainly  enlargement  of 
the  head,  which  becomes  too  large  and  heavy  for  the  child  to  hold  up.  In 
the  rather  rare  cases  in  which  the  patient  survives  to  middle  age,  the  head 
still  rolls  about  on  the  shoulders.  The  skull  becomes  so  thin  as  to  form  a 
very  slight  protection  for  the  brain  within;  in  places  the  bone  is  absent 
altogether,  although  new  islands  of  bone  may  form  in  these  spaces.  The 
fontanelles  remain  widely  open  and  the  whole  skull  is  so  large  with  its  over- 
hanging forehead  that  the  face  seems  to  be  an  insignificant  triangular  ap- 
pendage beneath.  The  orbits  are 
stretched  so  that  the  eyes  seem  to  be 
peering  upward  from  the  bottom  of 
a  space  far  too  large  for  them.  With 
such  extreme  distention  the  child, 
even  if  it  survives  for  some  time,  usu- 
ally becomes  imbecile,  but  there  are 
records  of  persons  who  retained  an 
acute  intelligence  in  spite  of  most  ad- 
vanced changes  of  this  sort.  Slight 
degrees  of  hydrocephalus  are  not  so 
easily  recognized  except  by  Dandy's 
newly  devised  method  of  filling  the 
ventricles  with  air,  after  which  their 
dilatation  is  easily  seen  in  a  radiogram. 

At  autopsy  the  convolutions  cf 
the  cerebrum  are  found  flattened  and 
smoothed  out,  the  ventricles  are  di- 
lated and  filled  with  fluid,  sometimes 
to  so  enormous  a  degree  that  the 
substance  of  the  brain  is  reduced  to  a 
thin  film  of  tissue  which  collapses  like 
a  wet  cloth  when  the  fluid  is  allowed 
to  escape.  This  is  true  not  only  of 
the  cerebral  hemisphere  but  also  of 

the  tissues  which  form  the  walls  of  the  third  and  fourth  ventricles.  The 
corpus  callosum,  the  septum  lucidum,  the  commissures,  and  the  fornix  be- 
come extraordinarily  attenuated,  and  even  the  corpora  striata  and  optic 
thalami  become  flattened,  although  they  resist  the  pressure  longer  than 
the  rest.  In  some  of  the  cases  the  spinal  cord  is  also  affected,  the  central 
canal  being  dilated  (hydromyelia).  Atrophy  of  the  ganglion  cells  of  the 
cortex  and  of  other  parts  of  the  brain  and  disappearance  of  the  axones 
which  belong  to  these  cells  is  an  inevitable  consequence  of  this  stretching 
of  the  tissue,  and  degenerations  of  the  tracts  in  the  cord  result,  although 
to  an  extent  less  than  might  be  expected. 


Fig.  252B. — Hydrocephalus   in  a    child 
following  cerebrospinal  meningitis. 


506 


TEXT-BOOK    OF    PATHOLOGY 


The  mechanism  of  this  retention  of  fluid  has  been  clearly  explained  in 
the  papers  of  Dandy  and  Blackfan,  and  more  especially  in  Dandy's  reports 
of  his  operative  and  experimental  studies.  The  cerebrospinal  fluid  is 
secreted  by  the  choroid  plexuses  in  the  cerebral,  third,  and  fourth  ventri- 
cles. This  is  proven  by  the  fact  that  if  the  foramen  of  Monroe  on  one 
side  be  plugged,  that  ventricle  becomes  greatly  dilated  with  fluid,  but  if 
afterward  the  choroid  plexus  be  removed  from  that  side,  the  ventricle 
collapses  and  no  more  fluid  appears  there,  so  that  it  soon  becomes  obliter- 
ated. In  the  normal  brain  the  cerebrospinal  fluid  passes  downward  into 
the  fourth  ventricle  from  which  it  escapes  into  the  meshes  of  the  sub- 
arachnoid  space  through  the  foramina  of  Majendie  and  Luschka. 
Reaching  the  cisterna  magna  and  the  other  spaces  on  the  under  surface  of 
the  brain  it  spreads  upward  and  forward  over  the  cerebellum  and  over  the 


Fig.  252C. — Hydrocephalus  following  cerebrospinal  meningitis  with  old  adhesions 
about  the  base  of  the  brain.  Transverse  section  looking  forward,  showing  great  dila- 
tation of  lateral  and  fourth  ventricles,  and  of  the  aqueduct  of  Sylvius. 

midbrain  as  it  passes  through  the  tentorium  to  the  surface  of  the  cerebral 
hemispheres,  flowing  always  in  the  meshes  of  the  subarachnoid  space 
until  it  finally  reaches  the  vertex  and  bathes  the  whole  surface  of  the 
brain.  Similarly,  it  flows  downward  into  the  spinal  meningeal  spaces. 
Absorption  into  the  circulating  blood  seems  to  take  place  throughout  this 
wide-spread  area,  although  it  is  most  active  over  the  cerebral  hemispheres, 
probably  because  of  the  greater  extent  of  the  absorbing  surface.  There 
are,  however,  other  ideas  as  to  the  mechanism  of  absorption  which  assume 
the  presence  of  specialized  arachnoidal  villi  in  close  relation  with  the 
venous  sinuses  of  the  dura  mater. 

Dandy  and  Blackfan  showed  that  cases  of  hydrocephalus  fell  into  two 
groups  according  to  their  behavior  when  phenolsulphonephthalein  was 
injected  into  the  cerebral  ventricle.  In  one  group  little  or  none  of  this 


HYDROCEPHALUS  507 

colored  material  appeared  in  the  spinal  fluid,  while  in  the  other  it  appeared 
there  at  once.  They  designated  these  groups  obstructive  and  communicat- 
ing hydrocephalus  respectively,  and  found  it  possible  to  explain  them  on 
anatomical  grounds  from  what  was  discovered  at  autopsy.  In  the  obstruc- 
tive group  the  fluid  cannot  escape  from  the  ventricles  because  there  is  an 
obstruction  somewhere  in  its  usual  path.  This  may  be  in  one  or  both  for- 
amina of  Monroe,  or  in  the  aqueduct  of  Sylvius,  or  there  may  be  an  occlu- 
sion of  the  foramina  of  Majendie  and  Luschka.  Naturally,  if  the  obstruc- 
tion is  in  the  foramen  of  Monroe  on  one  side,  the  dilatation  will  be  limited 
to  that  ventricle.  An  obstruction  in  the  aqueduct  of  Sylvius  will  cause 


Fig.  252D. — Hydrocephalus  following  obstruction  of  the  aqueduct  of  Sylvius,  showing 
dilatation  of  the  lateral  ventricles  and  of  the  foramina  of  Monroe.  The  basal  ganglia 
are  less  affected  and  become  prominent. 

the  distention  of  both  cerebral  and  third  ventricles.  In  the  fourth  ventricle 
the  foramen  of  Majendie  and  both  of  the  foramina  of  Luschka  must  be 
obstructed,  else  the  obstructive  type  of  hydrocephalus  is  incomplete.  In  all 
these  cases  the  fluid  is  retained  within  the  cavities  of  the  brain,  and  never 
reaches  the  subarachnoid  spaces  at  all.  It  is  very  different  with  the  second 
group,  the  so-called  communicating  forms.  In  these,  which  are  commonly 
the  late  results  of  meningitis  with  adhesions  obliterating  the  meshes  of 
the  arachnoid  and  the  cisternse,  the  obstruction  lies  in  these  adhesions 
which  also  bind  the  arachnoid  to  the  dura  about  the  midbrain  where  it  is 
closely  surrounded  by  the  tentorium  and  prevents  the  passage  of  the  fluid 


508  TEXT-BOOK   OF   PATHOLOGY 

into  the  subarachnoid  spaces  over  the  convexity  of  the  cerebrum.  Probably 
even  more  important  is  the  obliteration  by  adhesions  of  the  cisternse  from 
which  this  distribution  normally  occurs.  Colored  fluid  injected  into  the 
ventricles  can  pass  out  through  the  foramina  in  the  roof  of  the  fourth  ven- 
tricle and  down  into  the  spinal  meninges,  but  cannot  reach  the  cerebral 
subarachnoid  spaces  from  which  nearly  all  the  absorption  takes  place. 
Therefore  the  ventricles  become  dilated,  and  in  some  cases  there  is  also  a 
distention  of  the  spinal  meninges  (meningocele) .  This  is  the  type  seen  in 
meningococcus  and  tuberculous  meningitis,  but  it  must  be  remembered 
that  in  the  presence  of  an  inflammatory  process  there  is  another  reason  for 
the  disproportion  between  the  amount  of  fluid  secreted  and  that  absorbed. 

LITERATURE 

Dandy  and  Blackfan:  Amer.  Jour.  Dis.  Child.,  1914,  vii,  406;  1917,  xiv,  424. 
Dandy:  Johns  Hopkins  Hosp.  Bull.,  1919,  xxx,  29.     Annals  of  Surg.,  Dec.,  1918;  Aug., 
1919. 


CHAPTER  XXV 
TYPES   OF  INJURY  (Continued).— BACTERIAL  DISEASE 

General  character  of  bacterial  infection:  Nature  of  bacterial  action.  Pyogenic  micrococci. 
Streptococcus  infections — of  the  throat,  the  middle  ear,  the  digestive  tract.  Wound  infection: 
Erysipelas,  pneumonia,  endocarditis.  General  septicaemia;  acute  splenic  tumor. 

GENERAL  CHARACTER  OF  BACTERIAL  INFECTIONS 

As  a  type  of  injury,  the  harmful  effects  of  bacteria  play  an  exceedingly  great 
part  in  the  causation  of  disease,  and  must  generally  be  reckoned  with  at 
some  stage  or  other,  even  when  they  are  not  the  primary  cause  of  the  ail- 
ment. 

Of  course,  only  a  small  number  of  the  existing  bacteria  are  harmful  to 
man,  and  it  seems  that  we  must  believe  that  these  have  gradually  acquired, 
through  long  adaptation,  their  ability  to  thrive  in  contact  with  the  living 
tissue.  The  rest  live  outside  the  body  under  all  sorts  of  conditions,  requir- 
ing in  their  struggle  for  existence  heat,  moisture,  and  nutriment.  The 
latter  they  get  partly  from  animal  or  vegetable  matter,  in  which  they 
hasten  the  process  of  decay,  which  depends  largely  upon  their  ferment 
activities.  Such  saprophytes  may  occasionally  acquire  the  faculty  of 
parasitic  existence,  and  point  the  way  followed  by  those  which  we  no\v 
think  of  as  obligate  parasites. 

Many  of  the  disease-producing  organisms  scattered  ordinarily  in  small 
numbers  in  the  outside  world  may  gain  entrance  into  the  body  in  over- 
whelmingly effective  numbers,  merely  because  they  have  had  an  oppor- 
tunity to  multiply  in  some  culture-medium.  A  few  typhoid  bacilli  which 
might  readily  be  overcome  in  the  intestine  of  any  healthy  man  can,  as  in  a 
recent  case,  cause  a  fatal  epidemic  if  they  are  introduced  into  warm  food 
and  left  to  multiply  until  it  is  time  for  the  crowd  to  partake  of  refresh- 
ments. 

Bacteria  live  in  great  numbers  on  the  body  surface;  they  are  taken 
into  the  digestive  tract  in  great  quantities  in  the  food,  and  penetrate 
readily  into  all  the  external  orifices  of  the  body.  At  each  point  there  is  a 
mechanical  or  chemical  guard  of  a  sort,  but  nevertheless  there  is  constantly 
an  army  of  them  besieging  each  portal.  The  impermeability  of  the  horny 
layer  of  the  skin,  the  constant  irrigation  of  the  conjunct! val  sac,  the  cilia 
of  the  respiratory  tract,  the  acid  gastric  juice,  the  irrigation  of  the  urinary 
tract,  the  acid  vaginal  secretion— all  act  as  outpost  guards.  Nevertheless, 
in  each  of  these  positions  it  is  known  that  bacteria  are  not  entirely  des- 
troyed and  that  there  is  a  characteristic  flora,  including  pathogenic  forms, 
waiting,  as  it  were,  to  break  through  the  second  line  of  guards.  The 

509 


510  TEXT-BOOK   OF    PATHOLOGY 

whole  upper  respiratory  tract  is  smeared  with  bacteria;  the  mouth  is  a  per- 
fect incubator  of  dozens  of  forms,  and  while  the  stomach  and  duodenum 
are  relatively  free,  the  lower  intestine,  and  especially  the  colon,  contains 
myriads. 

Doubtless  a  few  bacteria  brought  thus  into  the  most  intimate  relations 
with  the  body  surfaces  pass  into  the  real  interior,  that  is,  into  the  tissues 
themselves  in  healthy  persons,  but  there  is  strong  evidence  to  show  they  are 
rapidly  overcome  and  destroyed  by  phagocytic  cells  and  by  the  destructive 
action  of  the  blood  and  tissue  fluids.  Were  it  not  for  these  defences  every 
one  would  quickly  die  from  infection.  Since  infection  does  occur  with 
fatal  results,  it  is  obvious  that  there  must  be  failure  of  the  defence  or  else 
the  introduction  of  such  overwhelming  numbers  of  bacteria  that  defence 
is  unsuccessful. 

The  chief  portals  of  entry  are,  of  course,  the  various  mucosse  of  the  body, 
which  are  really  as  much  exposed  to  bacteria  as  the  outside  skin,  and  the 
skin  itself,  which,  through  abrasions  or  wounds,  can  allow  their  entrance. 

Having  penetrated  into  direct  relation  with  the  tissues,  most  bacteria 
fail  to  multiply,  but  those  which  are  adapted  to  such  surroundings  may  do 
so,  although  constantly  hampered  by  the  antagonistic  action  of  the  body 
defences,  especially  such  as  are  presented  by  the  reaction  of  inflammation. 
Virulent  bacteria  in  a  person  whose  resistance  is  low  may,  however,  grow 
rapidly  and  be  quickly  transported  to  other  parts  of  the  body  by  the 
lymphatic  channels,  or  even  in  some  cases  by  the  blood-stream.  If  an 
intestinal  loop  is  ruptured,  pouring  great  quantities  of  infected  material  into 
the  peritoneum,  the  bacteria  are  taken  into  the  lymphatics  of  the  dia- 
phragm, and  hence  through  the  mediastinal  lymph-channels  to  the  retro- 
sternal  lymph-glands  with  the  greatest  celerity,  and  after  a  very  few 
minutes  may  be  found  in  the  circulating  blood. 

Bacteria  alone  introduced  into  the  tissues  or  body  cavities  are  relatively 
easily  killed.  If,  however,  foreign  bodies  or  dead  tissue  are  present  there, 
to  afford  a  shelter  against  the  disinfecting  action  of  the  tissue  juices  until 
multiplication  to  great  numbers  has  occurred,  the  bacteria  can  more  readily 
gain  a  dominating  position.  Bacteria  in  the  uterine  cavity  in  the  puerperal 
state  might  be  practically  harmless  were  it  not  for  the  protected  culture- 
medium  offered  by  remains  of  detached  and  dead  placenta,  in  which  they 
reinforce  themselves  by  growth  until  they  can  victoriously  invade  the 
uterine  wall. 

Changes  in  the  virulence  of  bacteria,  easily  produced  experimentally  by 
repeated  passage  through  the  animal  body,  appear  in  the  most  striking 
fashion  in  the  course  of  many  epidemics,  and  the  fading  out  of  the  epidemic 
seems  to  be  due  usually  to  the  lack  of  any  further  susceptible  material 
rather  than  to  any  decline  in  the  virulence  of  the  organism.  In  the  recent 
epidemics  of  streptococcus  pneumonia  this  intensification  of  the  activity 
of  the  streptococcus  seems  to  have  been  exemplified. 

It  is  not  always  easy  to  explain  the  very  obvious  changes  in  the  power 


GENERAL   CHARACTER   OF   BACTERIAL   INFECTIONS  511 

of  resistance  shown  to  bacteria.  Many  external  conditions,  such  as  chilling 
or  starvation,  may  aid  in  this,  but  previous  disease  seems  even  more 
potent  in  this  way.  Almost  every  one  harbors  pathogenic  bacteria  in  his 
throat,  but  it  requires  a  sudden  chilling  or  exposure  or  injury  to  favor  their 
invasion  into  the  lungs  and  the  production  of  pneumonia.  Similarly,  one 
sees  in  the  lungs  of  a  man  long  known  to  have  suffered  from  tuberculosis, 
old  scarred  lesions  at  the  apex,  clearly  stoutly  resisted  in  their  time,  and 
fresh  extensive  and  rapid  destruction  of  the  lower  lobes,  caused  by  the  same 
bacteria  which  have  seized  upon  a  period  of  lowered  resistance  to  push  their 
advantage. 

This  is  doubtless  the  explanation  of  the  so-called  secondary  infections, 
which  are  so  common  and  which  underlie  the  statement  that  a  "man  seldom 
dies  of  the  disease  with  which  he  sickens."  He  really  dies  of  the  secondary 
infection,  which  thrives  in  the  body  weakened  by  the  original  disease. 
One  might  say  that  the  fatal  outcome  in  cancerous  disease  is  usually  not 
from  the  effects  of  the  cancer,  but  from  the  bacteria  that  invade  the 
emaciated  subject.  And  so  with  destructive  chronic  tuberculosis  of  the 
lungs,  in  which  the  hectic  symptoms  seem  to  be  due  rather  to  the  strepto- 
cocci and  staphylococci  and  other  bacteria  which  secondarily  infect  the 
cavities  in  those  organs. 

Persons  who  die  after  long  illness  with  such  affections  as  chronic  nephritis, 
cardiac  disease,  or  cirrhosis  of  the  liver  may  show  no  special  symptoms  of 
infection  other  than  a  sudden  fever  at  the  end,  but  in  their  tissues  at  autopsy 
one  finds,  as  pointed  out  by  Flexner,  streptococci  or  other  bacteria  which 
have  finally  invaded  the  failing  tissue  and  have  added  the  intolerable  last 
straw.  Such  terminal  infections  are  extremely  frequent,  and  although  they 
may  not  produce  any  gross  lesions  in  the  organs,  they  are  very  often  repre- 
sented by  a  terminal  bronchopneumonia  or  diphtheritic  enteritis. 

Nature  of  Bacterial  Action. — We  are  by  no  means  clearly  informed  as 
to  how  bacteria  produce  their  injurious  effects.  It  is  easy  to  say  that 
they  do  so  by  elaborating  poisons,  but  in  reality,  except  in  the  case  of.^a 
few,  such  as  diphtheria  and  tetanus  bacilli,  which  produce  soluble  toxins 
of  great  intensity,  it  is  extremely  difficult  to  demonstrate  any  poisons  in 
the  cultures  of  bacteria,  even  though  they  are  known  to  be  exceedingly 
virulent.  It  was  thought  that  poison  might  be  retained  within  their 
bodies  (endotoxins),  and  liberated  only  upon  their  death  and  disintegration, 
so  that  the  destructive  effects  would  depend  upon  their  death.  It  is  true 
that  when  these  bacteria  are  pulverized  and  extracted,  poisonous  substances 
are  obtained  with  which  the  symptoms  of  the  disease  may  be  produced, 
but  they  scarcely  compare  in  virulence  with  those  formed  by  the  diphtheria 
and  tetanus  bacilli;  and  it  seems  that  perhaps  the  whole  explanation  is 
not  yet  before  us.  It  is  quite  conceivable,  however,  that  bacteria  in  the 
body  may  produce  a  more  active  poison  than  when  grown  in  artificial 
culture-media. 

The  effects  upon  the  tissues  differ  widely  with  the  different  bacteria,  but 


512  TEXT-BOOK   OF   PATHOLOGY 

in  general  they  produce  the  death  or  profound  injury  of  the  adjacent  cells, 
and  quickly  call  forth  an  inflammatory  reaction.  A  few,  such  as  the 
typhoid  bacillus,  although  causing  necrosis  of  the  neighboring  cells,  do 
not  elicit  the  ordinary  response  of  the  neutrophile  leucocytes,  but  rather 
produce  a  curious  reaction,  in  which  mononuclear  phagocytic  cells  pre- 
dominate. Others,  such  as  the  tubercle  bacillus,  may  live  a  long  time 
among  cells  which  are  not  only  alive,  but  actively  multiplying,  only  to 
cause  in  time  their  complete  destruction.  The  effect  seems  to  vary,  then, 
with  the  chemical  nature  of  the  substances  produced  in  the  body  of  the 
bacteria,  and  these  various  reactions  must  be  considered  later  in  some  detail. 
According  to  the  character  of  the  bacteria,  their  number,  their  concentra- 
tion, and  the  resistance  of  the  individual,  infection  may  assume  various 
forms.  Some  organisms,  notably  those  which  produce  soluble  toxins 
(diphtheria  and  tetanus),  appear  to  grow  only  at  the  point  of  inoculation 
or  first  infection,  although  they  distribute  themselves  in  small  numbers  in 
the  blood-stream  and  tissues.  From  this  local  growth  they  diffuse  their 
poisons.  Others,  having  gained  a  foothold,  tend  to  spread  diffusely  through 
the  tissues,  causing  havoc  wherever  they  go.  Such  are  the  streptococci, 
while  the  staphylococci  are  accustomed  to  concentrate  themselves  at 
various  points  in  the  tissues,  and  stir  up  an  intense  concentric  inflam- 
matory reaction  around  themselves  (abscess  formation).  Either  of  these 
forms  and  many  others  may,  however,  in  one  way  or  another  invade  the 
blood-vessels  and  pour  themselves  into  the  flowing  blood.  When  bacteria 
can  be  recognized  in  the  circulating  blood,  we  call  the  process  septicaemia, 
and  this  term  is  being  found  to  apply  properly  to  more  and  more  infectious 
diseases  as  careful  blood  cultures  are  made  (pneumonia,  typhoid  fever,  endo- 
carditis, etc.).  By  pycemia  we  mean  that  condition  associated  with  septi- 
caemia or  bacterisemia  in  which  suppurative  foci  are  formed  here  and  there. 
The  student  should  read  in  this  connection  the  interesting  works  of  Metch- 
nikoff,  Welch,  and  others  upon  these  general  topics  of  infection  and  immu- 
nity which  can  merely  be  outlined  here.  The  remarkable  progress  in 
knowledge  of  this  region  of  medicine  in  recent  years  has  made  the  gen- 
eral and  special  consideration  of  infection  and  resistance  the  subject  not 
only  of  many  text-books,  but  of  a  literature  so  extensive  as  to  be  almost 
beyond  the  compass  of  one  man's  reading. 

LITERATURE 

Metchnikoff:    Immunite  dans  les  maladie  infectieuses,  Paris,  1901. 

Welch:   "Surgical  Bacteriology,"  Dennis'  System  of  Surgery,  Philadelphia,  1895. 

Simon:   Infection  and  Immunity,  Philadelphia,  1912. 

Zinsser:    Infection  and  Resistance,  New  York,  1918. 

The  Pyogenic  Micrococci. — While  the  bacteria  belonging  to  this  group 
unquestionably  cause  different  diseases  according  to  the  special  peculiarities 
of  each,  there  is  still  a  striking  resemblance  in  their  mode  of  action,  and 
there  are  many  things,  such  as  endocarditis,  lobular  pneumonia,  and  men- 


STREPTOCOCCUS   INFECTIONS  513 

ingitis,  which  may  be  caused  by  each  of  them  in  nearly  the  same  fashion. 
We  may,  therefore,  consider  together  in  this  chapter  the  effects  produced 
by  the  Staphylococcus  pyogenes  aureus,  the  Staphylococcus  albus,  the 
Streptococcus  longus  or  hsemolyticus,  Streptococcus  mitis  or  viridans, 
the  pneumococcus  or  Micrococcus  lanceolatus  in  its  various  types,  the 
gonococcus,  the  meningococcus  or  Micrococcus  intracellularis  meningi- 
tidis,  together  with  other  forms  and  varieties.  No  attempt  will  be  made 
to  describe  the  organisms,  nor  to  discuss  their  systematic  relations,  which 
are  subjects  for  books  on  bacteriology.  Together  with  these  affections 
there  may  be  discussed  acute  rheumatic  fever,  the  cause  of  which  is  un- 
known, but  which  resembles  them  in  many  respects. 

STREPTOCOCCUS  INFECTIONS 

Since  the  time  of  Schottmuller,  who  first  made  use  of  the  hsemolytic 
power  of  some  streptococci  for  purposes  of  classification,  many  authors 
have  been  engaged  in  the  attempt  to  put  this  upon  a  satisfactory  basis,  but 
even  yet  without  any  very  enduring  result.  The  names  of  Gordon,  Andrews 
and  Horder,  Holman,  Smith  and  Brown,  Blake,  Smillie,  Swift,  and  Kinsella 
are  especially  connected  with  this  work,  and  certain  things  stand  out 
clearly  which  were  obscure  before.  It  is  agreed  that  the  possession  or  lack 
of  the  power  of  haemolysis  is  of  fundamental  importance,  so  that  strep- 
tococci are  divided  primarily  into  hsemolytic  and  non-hsemolytic  forms. 
Attempts  have  been  made  by  Holman  to  divide  these  groups  further  by 
studying  the  reactions  of  all  the  strains  with  various  sugars,  and  while 
this  gives  reliable  results,  it  is  found  that  most  of  the  subgroups  are  repre- 
sented by  rare  examples  because  they  are  not  the  forms  commonly  con- 
cerned in  the  production  of  human  disease,  and  we  still  find  authors  writing 
simply  of  hsemolytic  or  non-hsemolytic  strains.  Kinsella  and  Swift  showed 
by  the  method  of  complement  fixation  that  all  the  hsemolytic  strains  are 
alike,  while  the  non-hsemolytic  group  is  quite  heterogeneous.  Dochez  has 
found,  however,  by  testing  the  protection  conferred  by  specific  antisera 
that  the  hsemolytic  streptococci  fall  into  four  distinct  groups  which  are 
not  as  yet  to  be  distinguished  in  any  other  way.  Brown  states  that  strepto- 
cocci of  human  and  bovine  origin  can  be  differentiated  best  by  quantita- 
tive estimation  of  their  hsemolytic  power,  while  Avery  and  Cullen  make 
this  distinction  on  the  basis  of  the  maximum  acidity  produced  in  the  cul- 
ture-medium, which  is  greater  for  the  bovine  type.  Smith  and  Brown,  and 
later  Brown  in  his  monograph  on  the  use  of  the  blood-agar  plate  in  the 
study  of  streptococci,  describe  as  the  a  type  of  haemolysis  the  methsemo- 
globin  formation  and  slight  laking  found  round  the  colonies  of  the  non- 
hsemolytic  form,  S.  viridans,  while  their  £  type  of  hsemolysis  is  the 
complete  ring  of  laking  found  about  those  of  the  hgemolytic  form,  S. 
hsemolyticus.  The  r  type  is  a  non-hsemolytic  form  which  produces  no 
met  hsemoglobin . 

It  must  be  evident  from  this  that  great  difficulty  is  encountered  in 
34 


514  TEXT-BOOK    OF    PATHOLOGY 

making  any  finer  distinctions  among  these  extremely  common  and  wide- 
spread organisms.  None  of  the  old  lines  of  classification  based  on  the  length 
of  the  chains,  etc.,  are  used  any  more,  and  Streptococcus  mucosus,  which 
formerly  occupied  a  place  here,  is  now  recognized  as  Pneumococcus  Type 
III. 

It  seems  that  we  can  separate  rather  sharply  the  pathological  changes 
caused  by  the  two  main  types  of  streptococcus,  although  it  is  possible  that 
in  some  conditions  either  may  be  concerned.  At  least  it  is  true  that  those 
lesions  which  are  well  known  to  be  caused  by  either  one  of  them  are  per- 
fectly characteristic,  and  it  is  probable  that  in  time  all  will  be  found  to 
have  a  specific  peculiarity. 

The  Streptococcus  Hsemolyticus. — While  this  organism  is  found  in  water, 
milk,  etc.,  it  seems  probable  that  in  most  cases  it  is  transmitted  directly 
from  another  person  to  some  portal  of  entry  into  the  body.  This  is  espe- 
cially true  in  the  respiratory  infections,  less  so  in  the  infections  of  the  skin, 
digestive  tract,  etc. 

Infections  of  the  Respiratory  Tract. — Abundant  opportunity  to  observe 
such  infections  was  afforded  during  the  war  in  the  bronchopneumonia 
which  followed  the  epidemics  of  measles,  influenza,  and  other  diseases 
which  occurred  among  the  troops,  but  sporadic  cases  are  not  uncommon 
at  any  time.  The  invasion  seems  to  take  place  in  the  mucosa  of  the  nose, 
pharynx,  and  larynx,  extending  quickly  to  the  accessury  nasal  sinuses, 
and  later  to  the  trachea  and  bronchi.  Reddening  of  the  mucosa,  with  a 
sensation  of  soreness  of  the  throat,  followed  by  swelling  of  the  tonsils,  the 
appearance  of  patches  of  whitish,  necrotic  material  on  the  exposed  surfaces, 
fever,  and  general  illness  are  characteristic  and  last  some  days,  but  usually 
end  in  recovery.  More  severe  effects  of  such  angina  are  met  with,  and  may 
be  illustrated  by  the  case  of  one  of  our  colleagues  who  suffered  from  repeated 
attacks.  In  one  of  these  the  tonsils  became  greatly  swollen  and  reddened, 
with  thick  patches  of  greenish,  necrotic  tissue  and  fibrin,  which,  on  removal, 
left  rather  deep  raw  ulcerations.  The  whole  pharynx  was  intensely  in- 
flamed, and  firm  lumps  appeared  beneath  the  angle  of  the  jaw.  He  was 
profoundly  ill,  and  the  surgeons  incised  the  swelling,  which  proved  to  be 
due  to  infection  of  the  adjacent  lymph-glands,  from  which  a  quantity  of 
pus  containing  streptococci  was  drained.  After  that  he  recovered,  but  a 
year  later  the  tonsillitis  suddenly  recurred,  the  surfaces  of  the  tonsils,  as 
well  as  the  whole  lining  of  the  pharynx,  became  intensely  inflamed  and 
covered  with  a  necrotic  false  membrane.  There  were  tumefaction  and  in- 
duration of  the  glands  and  high  fever.  He  rapidly  became  delirious,  and 
then  comatose.  A  rash,  like  that  of  scarlet  fever,  appeared  over  the  whole 
body,  with  pin-point  haemorrhages  everywhere,  and  he  died  within  seventy- 
two  hours  of  the  onset. 

In  other  cases  arising  somewhat  differently,  from  extension  of  the  infec- 
tion from  a  suppurating  salivary  gland,  from  a  carious  tooth,  or  from  a  peri- 
tonsillar  abscess  (quinsy),  there  may  arise  another  form  of  angina,  the  so- 


STREPTOCOCCUS    INFECTIONS  515 

called  Ludwig's  angina,  in  which  all  the  loose  tissues  of  the  neck  become 
densely  infiltrated  with  inflammatory  exudate  in  response  to  the  dis- 
semination of  streptococci  there.  One  case  which  we  saw  recently  was 
thought  to  have  started  in  an  infected  abrasion  of  the  skin  of  the  neck,  but 
most  of  them  arise  from  extension  from  the  organs  about  the  pharynx. 
The  infiltration  among  the  muscles  and  about  the  vessels  and  the  pharynx 
is  so  dense  as  to  be  rigid  and  hard,  so  that  these  organs  are  solidly  embedded. 
If  death  is  postponed  for  a  few  days,  there  may  be  liquefaction  of  some  of 
the  necrotic  tissue  and  exudate. 

Important  are  the  numerous  cases  of  streptococcal  sore  throat  which  occur 
in  great  epidemics  with  high  mortality,  and  are  generally  traced  to  some 
dairy  in  which  one  or  more  cows  with  udders  infected  with  the  streptococcus 
give  a  milk  which  is  thick,  yellow,  and  stringy,  and  on  examination  proves 
to  be  really  a  mixture  of  milk  and  pus,  with  myriads  of  streptococci. 
Several  epidemics  of  this  kind  have  been  reported  recently  in  this  country 
(Pearce,  Capps,  and  others). 

Smith  and  Brown  and,  more  recently,  Brown  and  Orcutt  have  studied 
some  of  these  epidemics  and  have  decided  that  the  streptococcus  concerned 
is  a  human  parasite  infecting  the  udder  of  the  cow  or  introduced  directly 
into  the  milk  from  an  infected  milker.  It  is  not  the  bovine  form  which  is 
so  commonly  present  in  dairy  herds  as  the  cause  of  the  infectious  mammitis 
or  garget. 

Severe  streptococcal  infections  of  the  throat  are  well  known  to  accom- 
pany scarlet  fever,  smallpox,  diphtheria,  and  some  other  diseases,  and, 
indeed,  in  the  lack  of  all  knowledge  of  the  true  cause  of  scarlet  fever, 
there  are  those  who  would  ascribe  it  to  the  streptococcus. 

Measles  is  another  disease  which  produces  a  coryza  and  laryngitis  and 
appears  to  render  the  tissues  very  susceptible  to  the  invasion  of  strepto- 
cocci. We  were  never  able  to  study  the  tissues  of  any  case  of  measles  un- 
infected  with  streptococci,  and  the  nature  of  the  pharyngeal  and  laryngeal 
changes  due  to  the  measles  alone  is  not  known.  The  secondary  strepto- 
coccal infection  is,  however,  most  destructive.  There  is  rapid  loss  of  voice, 
and  at  autopsy  the  whole  mucosa  of  the  pharynx,  larynx,  and  trachea  is 
found  deeply  reddened  and  sprinkled  with  haemorrhages,  or  partly  covered 
with  greenish  pseudomembranous  exudate;  ragged  ulcerations  of  the  epi- 
glottis, pyriform  sinuses,  and  especially  of  the  vocal  cords  and  lining  mucosa 
of  the  larynx  are  common.  The  tissues  of  the  vocal  cords  are  often  so 
deeply  eroded  that  tone  production  is  impossible.  With  all  this  the  tonsils 
do  not  seem  to  be  very  intensely  affected.  The  streptococci  may  burrow 
deep  into  the  underlying  tissue  and  produce  a  phlegmonous  infiltration 
which  is  strewn  with  enormous  numbers  of  organisms. 

Streptococcal  infection  of  the  lungs  after  measles  becomes  an  extremely 
severe  affection  and  assumes  peculiar  characters  which  make  it  easily 
recognizable.  It  occurred  in  extensive  epidemics  and  the  mortality  was 
high.  Later,  when  measles  had  become  less  prevalent,  the  excessively 


516 


TEXT-BOOK    OF    PATHOLOGY 


virulent  streptococci  continued  to  produce  pneumonia  even  in  those  who 
had  previously  been  well.  Still  later,  in  the  course  of  the  great  epidemic 
of  influenza,  the  hemolytic  streptococcus  once  more  appeared  as  a  secondary 
invader  and  caused  a  rapidly  fatal  pneumonia.  When  that  epidemic  waned 
the  streptococcal  infections  became  relatively  more  numerous  and  once 
more  gave  rise  to  the  interstitial  type  of  bronchopneumonia  such  as  we 
observed  after  measles. 

During  and  after  the  epidemic  of  measles  the  changes  produced  by  the 
streptococcus  in  the  lungs  were  about  as  follows :  The  organisms  evidently 

extended  downward  into  the  finer 
bronchioles,  giving  rise  along  their 
path  in  the  trachea  and  larger 
bronchi  to  an  intense  inflammatory 
reaction.  Arrived  at  the  terminal 
bronchioles  they  multiplied  and  de- 
stroyed the  epithelium,  but  were 
rather  closely  restricted  to  the 
bronchioles;  a  few  escaped  into  the 
lymphatics  of  the  bronchial  wall 
and  of  the  interlobular  septa,  and, 
after  causing  thrombosis  of  these, 
extended  to  the  network  of  lym- 
phatics in  the  pleura.  The  imme- 
diate effect  was  the  rapid  production 
of  a  pleurisy  with  an  abundant  effu- 
sion of  brownish  turbid  fluid  loaded 
with  streptococci  in  chains.  Only 
much  later  did  this  fluid  assume  a 
purulent  character,  but  the  exudate 
on  the  pleural  surface  rapidly  be- 
came organized  into  a  layer  of  gran- 
ulation tissue. 

About  the  infected  bronchioles 
there  appeared  haemorrhage  with 
but  little  emigration  of  leucocytes; 
later  lymphocytes  and  very  dense 
fibrin  were  added  and  formed  compact  plugs  in  the  alveoli.  But  most 
striking  was  the  infiltration  of  the  alveolar  walls  themselves  with  mono- 
nuclear  wandering  cells  and  the  great  thickening  of  the  walls  of  the  bronchi. 
This  interstitial  infiltration  soon  accompanied  by  the  formation  of  new  con- 
nective tissue,  and  even  by  organization  of  the  exudate  within  the  alveoli 
gave  a  greatly  increased  density  to  the  area  thus  affected.  Interlobular 
septa  and  all  other  elements  of  the  framework  of  the  lung  became  much 
thickened  and  very  conspicuous  (Figs.  252E,  F,  and  G). 

It  is  easy  to  understand  that  such  a  process  would  produce  an  appearance 


Fig.  252E.— Interstitial  bronchopneu- 
monia following  measles,  and  caused  by 
the  haemolytic  streptococcus. 


STREPTOCOCCUS   INFECTIONS 


517 


Fig.  252F. — Interstitial  bronchopneumonia.     Later  stage;  showing  extreme  infiltration 
and  thickening  of  the  bronchial  walls. 


Fig.   252G. — Interstitial  bronchopneumonia  showing  clumps  of    streptococci  in  the 
bronchus  and  infiltration  of  its  wall. 

in  the  fresh  lung  very  different  from  that  seen  in  the  ordinary  forms  of  bron- 
chopneumonia.   At  autopsy  the  lungs  were  often  found  collapsed  by  the 


518  TEXT-BOOK    OF    PATHOLOGY 

great  effusion  of  fluid  in  the  pleura  and  their  tissue  was  deep  blue.  Through- 
out there  could  be  felt  hard  nodules  of  varying  size  which  on  section  pro- 
jected as  yellowish  masses,  evidently  surrounding  bronchioles  because 
each  showed  in  its  centre  the  lumen  of  a  bronchus  exuding  pus.  These 
were  always  broadly  surrounded  by  a  zone  of  haemorrhage.  These  char- 
acters suggested  the  name  interstitial  bronchopneumonia  which  we  have 
used  for  this  type  of  lesion  (Fig.  252E).  Hsemolytic  streptococci  were  in- 
variably found  in  predominant  numbers  and  often  in  pure  culture,  but 
other  organisms,  especially  the  bacillus  of  Pfeiffer,  were  sometimes  asso- 
ciated, and  we  have  always  felt  that  there  might  be  some  question  as  to  the 
part  it  played,  since  it  is  known  that  a  very  similar  nodular  interstitial 
bronchopneumonia  may  be  produced  by  the  Pfeiffer  bacillus  alone. 

There  were  other  cases  in  which  the  hsemolytic  streptococci  grew  in  ex- 
traordinary numbers  through  the  substance  of  the  lung  in  large  areas.  In 
these  there  was  no  interstitial  infiltration,  no  nodule  formation,  and  no  re- 
striction of  the  growth  and  spread  of  the  bacteria.  We  thought,  perhaps 
wrongly,  that  these  must  be  individuals  who  were  least  able  to  offer  any 
resistance  to  the  invasion  and  destructive  activity  of  the  organisms,  con- 
trasting in  this  respect  with  those  in  whom  the  interstitial  form  of  pneu- 
monia appeared.  There  is  the  possibility  that  an  anaphy lactic  sensiti- 
zation  may  play  a  part  in  this  as  particularly  suggested  by  the  observation 
that  in  some  of  the  cases  of  interstitial  pneumonia  there  may  be  patches  of 
diffuse  consolidation  in  which  the  alveoli  are  filled  with  an  exudate  of  poly- 
morphonuclear  leucocytes  with  millions  of  bacteria.  This  type  of  acute 
pneumonia  is  usually  patchy  and  without  very  definite  outlines ;  the  alveolar 
walls  are  not  infiltrated  with  cells,  but  there  may  be  extensive  hyaline  throm- 
bosis of  the  capillaries.  The  number  of  bacteria  found  among  the  leucocytes 
of  the  exudate  is  far  beyond  anything  I  have  ever  seen  in  other  forms  of 
pneumonia.  Certain  cases  show  the  extreme  to  which  this  condition  can 
go,  in  great  hasmorrhagic  patches  in  which  the  whole  central  part  of  the 
consolidated  area  is  dull  and  opaque,  and  on  section  proves  to  be  necrotic 
and  occupied  by  a  perfect  feltwork  of  chains  of  streptococci. 

Empyema  accompanies  the  diffuse  forms  of  pneumonia  as  well  as  the 
others,  and  often  become  the  most  prominent  feature  of  the  case  if  the 
patient  survives  long  enough.  Then  one  may  find  areas  in  the  lung  which 
have  become  yellow  and  opaque  and  completely  necrotic,  and  it  is  through 
the  disintegration  of  these  and  their  rupture  into  both  bronchus  and  pleura 
that  the  pleuropulmonary  fistulse  arise. 

In  most  of  these  cases  there  was  little  evidence  of  the  existence  of  a  gen- 
eral septicaemia.  There  is  often  a  moderate  acute  splenic  tumor,  and  the 
hyaline  degeneration  of  the  rectus  abdominis  muscles  which  may  also 
accompany  pneumococcus  and  typhoid  infections  is  frequent.  The  other 
organs  showed  only  slight  changes,  such  as  cloudy  swelling. 

During  the  influenza  epidemic  we  saw  a  few  cases  of  pneumonia  caused 
by  the  same  streptococcus,  and  these  were  of  the  maximum  intensity,  the 


STREPTOCOCCUS    INFECTIONS  519 

lungs  showing  patches  of  diffuse  consolidation  in  which  the  alveoli  were 
filled  with  fluid,  leucocytes,  and  myriads  of  streptococci.  The  oedema  and 
the  wide-spread  necrosis  of  the  lung  tissue  were  most  characteristic.  The 
intense  inflammatory  and  ulcerative  changes  in  the  larynx  and  pharynx 
and  the  infection  of  the  nasal  sinuses  were  as  striking  in  these  cases  as  in 
those  which  followed  measles.  It  is  to  be  emphasized  that  there  is  much 
in  the  anatomical  condition  which  is  specific  for  the  haemolytic  strepto- 
coccus so  that  one  may  recognize  the  type  of  pneumonia  caused  by  this 
organism  with  a  fair  degree  of  certainty. 

Infections  of  the  Middle  Ear. — The  haemolytic  streptococcus  is  a  common 
cause  of  middle-ear  inflammation  or  otitis  media,  but  is  by  no  means  the 
only  organism  which  can  do  this.  Staphylococci  and  pneumococci  may 
be  concerned  instead  and,  indeed,  the  pneumococcus  Type  III,  sometimes 
called  Streptococcus  mucosus,  gives  rise  to  the  most  severe,  treacherous,  and 
destructive  form.  Otitis  media  seems  to  be  the  result  of  the  passage  of 
bacteria  from  the  infected  and  inflamed  throat  along  the  Eustachian  tube 
to  the  middle  ear.  Of  course,  the  opening  of  the  tube  is  guarded,  as  Rich 
has  shown,  by  folds  of  mucosa  at  its  pharyngeal  end,  and  is  open  only  dur- 
ing certain  movements  of  the  muscles,  especially  the  tensor  palati.  But 
when  a  sneeze  is  stifled  by  holding  the  nose,  or  when  the  nose  is  blown  very 
hard,  infected  material  may  be  driven  up  the  tube.  In  a  case  which  I 
followed,  the  attempt  to  smother  a  sneeze  was  followed  by  a  sense  of  dis- 
comfort in  one  ear  and  next  day  by  a  sharp  pain.  The  drum  of  the  ear  may 
be  dulled  a  day  or  two  later  and  bulge,  or  pus  may  be  seen  showing  through 
it.  If  it  is  punctured  the  infection  may  clear  up  if  the  organism  concerned 
is  not  a  very  tenacious  one,  but  the  outcome  is  very  frequently  not  so 
happy.  Instead  the  infection  extends  into  the  cavities  of  the  mastoid 
process  of  the  temporal  bone,  which  fill  with  pus.  Necrosis  of  the  partitions 
of  bone  between  these  cavities  takes  place  and  may  extend  through  other 
portions  of  the  temporal  bone  until  it  reaches  the  dura  mater  with  its 
lateral  venous  sinus.  Libman  finds  that  bacterisemia  may  depend  upon 
the  thrombosis  of  the  communicating  jugular  vein,  and  that  it  may  be 
stopped  by  ligature  below  the  thrombus.  In  this  country  and  wherever 
operative  interference  is  reasonably  prompt,  thrombosis  of  the  lateral 
sinus  counts  as  a  late  complication,  and  any  further  extension  through 
the  dura  to  the  meninges  is  rare.  But  in  China  and  even  in  Austria  and 
Germany  the  disease  is  often  neglected  until  the  infection  has  extended  to 
produce  not  only  local  meningitis  or  meningeal  adhesions,  but  an  abscess 
in  the  temporal  lobe  of  the  brain.  I  have. been  especially  impressed  by 
the  frequency  of  such  abscesses  in  the  German  autopsy  rooms  as  the  cause 
of  death,  while  they  form  the  greatest  rarity  here.  The  exudate  in  the 
mastoid  cells  is  purulent  in  the  streptococcal  and  staphylococcal  infections, 
but  in  the  case  of  infection  with  the  pneumococcus  Type  III,  it  appears  as 
a  pinkish  gelatinous  material  which  fills  all  the  spaces  and  is  loaded  with 
the  organisms. 


520  TEXT-BOOK   OF   PATHOLOGY 

Infections  of  the  Digestive  Tract.— Vague,  and  for  the  greater  part  un- 
founded, statements  were  formerly  made  about  the  part  played  by  strepto- 
cocci in  the  causation  of  dysenteries,  but  since  the  recent  work  of  Shiga, 
Flexner,  and  others,  it  is  clear  that  those  affections  are  due  to  a  totally  differ- 
ent organism.  Nevertheless,  it  still  seems  probable,  although  not  proven, 
that  some  at  least  of  the  instances  of  terminal  diphtheritic  enteritis  and 
colitis  in  persons  dying  after  protracted  illnesses  may  be  due  to  streptococci. 

Definitely  of  streptococcal  origin  are  the  phlegmonous  gastritis  and 
phlegmonous  enteritis,  in  which  the  submucosa  of  the  stomach  or  of  the 
duodenum  and  jejunum  is  found  to  be  enormously  thickened  by  a  tense 
inflammatory  exudate  loaded  with  streptococci.  Invasion  through  some 
abrasion  or  ulceration  of  the  mucosa,  sometimes  produced  by  a  blow  on  the 
abdomen,  gives  origin  to  this  condition.  It  is  interesting  from  the  fact 
that  the  walls  of  the  digestive  tract  are  rendered  rigid  and  immovable  by 
the  exudate,  and  since  this  tract  is  unable  to  propel  the  intestinal  contents, 
obstruction,  with  its  characteristic  symptoms,  ensues,  just  as  in  paralytic 
ileus. 

That  the  streptococcus  may  play  an  important  part  in  appendicitis  has 
already  been  mentioned. 

Wound  Infection. — Streptococcal  infection  through  wounds  or  abrasions 
of  the  skin  are  perhaps  not  so  common  as  those  caused  by  the  staphylo- 
coccus,  but  under  certain  circumstances,  especially  familiar  to  surgeons  and 
pathologists,  they  occur  and  run  a  rapid  course.  A  prick  with  a  needle  or 
a  small  unobserved  cut  during  the  performance  of  an  autopsy  in  an  infected 
case  remains  unnoticed  for  several  hours,  after  which  it  shows  a  slight  reac- 
tion and  becomes  painful.  Little  is  to  be  observed  at  the  point  of  the  inocu- 
lation, but  the  whole  arm  aches,  red  lines,  indicating  an  acute  lymphangitis, 
run  up  the  forearm,  the  epitrochlear  and  axillary  glands  swell  and  become 
very  tender.  A  feeling  of  extreme  illness  with  fever  and  perhaps  a  chill 
ensues.  Infiltration  of  the  loose  tissues  of  the  arm  and  axilla  may  take 
place  and  require  surgical  intervention,  and  although  the  body  resistance 
is  likely  to  overcome  the  bacteria,  death  from  general  septicaemia  is  not 
rare. 

One  instance  of  this  sort  in  an  artist  colleague  who  was  making  a  drawing  at  an 
autopsy  had  interesting  complications.  The  swelling  and  tension  in  his  arm  were  such 
that  extensive  incisions  were  made,  in  the  midst  of  which  the  ulnar  nerve  was  injured 
with  a  clamp.  On  recovery  it  was  found  that  half  of  his  hand  was  paralyzed,  and  some 
months  later  a  second  operation  was  undertaken  to  find  the  point  of  injury.  The  nerve 
was  found  embedded  in  a  dense  scar,  which  was  dissected  away,  after  which,  doubtless 
through  allowing  new  nerve-fibres  to  grow  down  through  this  obstructed  point,  mobility 
and  sensation  gradually  but  completely  returned. 

More  extensive  wounds  with  laceration  of  tissue  and  soiling  are  prone 
to  develop  streptococcus  infections.  Fracture  of  the  skull  extending  into 
the  accessory  nasal  cavities  may  lead  to  a  suppurative  meningitis,  while 
compound  fractures  of  the  other  bones  formed,  in  pre-antiseptic  days,  the 


STREPTOCOCCUS   INFECTIONS  521 

most  feared  of  traumatic  injuries.  Of  course,  since  they  often  developed 
a  pysemic  condition,  it  is  likely  that  other  organisms,  including  the  staphylo- 
cocci,  were  frequently  concerned,  but  the  diffuse  inflammation  and  septi- 
caemia caused  by  the  streptococcus  were  not  uncommon.  Even  now,  with 
all  our  vaunted  knowledge  of  bacteriology  and  antiseptics,  the  surgeons 
must  be  careful  to  treat  soiled  and  lacerated  wounds  in  such  a  way  that 
the  circulation  is  not  interfered  with  by  suture  or  bandages,  lest  strepto- 
cocci multiply  in  the  hampered  tissues  and  finally  invade  the  whole  body. 
The  conditions  under  which  soldiers  in  the  trenches  in  the  Great  War  were 
exposed  to  lacerating  wounds  are  familiar  to  every  one,  and  although  the 
tetanus  bacillus  and  the  gas  bacillus  added  to  the  dangers,  the  most  fearful 
streptococcus  infections  were  described. 

Erysipelas. — The  hsemolytic  streptococcus  responsible  for  puerperal 
sepsis,  etc.,  is  also  the  cause  of  the  peculiar  infection  of  the  skin,  which 
starts  from  some  slight  wound  or  abrasion  and  which  has  always  been 
known  as  erysipelas.  It  is  commonly  seen  on  the  face  or  head,  but  it  is 
also  frequent  in  other  parts  of  the  body.  Erdman,  who  studied  800  cases, 
found  that  500  of  them  were  uncomplicated  cases  of  facial  erysipelas,  while 
far  smaller  numbers  were  affections  of  other  parts  of  the  body  or  migrating 
forms.  It  is  a  rapidly  spreading  inflammation  of  the  skin,  which  becomes 
reddened  and  elevated  into  a  dense,  advancing,  irregular  margin,  which 
pushes  ahead,  leaving  the  previously  affected  part  pale  again  or  somewhat 
pigmented.  Where  the  skin  is  loose,  it  becomes  oedematous  and  enormously 
swollen.  Where  it  is  stretched  or  tightly  bound  to  the  underlying  tissues, 
the  spread  of  the  disease  is  likely  to  stop,  and  hence  the  treatment  recom- 
mended by  Wolfler,  which  consists  in  stretching  the  skin  with  strips  of 
adhesive  plaster.  In  the  eyelids,  scrotum,  vulva,  etc.,  the  oedema  may  be 
such  that  the  tense  skin  becomes  necrotic.  This  is  likely  to  occur,  too, 
where  erysipelas  has  started  from  old  leg  ulcers,  or  where  it  occurs  in 
tuberculous  or  other  wasted  persons.  Great  blisters  or  bullae  are  formed 
sometimes.  The  red,  elevated,  glistening,  tense  margin  shows  the  char- 
acteristic anatomical  lesion,  which  consists  of  a  profuse  infiltration  of 
the  crevices  of  the  tissue  and  the  lymph-channels  with  streptococci.  None 
seem  to  be  found  in  the  blood-vessels,  but  their  presence  in  the  lymphatic 
canals  causes  an  inflammatory  reaction  which  may  be  perivascular  in  its 
distribution.  The  corium  is  cedematous,  and  there  are  great  quantities 
of  wandering  cells,  mostly  of  a  mononuclear  character.  Occasionally  the 
exudate  is  more  nearly  purulent,  and  abundant  abscesses,  loaded  with 
streptococci,  may  develop  in  the  depths  of  the  corium;  but  this  is  a  rare 
consequence,  and  usually  the  process  continues  to  spread  without  suppurat- 
ing, by  the  advance  of  the  streptococci,  and  fades  in  the  region  already 
traversed.  It  is  rather  remarkable  that  in  a  streptococcal  infection, 
which  elsewhere  is  met  with  an  outpouring  of  neutrophile  leucocytes,  there 
should  be  found  in  the  skin  chiefly  lymphoid  or  small  mononuclear  wander- 
ing cells. 


522  TEXT-BOOK   OF    PATHOLOGY 

The  disease  affects  infants  as  well  as  adults,  but  is  less  common  in  older 
children.  It  is  particularly  likely  to  recur,  and  those  persons  who  are  pre- 
disposed may  have  a  great  many  attacks,  which  in  the  end  cause  a  great 
thickening  and  induration  of  the  skin  affected.  It  is  not  limited  to  the 
external  skin,  but  may  extend  to  the  mucosae,  involving  the  pharynx,  the 
larynx  (often  with  fatal  oedema  of  the  glottis),  the  middle  ear,  the  vagina, 
etc.  Death  occurs  from  general  septicaemia,  pneumonia,  etc.,  but  most 
often  the  cases  recover.  Erdmann  has  seen  93  deaths  in  800  cases.  Were 
it  not  for  the  fact  that  erysipelas  commonly  appears  as  a  terminal  infection 
in  persons  already  weakened  by  alcohol  or  disease,  the  deaths  ascribed  to 
it  might  not  reach  so  high  a  number.  In  a  case  which  came  to  autopsy 
recently  there  was  found  a  wide-spread  tuberculosis  of  the  lymph-glands 
and  spleen,  but  during  the  last  two  days  of  life  erysipelas  had  set  in  and 
spread  rapidly  over  the  face  and  neck,  causing  such  oedema  of  that  side  of 
the  face  that  the  eye  was  not  only  closed,  but  presented  its  lids  as  great 
bulging  masses  which  projected  out  over  the  swollen  cheek.  The  Strep- 
tococcus haemolyticus  was  recovered  in  the  blood.  In  other  fatal  cases  the 
cloudy  swelling  of  the  viscera,  the  acute  splenic  tumor,  and  other  char- 
acteristic features  of  septicaemia  were  found.  In  women,  attacks  of  ery- 
sipelas often  appear  with  curious  regularity  with  the  periods  of  menstrua- 
tion. Jordan,  Jochmann,  Reiche,  and  others  have  described  cases  of  ery- 
sipelas caused  by  the  staphylococcus,  and  Neufeld  has  found  the  pneumo- 
coccus  responsible,  but  these  are  indeed  rarely  of  aetiological  importance. 

Chr.  Holmes  discusses,  in  an  interesting  paper,  the  mystery  which  has 
long  hung  about  the  pathogenesis  of  erysipelas,  and  fairly  demonstrates 
a  plausible  explanation  of  its  mode  of  onset.  Formerly  a  distinction  was 
made  between  spontaneous  and  wound  erysipelas,  it  being  recognized  that 
after  operation  or  lacerated  wounds  an  erysipelatous  infection  was  likely 
to  start  from  the  edges  of  the  wound.  This  distinction  was  given  up  because 
all  erysipelas  was  later  thought  to  begin  in  some  abrasion,  often  very  in- 
conspicuous in  nature.  Holmes  points  out  the  great  frequency  of  latent 
infection  of  the  nose,  nasal  sinuses,  etc.,  with  streptococci  and  pneumococci, 
the  overwhelming  preponderance  of  facial  erysipelas,  and  among  these 
cases  the  very  large  proportion  starting  from  the  nose.  Further,  he  collects 
many  cases  in  which  erysipelas  followed  operations  which  lay  open  infected 
nasal  sinuses,  infected  middle  ear  and  mastoid  cells,  etc.,  and  quite  logically 
draws  the  conclusion  that  in  all  probability  facial  erysipelas  is  most  com- 
monly the  result  of  the  extension  of  infection  from  the  nasal  cavity.  He 
further  points  out  the  frequency  of  extension  of  this  inflammation  to  the 
eyelids,  conjunctiva,  and  the  various  parts  of  the  eye,  where  it  may  pro- 
duce destructive  effects. 

Puerperal  Endometritis. — The  anatomical-  changes  and  mode  of  occur- 
rence of  infection  of  the  puerperal  uterus  have  been  described  in  an  earlier 
part  of  this  book,  and  it  need  only  be  said  here  that  while  the  non-haemo- 
lytic  forms  of  the  streptococcus  may  be  found  in  the  normal  puerperal 


STREPTOCOCCUS    INFECTIONS 


523 


uterus,  the  presence  there  of  the  hsemolytic  form  is  of  serious  import  and 
that  the  actual  cases  of  puerperal  endometritis  are  usually  caused  by  this 
organism. 

Endocarditis. — With  regard  to  the  role  of  the  various  forms  of  strepto- 
coccus in  the  production  of  endocarditis,  much  has  already  been  said 
(Chapter  XIV).  Since  writing  that  chapter,  however,  a  survey  has  been 
made  of  the  cases  of  endocarditis  which  have  come  to  autopsy  in  the  last 
ten  years,  with  the  result  that  it  seems  relatively  easy  to  recognize,  from 
their  gross  appearance,  the  forms  of  acute  endocarditis  which  are  caused 
by  the  Streptococcus  hamolyticus,  the  Streptococcus  viridans,  the  pneumo- 
coccus,  the  staphylococcus,  and  the  gonococcus.  This  statement  is  per- 
haps exaggerated,  since  at  best  only  the  more  typical  examples  can  be 
surely  recognized  before  cultures  are  made,  and  even  then  the  forms  of 
endocarditis  produced  by  the  Streptococcus  haBmolyticus,  Streptococcus 
mucosus,  the  pneumococcus,  and  the  staphylococcus  are  so  much  alike  that 
it  would  be  hazardous  to  venture  a  guess  as  to  the  organism  concerned. 
On  the  other  hand,  while  those  organisms  form  a  group,  the  lesions  caused 
by  the  Streptococcus  viridans,  by  the  gonococcus,  and  by  the  unknown 
infective  agent  of  rheumatism  are  so  different  from  them  and  from  one 
another  as  to  be  pretty  easily  recognized.  It  may  be  useful  to  express  this 
impression  in  the  form  of  a  table,  although  the  student  must  realize  that 
there  are  other  organisms,  such  as  the  Micrococcus  zymogenes,  influenza 
bacillus,  the  meningococcus,  and  many  others  which  can  produce  endo- 
carditis with  lesions  which  may  be  peculiar  to  themselves  or  only  slightly 
different  from  the  ordinary  forms. 


STREPTOCOCCUS  H^BMO- 

LYTICUS,      STREPTOCOC- 

CUS MUCOSUS,   STAPHY- 

STREPTOCOCCUS VIRIDANS 

GONOCOCCUS 

RHEUMATISM 

LOCOCCUS    AUREUS   AND 

ALBUS,  PNEUMOCOCCUS 

Large,    soft    vegeta- 

Firmer   yellow    or 

Enormous    v  e  g  e  t  a- 

Small,    warty    vegeta- 

tions    on     mitral, 

greenish  vegeta- 

tions with  extreme 

tions  on  mitral,  aor- 

aortic,   and   some- 

tions   on    mitral, 

ulceration,  destruc- 

tic,    and     tricuspid 

times  on  tri  cuspid, 
often    causing    ul- 

extending    far    on 
auricular  wall  and 

tion  of  valves. 

valves,     with     slow 
thickening  of  valves. 

ceration. 

chordae    tendineae. 

Also    on    aortic 

valves.       Little 

ulceration. 

Sometimes    purulent 
invasion    of    myo- 
cardium. 

Recurrences      with 
thickening    of   the 
valve.     General 

Vegetations    on    tri- 
cuspid     and     pul- 
monary valves,also 

Chronic  adhesive  peri- 
carditis.       Peculiar 
myocarditis. 

septicaemia. 

on  aortic  at  times. 

General     septicaemia 

Infarcts  and  minute 

General    septicaemia, 

Joint     inflammation  . 

with  petechise,  em- 

bacterial  emboli  in 

peritonitis,  joint  in- 

Less definite  signs  of 

bolic    lesions,    and 

kidneys,  etc. 

fections.      Gono- 

active    general    sep- 

cloudy swelling  of 

coccal    genital   in- 

ticaemia. 

the  viscera. 

fection. 

Rapid  course. 

Slow  course. 

Rapid  course. 

Chronic    course    with 

exacerbations. 

524  TEXT-BOOK    OF    PATHOLOGY 

The  Streptococcus  hsemolyticus,  whatever  its  mode  of  entrance,  is 
quick  to  gain  access  to  the  blood-stream  and  to  localize  itself  on  the  valves. 
The  vegetations  (Fig.  253)  produced  there  may,  of  course,  be  small  at 
first,  but  they  tend  to  grow  rapidly  into  irregular  masses  which  commonly 
extend  toward  the  base  of  the  valve,  and  in  the  case  of  the  aortic  valves 
often  appear  on  both  sides  of  the  cusp;  that  is,  within  the  sinus  of  Valsalva, 
as  well  as  on  the  ventricular  surface.  In,  such  a  case  perforation  of  the 
valve  is  likely  to  occur.  Two  cases  have  been  seen  recently  in  our  series 
in  which  such  large  holes  have  been  produced  as  to  allow  of  regurgitation 
through  the  valve  cusps.  The  bacteria  may  extend  into  the  musculature 


Fig.  253. — Endocarditis  due  to  the  Streptococcus  haemolyticus.     Great  friable  vegeta- 
tions on  the  mitral  valves  prone  to  ulceration. 

of  the  septum  or  other  part  of  the  heart-wall,  and  produce  a  deep,  abscess- 
like  excavation.  There  was  one  example  in  Baltimore  in  which  in  this  way 
an  abscess,  formed  in  the  septum  in  continuity  with  a  large  vegetation  on 
the  aortic  valve,  projected  beneath  the  pulmonary  orifice,  and  finally 
ruptured  there,  forming  a  communication  between  the  two  ventricles. 
In  another  case  there  were  vegetations  on  the  auricular  surface  of  the 
tricuspid  valves  so  large  as  to  make  the  orifice  extremely  narrow.  They 
bulged  up  as  rough  yellow  masses  into  the  auricle,  and  acted  as  an  extreme 
obstruction  to  the  flow  of  blood.  Curiously  enough,  it  sometimes  happens 
that  such  great  vegetations  exist  without  marked  circulatory  disturbances 
or  loud  murmurs,  but  this  is  not  always  the  case.  They  are  associated 


STREPTOCOCCUS   INFECTIONS 


525 


with  the  most  typical  evidences  of  the  existence  of  a  generalized  strepto- 
coccal  septicaemia  and  often  with  septic  infarction  (Fig.  254). 

The  Non-haemolytic  Streptococci.— We  distinguish  an  organism  which  is 
indifferent  to  blood  and  produces  no  methsemoglobin,  the  r  type  of  Brown, 
and  the  well-known  methsemoglobin  producing  Streptococcus  viridans, 
the  a  type  of  Brown.  The  part  played  by  these  in  the  production  of  disease 
is  not  quite  so  definite  as  that  of  the  hsemolytic  form,  except  in  the  case  of 
the  peculiar  endocarditis  caused  by  the  Streptococcus  viridans.  They  give 


If, 


fe.: ••;•;•••• •>.  •'-;;•.    •    „.  •  •  - 

',.'•-.".;:.•,      ••„.•.",*   .  .    ',  •     •••. 

SU>s:KV;cV<  v-:-.-'*^*' 

"  '' 


Fig.  254. — Margin  of  septic  infarction  in  the  liver.     The  capillaries  in  the  necrotic  region 
are  crowded  with  streptococci. 

rise  to  tonsillitis  of  a  relatively  mild  form  and  sometimes  to  an  acute  or 
subacute  arthritis. 

Endocarditis. — The  Streptococcus  mitior  or  viridans  of  Schottmuller 
produces  a  type  of  endocarditis,  already  mentioned  in  Chapter  XIV,  which 
is  slower  in  its  progress  and  subject  to  remissions  or  periods  of  partial  heal- 
ing, but  which,  nevertheless,  proceeds  relentlessly  to  the  death  of  the 
patient  (Fig.  255).  It  has  been  called  endocarditis  lenta,  or  subacute 
bacterial  endocarditis.  The  distinct  character  of  this  affection  was  pointed 
out  by  Schottmuller,  Lenhartz,  Harbitz,  and  others,  and  recently  Libman, 


526 


TEXT-BOOK    OF    PATHOLOGY 


in  several  papers,  has  added  to  the  clearness  of  its  outline.  The  disease 
begins  insidiously  with  pains,  fever,  evidences  of  involvement  of  the  heart 
valves,  and  progresses  through  several  months  or  a  year  to  death  from 
cardiac  decompensation,  cerebral  embolism,  nephritis,  or  an  intercurrent 
infection  such  as  pneumonia.  There  may  be  tonsillitis,  mild  joint  pains, 
and  enlargement  of  the  spleen.  There  is  a  progressive  angemia  with  leucocy- 
tosis,  a  brownish  pigmentation  of  the  face  in  some  cases,  petechial  haemor- 
rhages, and  tender,  erythematous  nodules  in  the  skin,  sometimes  with 
purpuric  patches.  Bacteria  are  found  circulating  in  the  blood,  although 


Fig.  255. — Endocarditis  due  to  the  Streptococcus  viridans.   Vegetations  on  auricle  wall, 
mitral  valve,  and  chordae  tendinese. 

in  the  later  stages  they  may  be  absent  for  a  time,  and  such  stages  Libman 
considers  to  be  characteristic  and  evidence  of  partial  or  temporary  healing. 
The  symptoms  are  continued,  however,  through  such  bacteria-free  stages 
possibly  by  the  casting  off  of  small  emboli.  Renal  changes  are  almost  con- 
stant, and  while  in  the  kidneys  examined  during  the  early  stages  they  are 
recognizable  as  hyaline  occlusions  of  the  capillaries  of  the  glomeruli,  they 
may  bring  with  them  later  much  more  extensive  destruction  of  renal  tissue 
as  the  result  of  glomerular  obliteration.  These  lesions  were  discovered 
by  Lohlein,  and  later  described  again  by  Baehr. 


STREPTOCOCCUS   INFECTIONS  527 

At  autopsy  it  is  found  that  there  are  old,  scar-like  thickenings  of  the 
affected  heart  valves  and  chordae  tendineae,  so  that  Libman  assumes  that 
the  Streptococcus  viridans  produces  its  infective  lesions  on  the  basis  of  old 
alterations  which  may  have  been  rheumatic  in  character.  It  is  also  con- 
ceivable that  it  itself  might  have  produced  the  healed  lesions,  so  that 
the  fresher  vegetations  are  merely  a  new  crop  in  the  old  site.  These  vege- 
tations are  found  especially  on  the  mitral  valve,  extending  down  on  the 
chordae  tendinese  and  covering  them,  coating  over  the  broken  ends  of  those 
which  are  ulcerated  and  eaten  through,  as  so  often  happens.  They  extend, 
too,  far  up  on  the  wall  of  the  left  auricle,  where  they  form  a  thick,  rough 
mat.  This  distribution  is  so  characteristic,  especially  taken  together  with 
the  coarse,  rough  character  of  the  vegetations  and  their  grayish-green  or 
pinkish-green  color,  that  the  gross  appearance  alone  is  almost  enough  to 
give  the  diagnosis.  There  is  usually  no  pericarditis  and  no  characteristic 
myocardial  change. 

Infarcts  are  to  be  found,  of  course,  in  the  swollen  spleen  or  in  the  kid- 
neys, and  sometimes  in  the  brain,  but  the  typical  picture  of  the  acute  septic 
changes  in  all  the  organs  is  not  so  striking  as  in  the  endocarditis  produced 
by  the  Streptococcus  hsemolyticus  and  other  more  virulent  organisms. 

General  Streptococcus  Septicaemia.— Although  the  clinical  and  anatom- 
ical features  of  a  general  septicaemia  or  invasion  of  the  streaming  blood  by 
bacteria  have  many  special  characters,  depending  on  the  type  of  organism, 
there  is  a  great  deaHn  common  among  them,  and  at  autopsy  one  frequently 
recognizes  the  existence  of  a  general  septicaemia  from  the  condition  of  the 
organs  without  being  able  to  say  whether  it  is  due  to  a  streptococcus, 
pneumococcus,  staphylococcus,  or  some  other  organism.  Of  course,  a 
staphylococcus  septicaemia  is  likely  to  be  marked  by  the  presence  of  numer- 
ous abscesses,  typhoid  septicaemia  by  lesions  peculiar  to  it;  septicaemia  due 
to  Friedlander's  bacillus  by  peculiarities  of  the  exudate,  and  so  on,  but 
there  are  still  features  common  to  septicaemia  in  general. 

While  at  times  it  is  possible  to  find  streptococci  or  other  organisms  cir- 
culating in  the  blood,  this  seldom  continues  for  any  great  length  of  time 
unless  there  is  a  constant  source  of  supply,  such  as  a  large  vegetation  loaded 
with  growing  bacteria,  hanging  upon  a  valve  of  the  heart,  and  shedding  the 
bacteria  continuously  into  the  blood-stream.  For  this  reason  we  have  be- 
come skeptical  of  the  existence  of  a  septicaemia  as  such,  and  think  of  the 
presence  of  bacteria  in  the  circulating  blood  as  the  temporary  result  of 
their  discharge  from  a  focus  of  infection  which  is  in  close  or  direct  communi- 
cation with  the  blood-stream.  That  the  bacteria  grow  and  multiply  in 
the  blood,  so  as  to  constitute  a  true  bacteriaemia,  seems  in  most  instances 
extremely  unlikely,  and  occurs,  if  at  all,  shortly  before  death  in  the  fatal 
cases  in  which  we  may  suppose  the  antibacterial  powers  of  the  blood  at  a 
low  ebb.  After  death  the  blood  becomes  filled  with  them,  so  that  cultures 
from  the  heart's  blood  at  autopsy,  unless  immediately  after  death,  are  of 
very  little  interest.  These  statements  seem  to  be  supported  by  the  experi- 


528  TEXT-BOOK    OF    PATHOLOGY 

ments  of  Hopkins  and  Parker  who  observed  the  fate  of  streptococci  in- 
jected into  the  blood-stream  in  cats  which  are  insusceptible  and  rabbits 
which  are  susceptible  to  infection.  In  both,  the  bacteria  disappeared  from 
the  blood  very  quickly,  but  in  the  rabbits,  after  foci  of  infection  were  estab- 
lished in  the  tissues,  the  organisms  were  once  more  shed  into  the  blood. 
Nevertheless  the  instances  in  which  there  are  foci  of  infection  quite  ade- 
quate to  allow  a  more  or  less  continuous  escape  of  bacteria  into  the  blood 
are  so  numerous  that  we  are  justified  in  describing  the  symptoms  and  ana- 
tomical effects  of  a  general  septicaemia. 

The  symptoms  begin  with  a  chill  and  high  fever,  which  continues  in 
various  forms,  sometimes  continuously  high,  but  more  often  with  remissions 
and  daily  exacerbations  with  chills.  The  blood  is  quickly  and  profoundly 
altered.  There  is  a  great  increase  in  the  number  of  leucocytes,  although 
in  the  severe  cases,  in  which  resistance  fails,  the  lack  of  any  increase 
or  an  absolute  decrease  in  their  numbers  may  be  an  index  of  an  unfavorable 
outlook  for  the  patient.  The  destruction  of  blood-corpuscles  proceeds 
rapidly,  and  extreme  pallor  may  quickly  ensue.  In  the  skin  and  in  the 
retinae  the  clinician  is  made  aware  of  the  presence  of  bacteria  by  the  appear- 
ance of  minute  points  of  yellow  opacity,  surrounded  by  little  flecks  of  haemor- 
rhage. These  are  due  to  the  plugging  of  tiny  blood-vessels  with  emboli 
of  bacteria,  or,  when  there  is  endocarditis,  with  fragments  of  the  vegeta- 
tions loaded  with  bacteria.  In  the  skin  the  thickness  of  the  tissues  makes 
them  appear  as  homogeneous  petechial  haemorrhages,  but  in  the  con- 
junctiva or  retina,  or  in  the  serous  surfaces  at  autopsy,  it  is  usually  possible 
to  distinguish  a  central  necrotic  fleck.  In  the  skin  such  emboli  may  pro- 
duce no  haemorrhage,  but  instead  tender,  nodular  swellings,  which  on  section 
reveal  a  focus  of  inflammatory  infiltration  around  the  obstructed  vessel. 
Extensive  purpuric  haemorrhages  may  spread  throughout  the  skin,  some- 
times becoming  confluent  over  considerable  areas.  In  other  cases  ery- 
thematous  rashes  appear,  resembling  those  of  scarlatina  or  of  measles. 

In  the  case  of  streptococcus  septicaemia  there  are  found  relatively  few 
focal  internal  lesions  produced  by  the  lodgment  of  the  bacteria.  The  most 
common  are  those  in  the  lungs,  which  may  take  the  form  of  broncho- 
pneumonic  patches  or  abscess-like  infiltrations,  and  those  in  the  joints, 
where  at  times  there  is  found  an  intense  inflammatory  reaction  with  a 
purulent  exudate  in  the  synovial  cavity. 

In  many  cases  these  focal  affections  are  absent.  Endocarditis  is,  of 
course,  focal  in  this  regard,  and,  as  stated,  the  dislodgment  of  fragments 
of  the  vegetations  mechanically  produces  lesions  elsewhere.  But  the  more 
direct  effects  of  the  diffusion  of  bacteria  in  the  blood  are  seen  in  the  cloudy 
swelling  of  the  liver  and  kidney,  and  such  other  organs  as  are  composed 
of  tissue  capable  of  showing  a  cloudiness  from  changes  in  the  water  or 
granule  contents  of  the  cells.  The  nature  of  this  is  discussed  elsewhere 
(Chapter  VII).  The  heart  muscle  partakes  of  this  dull,  opaque  appear- 
ance, which  is  intensified  there,  as  in  the  liver  and  kidney,  by  the  appear- 


STREPTOCOCCUS   INFECTIONS 


529 


ance  in  the  cells  of  many  minute  globules  of  fat.  The  acute  and  subacute 
nephritis  which  has  been  described  elsewhere  requires  time  to  develop, 
and  is  rather  an  accompaniment  of  those  streptococcal  infections  which 
have  already  lasted  for  some  time.  The  bone-marrow,  actively  exercised 
in  the  production  of  leucocytes,  is  often  found  to  have  assumed  the  opaque 
cellular  appearance  which  is  also  found  in  anaemias,  where  active  regen- 
eration of  the  blood  is  required.  In  septicaemia  death  may  occur  before 
this  stage  of  activity  is  reached,  but  if 
the  patient  survives  long  enough,  ex- 
amination of  the  marrow  will  reveal  a 
great  increase  in  the  number  of  myelo- 
cytes  which  form  the  polymorphonu- 
clear  leucocytes,  and  also  of  those  cells 
which  go  to  form  red  corpuscles. 

The  spleen  is  enlarged  and  soft,  with 
peculiar  alterations  of  its  substance 
which  are  discussed  under  the  non- 
committal phrase  acute  splenic  tumor. 


Acute  Splenic  Tumor. — In  practically  all 
acute  infectious  diseases,  but  especially  in 
such  intense  forms  as  the  septicaemias  under 
discussion,  the  spleen  becomes  tumefied,  so 
that  it  is  readily  palpable  beneath  the  margin 
of  the  ribs.  Its  size  varies  greatly,  but  its 
weight  may  reach  600  to  700  grams  or  more. 
The  capsule  is  tense,  but  the  organ  is  soft,  so 
that  when  it  is  cut  through  the  cut  surface 
swells  forward,  everting  the  edges  of  the  cap- 
sule (Fig.  256).  One  may  scrape  off  with  the 
knife  or  even  with  the  finger  a  quantity  of 
smeary,  paint-like  pulp.  Indeed,  the  spleen 
is  so  soft  sometimes  that  it  spreads  out  on  the 
pan  or  even  flows  as  a  semifluid  material. 
The  trabeculae  are  sunken  below  the  swollen 
surface,  or  else,  if  the  cut  surface  has  been 
scraped,  they  alone  may  be  left  as  shaggy 
threads  after  the  pulp  has  been  wiped  away  to  a  considerable  depth.  In  such  extreme 
examples  of  softness  it  is  difficult  even  to  see  the  Malpighian  bodies.  In  other  cases 
they  are  much  enlarged  and  conspicuous,  sometimes  with  an  opaque,  yellowish,  central 
fleck  in  each.  Ordinarily  the  splenic  pulp  in  such  swollen  spleens  has  a  velvety  or  pasty 
appearance,  and  is  very  opaque  and  of  a  dull,  pinkish-gray  color.  In  these  latter  par- 
ticulars the  acute  splenic  tumor  of  septic  conditions  is  very  different  from  that  of  typhoid 
fever,  which  is  deep  red  in  color,  and  almost  jelly-like  in  consistence,  owing  to  the  great 
quantities  of  red  corpuscles  held  in  its  pulp.  In  order  to  give  any  idea  of  the  nature  of 
the  change  in  the  spleen  it  is  necessary,  first,  to  refer  briefly  to  the  main  points  in  its 
structure,  as  worked  out  by  Weidenreich,  Mollier,  and  others.  The  Malpighian  bodies, 
rather  sharply  marked  out  from  the  actual  splenic  pulp,  are  collections  of  lymphoid 
cells  in  a  reticulum  formed  from  the  adventitia  of  the  arterioles,  so  that  they  are  peri- 
arterial  lymphoid  nodules.  After  leaving  the  Malpighian  body  the  branches  of  the 

35 


Fig.  256. — Acute  splenic  tumor  from  a 
case  of  endocarditis. 


530 


TEXT-BOOK    OF    PATHOLOGY 


arteriole  empty  each  into  one  of  the  peculiar  wide  venules,  which,  entangled  together, 
make  up  the  bulk  of  the  splenic  pulp.  These  venules  have  walls  which  are  formed  of 
peculiar,  elongated  endothelial  cells,  whose  central  nucleus  is  relatively  large,  causing 
a  bulging  at  the  middle  point  of  the  long  tapered  cell,  which  projects  somewhat  into  the 
lumen.  Cross-sections  of  the  venules  sometimes  pass  through  many  of  the  nuclei; 
sometimes,  on  the  contrary,  they  show  chiefly  sections  of  the  protoplasm  of  the  cell. 
Outside  these  each  venule  is  surrounded  by  a  basketwork  of  elastic  reticulum  fibrils, 
which  are  connected  with  the  general  reticulum  of  the  pulp.  Whether  there  is  also  an 


Fig.  257. — Acute  splenic  tumor:   septicaemia  associated  with  acute  endocarditis  and 

acute  diffuse  nephritis. 


intervening  structureless  membrane,  upon  which  the  endothelial  cell  lies,  is  not  per- 
fectly clear.  Weidenreich  states  that  there  is  such  a  membrane  perforated  here  and 
there.  In  the  spaces  between  these  venules  there  lie  the  cells  of  the  splenic  pulp, 
which  are  of  various  sorts,  and  it  is  in  connection  with  them  that  our  information  seems 
least  precise.  Many  red  corpuscles  are  normally  found  there,  and  many  mononuclear 
cells  of  various  forms.  Polymorphonuclear  leucocytes  occur,  but  are  less  abundant. 
It  is  difficult  to  say  whether  any  of  these  mononuclear  cells  are  peculiar  to  the  spleen, 
or  whether  they  contribute  largely,  or  at  all,  to  the  circulating  blood.  Morris  found 


STREPTOCOCCUS   INFECTIONS  531 

them  swept  out  in  numbers  in  the  blood  of  the  splenic  vein,  while  others  have  found 
the  reverse,  i.  e.,  the  mononuclear  cells  which  entered  the  spleen  with  the  arterial  blood 
retained  there,  while  polymorphonuclear  leucocytes  pass  through.  There  seems  no 
doubt  that  when  the  conditions  demand  it  myelocytes  can  be  formed  in  the  splenic 
pulp,  giving  it  some  of  the  characteristics  of  the  bone-marrow.  Further,  it  is  clear  that 
the  cells  of  the  pulp  are  active  as  phagocytes,  and  are  often  found  laden  with  pigment. 
This  is  true  of  the  endothelial  cells  of  the  venules,  just  as  it  is  of  Kupffer's  cells  of  the 
hepatic  capillaries.  As  in  the  lymph-glands,  it  appears  that  there  are  large,  pale 
reticulum  cells  in  the  splenic  pulp  which  can  act  as  phagocytes. 

In  acute  splenic  tumor  in  infectious  diseases  it  seems  that  there  may  be  a  variety  of 
changes.  In  some  infections  the  Malpighian  bodies  seem  little  changed,  and  in  the  fresh 
spleen  sink  into  insignificance,  in  contrast  with  the  great  swelling  of  the  splenic  pulp, 
which,  on  the  cut  surface,  bulges  or  flows  over  them,  so  as  almost  to  hide  them  from  view. 
In  other  cases  the  prominent  alteration  is  in  these  bodies. 

In  the  acute  splenic  tumor  accompanying  streptococcus  and  staphylococcus  septi- 
caemia, pneumonia,  etc.,  there  is  little  blood  in  the  spaces  between  the  venules  in  the 
splenic  pulp  (Fig.  257).  Indeed,  the  venules  themselves  seem  compressed  and  partly 
emptied  by  the  enormous  increase  in  the  number  of  nucleated  cells  between  them,  and 
it  is  this  great  accumulation  of  loose  cells  which  gives  the  pastiness  and  grayish  opacity 
to  such  spleens.  In  our  ignorance  of  the  exact  nature  of  the  process  one  gains  the 
impression  that  this  great  hyperplasia  is  analogous  to  that  seen  under  similar  conditions 
in  the  bone-marrow,  where  hyperplasia  of  cells  is  associated  in  our  minds  with  the  furnish- 
ing of  necessary  elements  to  the  blood.  Jawein,  however,  regarded  the  swelling  of  the 
spleen  as  a  process  associated  with  the  destruction  of  red  corpuscles,  and  found  that  it 
occurred  only  in  those  intoxications  and  infections  in  which  there  was  much  blood 
destruction.  The  advent  of  so  many  cells  would,  for  him,  represent  a  phagocytic 
function. 

While  in  the  typhoid  spleen  this  phagocytosis  of  red  cells  and  other  debris  is  a  very 
obvious  feature,  and  most  extensively  carried  on,  it  is  by  no  means  conspicuous  in  the 
spleens  of  septic  infections,  and,  indeed,  one  sees  relatively  little  phagocytosis  at  all  in 
this  pulp.  Bernhardt,  who  studied  especially  the  spleens  of  cases  of  scarlet  fever  and 
typhoid  fever,  draws  this  same  contrast  in  another  connection.  He  finds  that  in  scarlet 
fever  huge  numbers  of  blood-platelets  accumulate  and  are  engulfed  by  phagocytic  cells. 
Probably  this  occurs  also  in  other  infections,  but  in  order  to  prove  that  these  platelets 
are  not  merely  the  debris  of  red  corpuscles,  he  shows  that  in  typhoid  fever,  where  there 
is  such  active  phagocytosis  of  red  corpuscles,  platelets  are  relatively  few  in  number  in  the 
spleen.  This  is  another  theory  of  phagocytosis  to  explain  the  swelling  of  the  spleen, 
but  hardly  more  completely  satisfactory  than  that  of  Jawein.  Occasionally  one  sees 
great  numbers  of  polymorphonuclear  leucocytes  in  the  meshes  of  the  splenic  pulp,  but 
this  is  not  constant. 

In  diphtheria  Washkewitz  points  out  that  the  especial  enlargement  of  the  Mal- 
pighian bodies  is  due  to  the  appearance  of  a  central  mass  of  large,  pale  phagocytic  cells, 
which  she  thinks  are  probably  derived  from  the  lymphoid  cells  and  not  from  the  retic- 
ulum, as  Ziegler  had  thought.  These  conspicuous  pale  central  masses  of  large  cells  in 
the  Malpighian  bodies  are  by  no  means  confined  to  diphtheria,  but  occur  in  many 
types  of  infections,  especially  in  children  and  young  people.  We  have  reviewed  the  last 
500  autopsies  in  this  regard,  and  have  found  many  cases  in  which  they  occur.  They  are 
all  in  cases  of  infection  of  one  sort  or  another,  with  bronchopneumonia,  tuberculosis, 
diphtheria,  peritonitis,  and  many  toxic  processes,  among  which  skin  burns  are  notable. 
But  they  are  not  particularly  a  feature  of  the  acute  splenic  tumor,  in  whicji  the  splenic 
pulp  is  especially  swollen.  The  large  cells  have  pale,  vesicular  nuclei,  abundant  pale- 
staining  protoplasm,  and  are  frequently  loaded  with  fragments  of  other  cells  which,  they 
have  engulfed.  They  themselves  often  show  degenerative  changes;  their  nuclei  become 
fragmented,  and  in  time  the  mass  may  come  to  look  like  a  focal  necrosis  with  clumps  of 
broken  nuclei. 


532  TEXT-BOOK   OF   PATHOLOGY 

It  must  be  said  that  further  work  is  required  to  make  clear  the  complex  nature  of 
acute  splenic  tumor,  which  in  some  cases  seems  to  be  a  response  to  the  presence  of  the 
debris  of  red  corpuscles  or  other  cells,  in  others  to  the  diffusion  of  a  toxin  or  bacteria. 
The  part  of  the  spleen  in  reconstructing  the  blood  seems  to  be  little  understood  in  spite 
of  numerous  studies  which  have  been  made  recently,  but  more  will  be  said  on  this  point 
in  connection  with  the  diseases  of  the  blood. 

F.  A.  Evans  has  carried  out  in  our  laboratory  since  this  was  written  a  study  of  the 
forms  of  acute  splenic  tumor  in  human  beings  and  those  produced  experimentally  in 
animals,  employing  vital  stains  and  the  oxydase  reaction  in  the  attempt  to  distinguish 
the  various  cells  found  there.  He  confirms  the  sharp  distinction  made  between  the 
red  type  found  in  typhoid  fever  and  the  gray  one  in  the  infections  with  all  the  pyogenic 
bacteria.  The  red  type  is  distinguished  by  hyperplasia  and  phagocytic  activity  of  the 
reticulo-endothelial  macrophages  and  decrease  in  the  number  of  the  other  cells  of  the 
pulp.  The  gray  type,  on  the  contrary,  shows  a  great  increase  in  the  pulp  cells,  es- 
pecially the  oxydase-containing  myeloid  elements,  with  no  change  in  the  reticular  and 
endothelial  cells.  These  changes  result  largely  from  a  functional  demand  for  leucocytes. 

LITERATURE 

Capps  and  Davis:  Trans.  Assoc.  Amer.  Phys.,  1914,  xxix,  279. 
Smith  and  Brown:  Jour.  Med.  Research,  1915,  xxxi,  455. 
Holman:  Ibid.,  1916,  xxxiv,  377. 
Kinsella,  Kinsella  and  Swift:  Jour.  Exper.  Med.,  1918,  xxviii,  169,  181.     Arch.  Int. 

Med.,  1917,  xix,  367. 

Smillie:  Jour.  Infectious  Dis.,  1917,  xx,  45. 
Gay:  Jour.  Laboratory  and  Clin.  Med,,  1918,  iii,  No.  12.    (Extremely  good  review  of 

recent  literature.) 

Avery  and  Cullen:  Jour.  Exp.  Med.,  1919,  xxix,  215. 
Hopkins  and  Parker:  Ibid.,  1918,  xxvii,  1. 
Brown:  Monograph  Rockefeller  Institute,  No.  9,  1919.    Jour.  Exp.  Med.,  1920,  xxxi, 

35,  49. 

Evans:  Johns  Hopkins  Hosp.  Bull..  1916,  xxvii,  356. 
MacCallum:  Monograph,  Rockefeller  Institute,  No.  10,  1919. 
Libman:   "Otitis,"  Amer.  Jour.  Med.  Sci.,  1909,  cxxxviii,  409. 
MacCallum:    "Phlegmonous  Enteritis,"  Johns  Hopkins  Hosp.  Bull.,  1906,  xvii,  252. 
Erdmann:   Jour.  Amer.  Med.  Assoc.,  1913,  Ixi,  2048. 

Jochmann:  Mohr  u.  Staehelin,  Handb.  d.  inneren  Medizin,  Berlin,  1911,  i,  578,  717. 
Joseph  Koch:  Ergeb.  d.  allg.  Path.,  1909,  xiiii,  135. 
Fehleisen:    Aetiologie  des  Erysipels,  Berlin,  1883. 

Lenhartz:    "Septische  Infektionen,"  Nothnagel,  Spec.  Path.  u.  Therap.,  1899. 
Holmes:    Annals  of  Otology,  Rhinology,  and  Laryngology,  xvi,  457,  1907. 
Libman:   Trans.  Assoc.  Amer.  Phys.,  1912,  xxvii,  157;    1913,  xxviii,  309. 
SchottmuUer:    Munch,  med.  Woch.,  1903,  1,  849. 
Lohlein:    Med.  Klinik,  1910,  vi,  375. 
Baer:    Jour.  Exp.  Med.,  1912,  xv,  330. 
Jawein:    Virch.  Arch.,  1900,  clxi,  461. 
Washkewitz:    Virch.  Arch.,  1900,  clix,  137. 
Bernhardt:   Ziegler's  Beitrage,  1913,  Iv,  35. 
Weidenreich:    Arch.  f.  mikr.  Anat.,  1901,  Iviii,  247. 
Mollier:  Arch.  f.  mikr.  Anat.,  1911,  Ixxvi,  608. 


CHAPTER  XXVI 

TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued).— STAPHY- 
LOCOCCUS  INFECTIONS 

General  character.  Furunculosis.  Paronychia,  impetigo,  etc.  General  septiccemia, 
pyaemia,  suppurative  nephritis,  endocarditis,  lobular  pneumonia,  osteomyelitis. 

THE  Staphylococcus  pyogenes  aureus,  Staphylococcus  albus,  and  other 
less  important  forms,  including  the  Staphylococcus  citreus,  are  concerned 
in  these  infections.  Much  of  their  peculiar  effect  is  dependent  upon  their 
tendency  to  grow  in  clumps  and  to  cling  together,  rather  than  to  spread 
diffusely.  Hence  in  the  tissues  there  is  a  focal  character  in  the  lesions 
they  produce,  in  contrast  with  the  more  spreading  lesions  of  the  strepto- 
coccus. For  the  same  reason  the  entrance  of  the  Staphylococcus  into  the 
circulating  blood  results  in  its  deposition  at  numerous  points,  where  it 
grows  into  compact  colonies  which  produce  focal  lesions.  Unlike  the 
streptococcus,  which  grows  most  commonly  on  mucous  membranes,  such 
as  that  of  the  pharynx,  and  enters  the  body  thence,  the  staphylococci  are 
dwellers  on  the  skin,  and  infection  is  usually  from  abrasions  or  cracks  in  the 
skin,  although,  as  shall  be  stated,  infection  from  the  genito-urinary  tract 
is  not  uncommon. 

Owing  to  the  attributes  just  mentioned  the  formation  of  abscesses  is  the 
usual  effect  of  the  invasion  of  this  organism,  a  process  already  described 
in  Chapter  XIV.  No  matter  how  extensive  the  lesions,  they  have  the 
same  general  character  of  concentration  which  makes  possible  the  lique- 
faction of  the  tissue  and  exudate. 

Furunculosis. — Cultures  from  the  skin  of  healthy  persons  show  (J. 
Koch)  a  great  number  of  staphylococci,  partly  saprophytic,  partly  truly 
pathogenic.  The  hsemolytic  power  of  these  cocci  seems  to  be  almost  a 
measure  of  their  pathogenic  character.  Even  in  the  depths  of  the  skin, 
probably  in  the  sebaceous  glands  and  the  clefts  about  the  roots  of  the 
hairs,  there  are  constantly  present  staphylococci  which  grow  white  on 
culture-media  (Staphylococcus  epidermidis  albus,  Welch),  and  it  is  thought 
that  these  are  responsible  for  stitch  abscesses  when  sutures  are  made 
through  the  skin.  To  avoid  them,  subcutaneous  sutures  have  been 
employed  by  surgeons  with  great  success.  With  such  a  flora  present,  it  is 
very  easy  to  understand  that  abrasions,  or  even  a  constant  rubbing  which 
does  not  erode  the  skin,  as  in  the  case  of  a  collar  or  cuff,  might  give  an 
opportunity  for  the  beginning  of  furunculosis  which  is  so  familiar.  It 
depends  evidently  upon  a  predisposing  lowering  of  resistance,  which, 
according  to  Wright,  may  be  recognized  in  the  decreased  activity  of 

533 


534  TEXT-BOOK   OF   PATHOLOGY 

phagocytic  leucocytes  (lowered  opsonic  power  of  the  plasma).  At  any  rate, 
once  begun,  furuncles  or  boils  are  likely  to  continue  to  appear,  sometimes 
in  hundreds.  Athletes  in  training,  who  are  roughly  rubbed  down,  are  a 
prey  to  them,  and,  on  the  other  hand,  persons  long  ill  with  such  wasting 
diseases  as  typhoid  fever,  are  likely  to  have  a  crop  of  boils.  The  active 
immunization  by  the  injection  of  repeated  doses  of  killed  cocci  usually  has 
an  extraordinary  effect  in  raising  the  resistance  and  completely  stopping 
their  appearance.  They  begin  usually  about  a  hair,  and  the  abscess 
develops  until  the  hair  can  be  seen  standing  up  in  the  middle  of  a  small, 
opaque  yellow  fleck.  From  that  the  infection  burrows  deeper  and  spreads 
laterally  a  little  under  the  corium,  which  in  the  thicker  parts  of  the  skin 
prevents  for  some  time  the  complete  evacuation  of  the  pus  to  the  outside. 
In  time,  however,  through  the  bursting  of  the  central  necrotic  cap  of  skin, 
it  escapes  and  the  hole  thus  left  heals  up  by  the  formation  of  granulation 
tissue.  The  surgeon  can  hasten  this  process  by  stretching  or  bursting 
open  the  hole  with  as  little  injury  as  possible  to  the  adjacent  tissue.  If  he 
squeezes  or  cuts  that  adjacent  tissue  so  as  to  impair  its  blood  supply, 
extension  of  the  infection  is  almost  inevitable. 

When  the  resistance  is  very  low,  the  cocci  may  quickly  extend  to  form 
a  whole  group  of  connected  abscesses,  with  several  projecting  necrotic 
points  side  by  side  in  the  skin.  The  whole  swollen  mass  is  honeycombed 
with  channels  full  of  pus  in  the  necrotic  tissue,  and  the  further  expansion 
proceeds  rapidly.  Such  a  threatening  affection  is  known  as  a  carbuncle, 
and  requires  prompt  surgical  intervention.  They  occur  anywhere,  but 
most  commonly  on  the  back  of  the  neck  or  on  the  lip  or  buttocks.  Those 
on  the  upper  lip  are  particularly  to  be  feared,  since  extension  along  the 
lymphatics  or  thrombophlebitis  extending  upward  through  the  nose  to  the 
cavernous  sinus  may  lead  to  meningitis. 

Infection  of  the  finger  extending  about  the  nail  (paronychia,  panaritium) 
or  of  the  palmar  surface  are  guided  in  their  extension  by  the  fasciae  of  the 
finger  and  hand.  Involvement  of  the  tendon-sheaths  is  a  particularly 
destructive  complication. 

Impetigo  contagiosa,  a  skin  disease  of  children,  appears  to  be  caused  by 
the  staphylococcus.  It  produces  pustules  about  the  face,  especially  around 
the  nose  and  mouth,  which  burst  and  dry  up  into  a  honey-yellow  crust 
without  much  surrounding  reaction.  It  may  spread  over  the  entire  body, 
especially  where  the  child  can  scratch  the  skin,  and  is  contagious  for  other 
children,  although  not  all  are  susceptible. 

General  Septicaemia.— While  the  Staphylococcus  aureus  is  perhaps  the 
most  common  cause  of  the  forms  of  furunculosis  just  described,  the 
Staphylococcus  albus  takes  part,  and  in  infections  which  become  general, 
it,  too,  is  quite  often  found.  General  distribution  of  staphylococci  through 
the  blood-stream  occurs  readily,  even  from  small  infected  scratches  or  cuts, 
or  from  some  other  local  infection,  all  of  which  may  heal  up  and  disappear 
before  the  general  infection  is  well  under  way.  The  wide-spread  character 


STAPHYLOCOCCUS   INFECTIONS 


535 


of  such  general  infections  may  be  most  clearly  brought  out  by  describing 
cases  which  have  recently  come  to  my  attention  at  autopsy. 

A  man  fell  in  a  Pullman  car  against  some  projection  which  caused  an 
abrasion  between  his  shoulders;  death  occurred  two  weeks  later,  and  at 
the  autopsy,  although  the  abrasions  were  partly  healed,  huge  abscesses 
were  found  among  the  muscles  of  the  back;  the  right  knee  was  distended 
with  a  purulent  fluid,  and  an  abscess,  filled  with  thick  greenish  pus,  bur- 
rowed among  the  muscles  of  the  thigh. 


Fig.  258. — Multiple  abscesses  in  the  heart- 
wall  from  a  case  of  general  staphylococcus 
septicaemia. 


Fig.  259. — Staphylococcus  septicae- 
mia. Minute  abscesses  in  the  pericar- 
dium surrounded  by  haemorrhagic 
flecks. 


A  plumber,  who  had  cut  his  finger  with  a  piece  of  tin  some  weeks  before 
his  death,  making  a  trifling  wound  which  had  healed  completely,  was 
brought  to  the  hospital  in  a  condition  of  delirium  without  definite  localizing 
symptoms.  At  the  autopsy  there  was  found  a  general  infection  with  the 
Staphylococcus  aureus,  which  was  cultivated  from  the  blood.  There  were 
small  abscesses  in  nearly  all  the  organs,  everywhere  presenting  themselves 
as  opaque  yellowish  spots  surrounded  by  a  zone  of  haemorrhage.  The 
heart  muscle  was  studded  everywhere  with  them  (Fig.  258),  while  upon 


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the  aortic  valves  there  were  soft  vegetations.  The  pericardium  showed 
numerous  haemorrhagic  flecks  (Fig.  259),  with  central  opacities,  as  did  the 
pleural  and  peritoneal  surfaces.  Throughout  the  intestinal  mucosa  there 
were  haemorrhagic  nodules,  and  similar  foci  appeared  in  the  kidneys  and 
liver.  In  the  lungs  the  abscesses  were  larger,  with  central  softening,  and  a 
zone  of  haemorrhagic  pneumonic  consolidation  about  each. 

Sometimes  it  is  difficult  to  determine  upon  the  portal  of  entry  of  the  cocci, 
as  in  the  case  of  a  sailor  brought  off  a  ship  to  the  hospital.  He,  too,  was 
in  a  state  of  coma,  extremely  anaemic,  with  signs  of  patchy  bronchopneu- 
monic  consolidation,  and  with  abundant  staphylococci  in  a  culture  from 
the  circulating  blood.  At  autopsy  practically  the  same  wide-spread  focal 
lesions  were  found  as  described  in  the  preceding  case,  the  heart  muscle 


Fig.  260.— Staphylococcus  septicaemia.     Multiple  abscesses  01  the  kidney. 

and  kidneys  being  especially  thickly  set  with  small  abscesses  (Fig.  260). 
No  source  of  infection  could  be  found  after  the  most  minute  search,  until 
a  decayed  canine  tooth  was  pulled  from  the  upper  jaw,  when  a  gush  of  pus 
came  from  the  antrum,  which  evidently  represented  the  portal  of  entry. 
It  should  be  noted  that  in  such  infections,  especially  when  they  are  not 
quite  so  severe  and  rapidly  fatal,  localization  of  the  bacteria  in  the  joints 

the  production  of  a  purulent  synovitis  is  not  uncommon. 
Suppurative  Nephritis.-Aside  from  their  appearance  as  part  of  a  general 
pyaemia,  Staphylococcus  infections  of  the  cortex  and  medulla  of  the  kidney 
nsported  there  by  the  blood-stream,  come  to  the  attention  of  the  surgeon 
e  commonly  than  is  generally  thought.     Jordan,  Brewer,  and  others 
scribed  them  as  multiple  foci,  involving  necrosis  of  the  renal  tissue 
cortex,  and  extending  into  the  pyramids.     They  are  probably  formed 


STAPHYLOCOCCUS   INFECTIONS 


537 


in  the  effort  of  the  kidney  to  excrete  the  staphylococcus  brought  by  the 
blood-stream,  and  may  develop  about  the  bacteria,  which  accumulate  with 
casts  in  the  tubules  (staphylococci  are  known  to  be  abundantly  excreted  in 
the  urine  in  general  infection).  Brewer  looks  upon  them  as  rather  of 
embolic  origin,  and  therefore  starting  from  the  neighborhood  of  the  plugged 
arteriole  or  glomerulus.  They  may  produce  multiple  extensive  hsemor- 
rhagic  patches  of  necrosis  in  the  substance  of  the  kidney  (Fig.  261).  Simi- 
larly, as  the  only  internal  lesion  produced  by  transportation  of  cocci  from 


Fig.  261.— Hsemorrhagic  septic  infarctions  of  the  kidney  produced  by  the  Staphylo- 
coccus aureus  (Brewer). 

some  cutaneous  infection,  there  may  be  formed  a  perirenal  abscess  which 
can  later  encroach  upon  the  kidney. 

There  is  always  the  question  as  to  whether  such  hsematogenous  infec- 
tions of  the  kidney  are  to  be  regarded  as  the  basis  for  the  forms  of  sup- 
purative  pyelonephritis  associated  with  infections  of  the  urinary  bladder. 
As  in  the  case  of  tuberculosis  of  these  organs,  there  are  those  who  regard 
the  process  as  the  result  of  ascending  infection  from  the  bladder,  while 
others  assume  it  to  be  hamatogenous  or  indirect.  It  seems  that  both 


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types  may  occur,  although  when  abscesses  appear  in  the  kidneys  as  the  di- 
rect continuation  of  an  illness  which  begins  with  obstruction  to  the  out- 
flow of  urine  from  the  bladder,  infection  by  catheterization,  cystitis,  and 
ureteritis,  it  is  almost  impossible  to  resign  oneself  to  the  idea  that  in  those 
cases  the  bacteria  enter 'the  kidney  by  the  blood-stream.  All  this  can  be 
more  appropriately  discussed  in  another  place,  since  the  staphylococcus 


li 


Fig.  262.— Abscesses  in  the  lung.     These  abscesses  were  close  set,  and  caused  relatively 
little  reaction.     Usually  they  are  isolated,  hjemorrhagic,  and  much  larger. 

is  not  often  primarily  concerned  in  such  cases.     On  the  other  hand,  the 
chills  which  follow  catheterization  are  really  in  most  cases  the  expression 
f  a  general  staphylococcus  septicamia  of  mild  character  initiated  by  the 
trauma  in  the  operation. 

Endocarditis  is  a  very  common  accompaniment  of  staphylococcus  infec- 
ion,  the  mitral  and  aortic  valves  being  especially  affected,  while  the  vege- 
tations are  occasionally  found  upon  the  tricuspid  or  upon  the  walls  of  the 


STAPHYLOCOCCUS   INFECTIONS  539 

heart.    They  are  usually  rather  large,  soft  thrombus  masses,  which  readily 
crumble  and  give  rise  to  emboli. 

Lobular  Pneumonia. — As  in  the  case  of  streptococcal  infections  of  the 
lung,  there  is  nothing  especially  characteristic  about  many  of  the  cases  in 
which  the  staphylococcus  forms  the  infectious  cause  of  bronchopneumonia, 
except  in  those  instances  in  which  the  concentration  is  such  as  to  produce 
definite  abscesses  (Fig.  262).  The  mode  of  entrance  into  the  lung  tissue  is 
probably  in  part  responsible  for  this.  Chickering  and  Park  describe  an 
epidemic  of  pneumonia  following  influenza  in  the  course  of  the  great 
epidemic,  caused  by  the  Staphylococcus  aureus,  and  characterized  by 
the  presence  of  many  minute  abscesses  throughout  the  lungs. 

LITERATURE 

Chickering  and  Park:  Jour.  Amer.  Med.  Assoc.,  1919,  Ixxii,  617. 

Osteomyelitis. — It  is  in  producing  a  destructive  lesion  in  the  bones, 
involving  periosteum,  cortex,  marrow,  and  even  extending  to  the  cartilages, 
that  the  staphylococcus  plays  one  of  its  most  characteristic  roles,  although 
here,  too,  other  organisms,  such  as  the  pneumococcus,  the  typhoid  bacillus, 
and  others  may  take  its  place  and  cause  similar  lesions.  In  the  great 
majority  of  the  cases,  however,  the  staphylococcus  is  found.  Here  it 
shows  particularly  well  its  tendency  to  localize  itself  and  grow  in  a  place 
already  injured  mechanically.  If  several  ribs  or  other  bones  are  fractured 
in  a  rabbit,  it  is  said  that  a  subsequent  injection  of  a  culture  of  the  Staphy- 
lococcus aureus  will  produce  an  abscess  at  the  site  of  each  fracture.  These 
may  be  considered  as  points  of  lowered  resistance,  or  perhaps  the  inter- 
ruption of  blood-vessels  allows  the  bacteria  to  be  caught  there  instead  of 
being  swept  on  by  the  blood-stream.  In  the  same  way  in  human  beings 
a  blow  upon  a  bone  appears  to  predispose  it  to  the  settling  there  of  bac- 
teria. 

The  organisms  reach  the  bone  either  from  a  recognized  focus  of  infection, 
or  from  some  small  infected  abrasion  or  wound  which  heals  and  is  for- 
gotten before  the  disease  of  the  bone  is  evident.  It  is  the  latter  case  which 
has  given  rise,  no  doubt,  to  the  idea  that  there  may  be  a  primary  osteomye- 
litis, a  situation  which  is  realized  in  cases  of  infected  compound  fractures. 
The  long  bones  are  affected  far  more  often  than  the  others;  nevertheless 
osteomyelitis  involving  the  tarsal  and  carpal  bones,  the  vertebrae,  the 
clavicles,  and  the  bones  of  the  pelvis  is  not  rare.  The  disease  occurs  most 
frequently  in  children  and  young  persons,  the  cases  being  most  numerous 
in  those  between  the  ages  of  thirteen  and  seventeen,  after  which  they  fall 
off  rapidly. 

The  cocci  usually  lodge  in  the  shaft  of  one  of  the  long  bones  in  such  a  position  as  the 
upper  third  of  the  tibia  or  the  lower  third  of  the  femur,  and  there  produce  an  abscess  in 
the  cancellous  substance  of  the  bone  which  involves  the  cortex  and  the  periosteum, 
lifting  up  the  latter  from  the  surface  of  the  bone.  As  in  other  abscesses,  the  presence  of 


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the  bacteria  leads  to  necrosis  of  the  tissue  round  about,  and  from  the  fact  that  this 
necrosis  extends  far  wide  of  the  clump  of  cocci,  it  may  be  agreed  that  they  produce  a 


Fig.  263.— Large  Fig.    264. — Osteomyelitis    show-      Fig.  265.— Chronic  perios- 

necrotic  fragment  of  ing  the  sequestrum,  the  involucrum          titis  with  osteophytes. 

bone  or  sequestrum  with  orifices  which    represent  the 

from   the    tibia   in  sinuses,  and  periosteal  osteophytes. 
osteomyelitis. 


toxic  substance.     (This,  in  fact,  is  well  proved  for  the  staphylococci.)     The  leucocytes 
which  accumulate  liquefy  the  necrotic  tissue  and  attack  the  bony  lamellae,  which  they 


STAPHYLOCOCCUS   INFECTIONS  541 

reduce  to  fragments.  Frequently  large  portions  of  the  cortex  thus  become  necrotic 
and  rarefied,  and  finally  isolated  from  the  still  living  bone  as  a  sequestrum  (Fig.  263) 
which  practically  floats  in  a  pus-filled  cavity.  Generally  it  is  not  so  completely  loosened 
for  some  time,  but  in  its  extent  it  may  amount  to  nearly  the  whole  shaft  of  the  bone. 
I  recall  vividly  one  such  case  from  my  assistant  time  in  the  surgical  wards,  upon  which 
I  was  allowed  to  operate.  It  was  a  boy  of  about  twelve,  whose  left  leg,  as  he  was 
brought  into  the  hospital,  was  greatly  swollen  below  the  knee,  tense,  and  cedematous. 
He  was  suffering  a  great  deal  of  pain  and  had  a  high  temperature,  but  there  was  found 
no  obvious  point  of  infection  elsewhere,  from  which  the  disease  of  his  leg  might  have 
started.  A  long  incision  was  made,  and  quantities  of  rather  gritty  brown  pus  flowed  out. 
The  periosteum  had  been  lifted  up  from  nearly  the  whole  length  of  the  tibia,  and  evi- 
dently had  been  torn  to  let  the  pus  escape  into  the  intermuscular  tissues.  The  bone 
itself  was  already  rough,  and  some  portions  of  it  were  easily  pulled  away.  These  were 
ragged,  as  if  worm-eaten.  Much  of  the  rest  was  chiseled  or  gouged  away,  leaving,  as 
I  remember  it,  the  posterior  half  of  the  bone  exposed  in  the  wound  which  remained  open. 
Healing  occurred  in  a  remarkable  fashion  by  the  growth  of  the  most  luxuriant  granula- 
tion tissue,  from  the  crevices  in  which  tiny  fragments  of  bony  lamellae  were  discharged 
for  some  time.  Even  when  the  skin  covered  most  of  the  granulating  surface,  a  fistula 
extending  to  the  bone  at  one  point  remained  for  a  time  and  discharged  bony  granules, 
but  this  in  time  healed  up.  This  boy  remained  well,  but  it  is  frequently  the  case  that 
before  one  focus  is  completely  cleaned  out  and  healed,  another  appears  in  some  far-dis- 
tant bone.  Occasionally  they  follow  one  another  in  rapid  succession,  destroying  or 
mutilating  one  bone  after  another,  and  ending  often  in  the  development  of  a  general 
septicaemia  with  hundreds  of  small  abscesses  in  the  internal  organs. 

When  not  treated  by  radical  surgery,  the  most  remarkable  results  may  ensue,  especi- 
ally when  the  infective  agent  is  not  so  virulent  as  to  lead  rapidly  to  very  extensive 
destruction  or  to  general  septicaemia.  While  in  the  acute  forms  the  necrotic  bone  is 
rapidly  rarefied  and  partly  disintegrated,  it  may  happen  that  in  the  more  slowly  pro- 
gressing forms  there  is  time  for  prolonged  activity  on  the  part  of  the  osteoblasts  which 
cover  the  bony  lamellae  in  the  neighborhood  of  the  focus  of  infection,  before  that  sur- 
rounding bone  tissue  is  involved  in  the  necrosis.  Then  each  lamella  becomes  greatly 
thickened,  and  the  bone  becomes  compact  as  ivory  (eburnation  or  sclerosis).  It  is  for 
this  reason  that  the  necrotic  sequestrum  is  sometimes  found  to  be  extremely  dense  and 
hard.  In  such  subacute  cases,  which  are  more  localized,  the  extension  of  the  infection 
and  inflammatory  exudate  to  the  periosteum  lifts  up  and  ruptures  only  a  small  part  of 
it.  The  pus  then  burrows  in  a  channel  among  the  muscles  to  the  skin,  where  it  causes 
a  bluish-red  bulging,  which  finally  ruptures  like  an  abscess.  In  this  way  a  sinus  is 
formed  through  which  a  probe  can  be  passed  down  until  it  scrapes  upon  the  rough  dead 
bone.  Through  this  sinus  fragments  of  bone  may  be  discharged  with  the  pus  for  a 
long  time.  If  any  considerable  mass  of  the  cortex  has  been  thus  converted  into  a  loose 
sequestrum,  extensive  healing  processes  go  on  about  it,  even  though  it  maintains  a  con- 
stant source  of  infection.  It  is  true  that  the  bacteria  may  die  out,  but  even  then  the 
mass  of  dead  bone  acts  as  a  foreign  body  of  which  the  tissues  cannot  get  rid.  Instead, 
abundant  new  bone  with  much  granulation  tissue  is  formed  about  it,  usually  still  per- 
forated by  the  sinus  or  sinuses  which  extend  to  the  skin.  In  time  there  may  be  pro- 
duced in  this  way  (Fig.  264)  a  sheath  of  new  bone  which  practically  represents  the  old 
shaft  (the  involucrum)  inside  which  the  sequestrum  persists.  A  great  part  of  this  is 
formed  by  the  periosteum,  but  those  portions  of  the  shaft  which  remain  alive  produce 
much  new  tissue  by  the  aid  of  their  endosteal  cells.  It  is  easy  to  understand  that  if  that 
portion  of  the  cortex  of  the  shaft  which  is  destined  to  become  necrotic  and  sequestrated 
can,  in  the  mean  while,  undergo  sclerosis  or  eburnation  by  the  new  formation  of  layers 
of  bone  in  all  its  Haversian  systems  and  on  the  surfaces  of  all  its  lamellae,  the  rest  of  the 
bone  will  do  the  same.  It  is  for  this  reason  that  whatever  remains  of  such  a  shaft  is 
found  to  be  heavy  and  dense.  Indeed,  if  the  infectious  process  proceeds  very  slowly 


542  TEXT-BOOK   OF   PATHOLOGY 

and  without  gross  destruction  of  the  cortex,  the  whole  bone  may  preserve  its  form,  but 
become  almost  solid  and  very  dense  and  heavy.  Quite  aside  from  the  actual  area  of 
necrosis  or  in  its  absence,  the  inflammation  which  involves  the  periosteum  results 
in  its  producing  a  great  deal  of  new  bone  superficially  applied  to  the  shaft,  so  that  the 
surface  of  a  bone  in  old  osteomyelitis  is  usually  greatly  roughened  by  such  osteophytes 
(Fig.  265).  As  we  shall  see,  a  quite  similar  process  of  periosteal  bone  formation  is  fre- 
quent in  other  slowly  progressing  inflammatory  affections,  and  is  especially  striking  in 
syphilis. 

When  osteomyelitis  caused  by  the  staphylococcus  involves  the  bones 
of  the  skull,  or  in  the  cases  in  which  otitis  media  is  due  to  its  agency  (it  is 
very  frequently  active  here,  and  the  cause  of  nearly  all  the  chronic  forms), 
when  metastatic  abscesses  occur  in  the  brain,  or  when  extension  of  the 
infection  takes  place  from  furunculosis  of  the  nose  or  lip,  acute  meningitis 
may  arise,  involving  the  coverings  of  the  brain  and  extending  to  the 
pia-arachnoid  of  the  spinal  cord.  Its  nature  is  similar  to  that  caused  by 
the  streptococcus,  pneumococcus,  and  other  organisms,  and  it  will  more 
conveniently  be  described  elsewhere.  One  form  of  meningitis  is  of  inter- 
est, however,  in  this  connection,  namely,  the  purulent  pachymeningitis 
or  inflammation  of  the  dura.  That  this  should  occur  with  osteomyelitis 
of  the  bones  of  the  skull  is  self-evident,  but  one  occasionally  sees  cases  of 
another  type  in  which,  from  an  abscess  in  the  perirectal  tissue,  extension 
of  the  infection  occurs  along  the  nerves,  to  enter  the  sacral  foramina  or 
even  the  lumbar  foramina  to  the  space  outside  the  dura  and  within  the 
spinal  canal.  The  outer  surface  of  the  dura  then  becomes  bathed  in  pus. 

LITERATURE 

Neisser  and  Lipstein:   Handb.  v.  Kolle  u.  Wassermann,  1903,  iii,  105. 

Jos.  Koch:  Ergebn.  d.  allg.  Path.,  1909,  xiii,  205. 

Lenhartz:  Nothnagel's  Handb.  d.  spez.  Path.  u.  Therap.,  1903,  iii,  Teil  2,  329. 

Lexer:    " Osteomyelitis,"  Volkmann's  klin.  Vortrage,  173. 


CHAPTFR  XXVII 

TYPES    OF   INJURY.     BACTERIAL  DISEASE   (Continued).— PNEU- 
MOCOCCUS  INFECTION 

Character  of  organisms.  Lobar  pneumonia:  consolidation,  resolution,  organization,  etc. 
Septiccemia.  Endocarditis. 

Character  of  Organisms. — The  pneumococcus  or  Micrococcus  lanceolatus 
is  best  known  on  account  of  its  preeminent  relation  to  the  clear-cut  disease, 
lobar  pneumonia.  It  is  true  that  it  is  concerned  in  many  other  infectious 
processes,  including  otitis  media,  meningitis,  various  inflammations  of  the 
nasal  sinuses,  pleurisy,  pericarditis,  general  peritonitis,  and  even  general 
septicaemia,  as  well  as  the  more  indefinite  forms  of  lobular  or  patchy  pneu- 
monia. On  the  other  hand,  a  few  other  organisms,  such  as  Friedlander's 
capsulated  bacillus,  have  been  detected  at  times  as  the  cause  of  unmistak- 
able acute  lobar  pneumonia. 

The  pneumococcus  is  very  widely  distributed,  and  occurs  in  the  mouths  and  upper 
respiratory  tracts  of  most  normal  persons.  It  varies  greatly  in  virulence,  as  has  been 
shown  by  animal  inoculations,  and  those  cultivated  from  pneumonic  lungs  are  not  neces- 
sarily more  virulent  than  those  from  the  mouths  of  healthy  persons.  It  produces  a 
toxic  substance  which  is  feebly  hsemolytic,  but  which  must  be  extracted  from  the  dis- 
solved bodies  of  the  organism.  It  has  the  power  of  converting  haemoglobin  into  met- 
hsemoglobin,  and  can  be  neutralized  by  cholesterine.  Studies  of  Neufeld,  and  especially 
of  Cole  and  his  assistants,  have  revealed  the  fact  that  there  are  several  kinds  of  pneu- 
mococci  which  can  be  distinguished  sharply  from  one  another  by  their  biological  charac- 
ters, although  morphologically  and  culturally  they  are  alike.  By  the  aid  of  sera  pro- 
duced by  inoculating  living  pneumococci  of  different  strains  into  large  animals  Cole, 
Dochez,  and  Gillespie  have  been  able  to  distinguish  sharply  at  least  four  types,  which 
have  been  found  to  occur  in  150  cases  of  pneumonia  in  the  following  proportions: 

Type  I . .  57 

Type  II 44 

Type  III  (Pneumococcus  muccsus) 17 

Type  IV  (heterogeneous) 32 

A  potent  serum  was  obtained  for  Type  I,  a  less  satisfactory  one  for  Type  II.  Attempts 
to  produce  a  protective  serum  against  Type  III  failed  completely,  but  this  organism, 
which  is  the  Streptococcus  mucosus  of  Schottmiiller,  is  readily  distinguished  by  its  very 
large  capsule,  its  stringy  growth  in  culture,  and  by  the  glutinous  exudate  in  the  lungs  in 
pneumonia  caused  by  it.  It  produces  the  severest  infections.  Type  IV  is  made  up  of 
a  great  many  different  strains,  none  of  which  ordinarily  produces  a  very  severe  pneu- 
monia. They  are  the  forms  found  in  the  mouths  of  healthy  persons;  they  are  overgrown 
by  Types  I,  II,  or  III  in  pneumonias  caused  by  those  types,  but  reappear  in  the  mouth 
on  convalescence  after  the  infecting  type  has  disappeared.  Protective  sera  can  be  pro- 
duced for  each  member  of  Type  IV,  but  they  are  quite  specific,  and  powerless  against  any 

543 


544  TEXT-BOOK   OF   PATHOLOGY 

other  member  of  the  group.  So,  too,  the  sera  for  Types  I  and  II  have  no  protective  effect 
against  Types  III  or  IV,  nor  against  one  another,  but  are  quite  specific  for  the  homologous 
organisms.  Although  infections  produced  by  Type  III  are  so  far  insusceptible  of  treat- 
ment by  any  serum,  the  serum  for  Type  I  is  used  in  large  doses,  with  excellent  effect. 
Infections  with  Type  IV  are  so  mild  as  scarcely  to  require  serum  treatment.  With  the 
aid  of  these  specific  sera  the  organism  in  any  case  of  pneumonia  can  be  referred  to  its 
type  either  by  inoculating  mice  and  ascertaining  which  protective  serum  causes  them 
to  survive,  or  by  testing  the  agglutination  of  the  organisms  with  each  serum.  It  is 
impossible  to  discuss  here  the  rather  indefinite  toxins  which  have  been  extracted  from 
various  types  of  pneumococcus.  The  student  is  referred  to  the  papers  of  Cole.  Some 
promising  results  have  been  obtained  by  Cole,  Cecil,  and  Austin  in  protecting  large 
bodies  of  troops  from  pneumonia  by  the  use  of  a  prophylactic  vaccine. 


LOBAR  PNEUMONIA 

Pneumonia  is  an  acute  infectious  disease  which  begins  suddenly,  usually 
with  a  sharp  pain  in  the  chest  and  with  a  chill  and  high  fever.  It  proceeds 
with  extensive  consolidation  of  the  lung,  evidences  of  intoxication,  and 
various  metabolic  disturbances,  to  the  death  of  the  patient  or  to  sudden 
disappearance  of  the  symptoms  and  rapid  passing  away  of  the  consolida- 
tion (crisis),  or  to  a  slower  and  more  gradual  defervescence  and  relief  from 
the  symptoms  of  the  disease  (recovery  by  lysis).  Occasionally,  while  the 
symptoms  of  the  acute  illness  disappear  completely  and  convalescence 
seems  complete,  a  form  of  consolidation  of  the  lung  persists  and  is  found  to 
be  due  to  a  replacement  of  the  exudate  by  fibrous  tissue.  Other  com- 
plications which  delay  recovery  or  lead  to  death  will  be  discussed  later. 
Since  most  persons  harbor  pneumococci  in  their  mouths,  and  since  pneu- 
monia seems  not  to  be  a  particularly  contagious  disease,  although  rarely 
occurring  in  small  epidemics,  the  question  arises  as  to  the  mode  of  entry 
of  the  organisms  into  the  lungs  and  the  conditions  under  which  they  pro- 
duce pneumonia.  It  is  shown  that  many  persons  who  do  not  contract 
diphtheria  are  carriers  of  virulent  diphtheria  bacilli,  and  the  same  is  true, 
in  a  modified  way,  of  other  organisms.  Therefore  unless  it  should  prove 
that  those  who  develop  pneumonia  do  so  always  from  the  invasion  of  a 
pneumococcus  of  a  type  different  from  that  which  they  have  harbored  in 
their  mouths,  we  must  search  for  some  predisposing  cause  for  their  invasion. 
It  has  long  been  known  (Litten)  that  crushing  or  contusion  of  the  thorax 
is  frequently  followed  by  pneumonia,  and  there  is  also  the  general  impression 
that  alcoholism  predisposes  to  it,  and  that  some  sudden  exposure  to  cold 
is  likely  to  precipitate  invasion  of  the  infection.  Meltzer  has  attempted  to 
demonstrate  with  more  precision  that  it  requires  local  predisposing  causes 
in  the  lungs  to  permit  the  bacteria  to  gain  a  foothold  there.  He  found  that 
a  diffuse  lobar  pneumonia1  could  be  produced  in  dogs  if  large  quantities  of 
a  liquid  culture  of  pneumococci  were  blown  into  the  bronchi  and  forced 
into  the  air-cells  with  the  fluid  and  air-bubbles  from  his  cannula.  He 
suggests  that  in  man  mucus  in  the  bronchi  maybe  the  agent  which  imprisons 
behind  it  a  sufficient  number  of  bacteria  to  gain  a  start  and  produce  an. 


LOBAR   PNEUMONIA  545 

effective  growth.  Blake  and  Cecil  have  experimented  with  virulent  cul- 
tures of  pneumococcus  and  have  found  that  lobar  pneumonia  can  be  pro- 
duced in  monkeys  by  the  mere  injection  of  minute  quantities  of  the  culture 
into  the  trachea.  They  attribute  the  failure  of  previous  experimenters  to 
produce  any  pneumonia  except  by  the  use  of  extreme  doses  and  mechanical 
obstruction  of  the  bronchi  to  the  fact  that  they  always  employed  relatively 
insusceptible  animals.  In  their  own  experiments  the  infection  seemed  to 
begin  at  the  hilum  of  the  lung  and  extend  radially  through  the  tissue  from 
the  bronchial  wall,  largely  by  way  of  the  lymphatics.  It  is  too  soon,  how- 
ever, to  feel  sure  that  this  interpretation  of  the  genesis  of  the  lobar  consoli- 
dation will  prevail.  By  whatever  means  the  cocci  gain  a  wide  distribution 
throughout  all  the  small  bronchioles  and  most  of  the  air-cells  of  the  lobe, 
they  are,  as  Ribbert  has  pointed  out,  more  abundant  in  the  terminal  por- 
tion of  the  bronchioles  and  less  abundant  toward  the  outer  limit  of  the  air- 
cells  which  communicate  with  that  bronchiole. 

Ether  Pneumonia. — Pneumonia  which  occurs  after  a  surgical  operation 
with  general  anesthesia  is  not  infrequent,  and  presents  some  problems 
of  interest.  It  was  thought  to  be  lobular  in  character,  and  due  to  the  aspi- 
ration of  various  bacteria  with  saliva,  etc.,  during  the  anaesthesia,  owing  to 
the  abolition  of  the  normal  reflexes  which  would  prevent  the  access  of  such 
materials  to  the  lungs.  A.  O.  Whipple  has  shown,  however,  in  an  interesting 
study  of  many  cases  of  this  kind  that  some  of  these  consolidations  are 
lobar  in  type  and  that  they  are  usually  caused  by  infection  with  pneumo- 
cocci  of  Group  IV,  which  are  known  to  be  common  in  the  throats  of  per- 
sons who  are  not  ill. 

LITERATURE 

Whipple,  A.  O. :  Surg.,  Gyn.,  and  Obst.,  1918,  xxvi,  29. 

Anatomical  Changes. — The  inflammatory  reaction  is  commonly  divided 
into  several  stages.  Of  these,  the  first,  the  so-called  stage  of  engorgement, 
is  rarely  seen  at  autopsy,  except  perhaps  at  the  edges  of  an  advancing 
consolidation,  and  it  must  be  conceded  that  its  characters  are  to  some 
extent  constructed  from  the  known  course  of  inflammation  elsewhere. 
The  capillaries  of  the  alveolar  walls  are  dilated  with  blood,  and  there 
exudes  into  the  air-cells  fluid  from  the  blood,  together  with  leucocytes 
and  red  corpuscles.  The  second  stage,  which  is  the  earliest  one  com- 
monly seen,  is  called  the  stage  of  red  hepatization  (because  the  lung  is 
red  and  solid,  like  the  liver).  At  this  stage  an  abundant  inflammatory 
exudate  is  found  to  have  filled  the  alveoli  and  to  have  clotted.  As 
in  the  case  of  a  perfectly  fresh  clot  of  blood  in  a  glass  dish,  which  is 
so  firm  and  dry  that  the  dish  can  be  inverted  without  spilling  it,  these 
clots  in  the  air-cells  are  firm  and  dry.  In  sections  they  are  seen  to 
fill  the  air-cell  (Fig.  266)  and  to  be  composed  of  a  coarse-meshed  net- 
work of  fibrin  in  which  are  entangled  numerous  pneumococci,  many  red 
corpuscles,  many  polymorphonuclear  leucocytes,  and  some  desquamated 
epithelial  cells.  Furthermore,  at  this  stage,  and  even  in  the  earlier  stage, 
36 


546 


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there  are  seen  quite  numerous  mononuclear  wandering  cells  or  lympho- 
cytes. This  feature  has  been  pointed  out  by  Pratt,  and  is  far  less  char- 
acteristic of  later  stages.  Perhaps  the  most  distinctive  thing  about 
the  exudate  from  the  microscopical  point  of  view  is  its  freshness  and 
good  state  of  preservation.  The  red  cells  are  intact,  and  stand  out  clearly 
with  their  normal  haemoglobin  content;  in  other  words,  they  show  as  yet 
no  sign  of  laking  or  haemolysis.  The  leucocytes  are  clearly  outlined 


Fig.  266.— Lobar  pneumonia;   red  hepatization.     A  single  alveolus  showing  fresh  exu- 
date with  well-preserved  cells.     A  megalocaryocyte  in  one  of  the  capillaries. 

and  turgid.  All  these  cells  can  be  seen  clearly  because  they  are  rela- 
tively few  in  numbers  and  stand  out  distinctly  in  the  fibrin  network. 
Many  of  the  leucocytes  show  active  phagocytosis  and  contain  several 
pneumococci. 

In  its  gross  appearance  at  this  stage  such  a  lung  is  very  characteristic. 
The  consolidation  may  involve  one  or  more  lobes,  which  are  dense  and 


LOBAR   PNEUMONIA 


547 


hard  and  heavy.  Their  pleural  surface  has  lost  its  normal  gloss  and  is 
seen  to  be  covered,  over  the  consolidated  area,  with  a  delicate,  scarcely 
perceptible  layer  of  yellowish  fibrin.  On  section  the  bronchi  are  reddened 
and  may  be  plugged  in  their  smaller  branches  with  moulds  of  fibrin.  The 
cut  surface  of  the  lung  is  usually  dry,  rough,  and  of  a  deep  red  color. 
The  roughness  is  due  to  the  slight  projection  from  each  alveolus  of  its  plug 
of  coagulated  exudate.  In  sharp  contrast  with  this  flat  plateau  of  con- 


ft«-».;v  ••-.'  '^v" '»«••••>-**    '' 

||V\^;^;^V;;^ 

?,-     *'V.      .\  ".    e          -t      '®         *§,  fe    *    ^       '* 


Fig.  267. — Lobar  pneumonia;    gray  hepatization,  showing  retraction  and  consolidation 
of  fibrin  and  partial  disintegration  of  leucocytes. 

solidated  lung,  the  remainder  collapses  and  allows  the  escape  of  some 
of  its  content  of  air.  It  still  crackles  and  crepitates  under  the  finger,  while, 
of  course,  the  consolidated  lobe  is  firm  and  airless.  In  spite  of  what  was 
said  about  the  stage  of  engorgement,  it  is  rather  rare  to  find  anything  but 
an  abrupt  transition  from  the  consolidated  to  the  unaffected  lung  substance. 
The  third  stage  is  the  stage  of  gray  hepatization,  although  it  is  usual— 


548 


TEXT-BOOK   OF   PATHOLOGY 


indeed  almost  the  rule— to  find  the  consolidated  lung  in  an  intermediate 
condition,  and  of  a  color  half-way  between  red  and  gray.  The  nature  of 
that  intermediate  stage  will  be  readily  understood  from  a  description  of  the 
gray  hepatization. 

In  section  the  alveoli  are  found  to  be  densely  packed  with  a  cellular  exu- 
date  (Fig.  267).  By  this  time,  although  the  bacteria  have  increased  in 
number  and  the  alveoli  are  crowded  tightly  with  many  more  polynuclear 
leucocytes,  which  frequently  contain  the  cocci,  the  fibrin  is  not  observed 


/v 

/  - 

<» 

* 


'&-(  .  •'.'•-•M't* 

•-,.»-     •'«•»?  9  ®     gWKfc'l 

p.^wfo       %r--^i> 
^ 
'^ 


& 

& 


^ 


ft®*fii 

<»*  v 


\  *• 

ft 
J^ 


Fig.  268.— Lobar  pneumonia;  red  hepatization,  showing  megalocaryocytes  in  the  capil- 
laries. 

to  have  increased  specially  in  quantity.  Instead,  it  is  packed  together, 
often  in  pretty  compact  masses,  and  scarcely  shows  any  longer  the  graceful 
network  which  was  to  be  seen  in  the  earlier  stages.  Red  corpuscles  are 
hardly  to  be  found  in  the  advanced  stage  of  gray  hepatization,  except  that 
with  careful  scrutiny  the  shadowy  outlines  of  those  which  have  lost  their 
haemoglobin  may  be  made  out  here  and  there  among  the  closely  crowded 
leucocytes.  The  capillaries  of  the  alveolar  wall  are  quite  patent,  as  can 
be  shown  easily  by  injection,  but  they  seem  compressed  by  the  mass  of 


LOBAR   PNEUMONIA  549 

exudate  and  no  longer  look  distended  with  blood.*  In  this  stage  and  in  the 
stage  of  red  hapatization  one  may  often  find  capillaries  obstructed  by  a 
huge  cellular  mass  which  proves  to  be  a  megalocaryocyte  from  the  bone- 
marrow,  swept  into  the  lung  in  the  general  rush  of  leucocytes  from  the 
marrow  (Fig.  268).  In  both  stages,  too,  one  may  make  out  the  fact  that 
the  fibrin  threads  in  any  one  air-cell  often  seem  to  twist  themselves  into  a 
thin  cord,  and  pass  directly  through  the  alveolar  wall,  to  spread  out  again 
into  the  network  of  the  next  air-cell.  This  is  because  of  the  presence  of 
the  so-called  "pores  of  Cohn,"  which  may  be  normal  apertures  in  the  wall, 
although  it  has  been  contended  by  many  that  they  occur  only  in  lungs 
somewhat  altered  by  emphysema. 

The  most  distinctive  feature  of  the  stage  of  gray  hepatizatlon  from  the 
microscopical  point  of  view  is  the  degenerated  condition  of  the  cells  of  the 
exudate.  Not  only  have  the  red  cells  undergone  laking  and  disintegra- 
tion, but  the  leucocytes  have  lost  their  clear  outline,  if  not  their  whole 
protoplasm,  and  have  become  granular,  ragged,  partly  disintegrated  cells, 
which,  however,  still  show  evidences  of  their  phagocytic  activity.  Most 
of  them  contain  fine  droplets  of  fat,  and  some  contain  yellow  pigment,  evi- 
dently produced  at  the  expense  of  the  haemoglobin  of  the  broken  red  cor- 
puscles. Desquamated  epithelial  cells  are  rather  more  abundant,  and  they 
too  contain  fat-droplets  and  pigment-granules. 

In  the  gross  appearance  (Fig.  269)  the  lung  at  this  stage  is  still  more 
enlarged,  dense,  and  heavy.  Its  surface  is  covered  with  a  much  thicker 
layer  of  fibrin,  which  can  be  peeled  off,  leaving  a  dull  pleural  membrane. 
Not  only  does  this  cover  the  consolidated  lobe,  but  it  often  extends  over  the 
whole  lung  and  the  parietal  pleura.  Frequently  there  is  a  considerable  accu- 
mulation of  turbid  fluid  in  the  pleural  cavity,  separating  the  surfaces,  which 
elsewhere  may  be  found  glued  together  by  the  exudate.  On  section  the  cut 
surface  of  the  consolidated  lung  is  found  to  be  gray,  yellowish  gray,  grayish 
white,  or  yellowish  white,  although,  as  mentioned,  the  cases  in  which  some 
redness  persists  at  death  are  much  more  common.  The  surface  is  not  dry 
nor  so  rough  as  before,  but  gives  the  impression  that  the  alveoli  are  filled 
with  coarse  plugs  of  softer,  almost  unctuous  material,  a  condition  which  is 
doubtless  due  to  the  retraction  of  the  fibrin  setting  free  serum  in  each 
alveolus,  and  to  the  much  greater  number  of  leucocytes,  together  with  the 
accumulation  of  fat-droplets  in  their  substance.  The  color  is  easily  ex- 
plained by  the  laking  of  the  red  corpuscles,  the  yellowish  tint  being  con- 
tributed, no  doubt,  by  the  hsemosiderin  which  is  produced  from  their 
haemoglobin,  and  by  the  fat-content  of  the  leucocytes,  aided  by  the  gen- 
erally anaemic  state  of  the  lung. 

*  This  was  the  current  view,  but  recently  Kline  and  Winternitz  have  stated  that  it  is 
not  true  that  one  can  easily  inject  the  blood-channels  in  the  consolidated  lung.  Instead, 
the  area  of  consolidation  remains  almost  uncolored  by  the  mass,  and  the  capillaries  are 
found  to  be  extensively  plugged  with  fibrin.  They  think  this  may  aid  resolution  by 
keeping  away  the  blood-plasma,  with  its  antitryptic  ferment. 


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A  later  stage,  that  of  resolution,  is  seldom  seen  at  autopsy,  but  it  can 
occasionally  be  studied  when  the  person  dies  from  some  other  cause,  as, 


Fig.  269.— Lobar  pneumonia:  gross  appearance  of  the  lung  in  early  gray  hepatization 
with  involvement  of  both  lobes. 

for  example,  the  development  of  pneumonia  in  the  other  lung,  meningitis, 
or  pericarditis.    In  two  cases  which  I  have  seen  in  this  stage  the  change  in 


LOBAR   PNEUMONIA  551 

the  lung  was  quite  wonderful.  The  enormously  enlarged  organ  was  in 
each  instance  very  soft  and  friable,  and  had  assumed  a  very  distinct  trans- 
lucence,  so  that  one  could  discern  blood-vessels  in  the  depths  of  the  tissue. 
The  alveolar  contents  had  lost  to  a  great  extent  their  appearance  of  being 
in  the  form  of  plugs,  and  the  whole  lung  appeared  gray  and  jelly-like. 

In  section  the  change  was  not  so  obvious,  since  it  apparently  consisted 
only  in  a  more  advanced  disintegration  of  the  leucocytes  and  fibrin.  It  is 
well  known,  however,  that,  through  the  agency  of  the  proteolytic  ferments 
of  the  leucocytes  themselves,  the  whole  mass  of  exudate  is  liquefied  in  a  few 
days,  and  while  some  of  it  is  expectorated,  the  greater  quantity  is  absorbed 
by  the  lymphatics  and  carried  away. 

The  stage  of  healing  is  even  more  rarely  to  be  seen.  It  must  consist  in 
the  relining  of  the  alveoli  with  alveolar  epithelium  after  the  complete 
removal  of  the  exudate.  It  is  to  be  noted  that  throughout  this  intense 
inflammatory  affection  of  the  lung  there  is  very  little  infiltration  of  the 
lung  tissue  itself  with  the  exudate.  The  alveolar  walls,  bronchial  walls, 
and  perivascular  tissues  remain  throughout  almost  free  from  bacteria  and 
exudate.  It  is  rather  as  though  the  whole  process  were  taking  place 
upon  a  mucous  membrane  without  any  invasion  into  the  depths,  and  it 
results  that  after  the  exudate  is  removed  there  is  no  damage  to  repair 
other  than  the  loss  of  the  epithelial  cells,  which  are  quickly  made  good  by 
those  which  remain,  so  that  it  would  be  impossible  to  say  two  weeks  later 
that  that  lung  had  been  the  seat  of  a  pneumonia. 

In  sharp  contrast  to  this  are  the  effects  of  the  streptococcus  and  influenza 
bacillus,  described  elsewhere. 

Lobar  pneumonia  caused  by  the  Pneumococcus  mucosus  differs  from  that 
produced  by  the  members  of  the  other  types  in  the  viscidity  of  the  exudate 
and  in  the  severity  of  the  disease,  and  the  same  may  be  said  of  the  rarer 
cases,  in  which  the  capsulated  bacillus  of  Friedlander  is  the  cause.  In  one 
case  of  this  kind  which  we  saw,  the  exudate  was  so  glutinous  that  it  could 
be  lifted  up  from  the  cut  surface  in  long  strings  which  hung  from  the 
knife. 

Complications  of  pneumonia,  which  are  perhaps  commoner  in  the  case 
of  various  types  of  lobular  pneumonia,  are  abscess  formation,  organization 
of  the  exudate,  and  gangrene. 

Abscess  Formation.— In  the  late  stage  of  a  severe  pneumonia  the  con- 
solidated tissue  appears  to  succumb  sometimes,  to  an  especially  intense 
injury  on  the  part  of  the  bacteria,  so  that  the  alveolar  walls  give  way 
throughout  a  limited  area,  and  the  lung  substance  breaks  down  into  a 
purulent  fluid.  Such  an  abscess-like  focus  may  extend  into  the  pleural 
cavity,  producing  a  purulent  pleurisy  or  empyema.  One  is  inclined  to  sus- 
pect in  such  cases  the  presence  of  a  mixed  infection  with  streptococci  or 
staphylococci. 

Organization  or  Carnification— Ordinarily,  when  a  fibrinous  exudate  is 
thrown  out  on  any  such  surface  as  that  of  the  pericardium  or  the  pleura, 


552 


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healing  leads  to  its  replacement  by  granulation  tissue,  which  in  those  situ- 
ations is  likely  to  end  in  the  formation  of  fibrous  adhesions  between  the 
opposed  surfaces.  It  is,  therefore,  rather  remarkable  that  in  pneumonia 
the  exudate,  which  is  apparently  quite  the  same  in  character,  should  be 
completely  removed  without  the  least  attempt  at  such  replacement  or 
organization.  Possibly  the  rapidity  with  which  the  whole  reaction  pro- 
ceeds is  accountable  for  this,  or  there  may  be  some  other  explanation. 


^•^:;'f>v::ikv^  -;"o?'Vy># 

';  •     *V\>P    -,\Wel    *      .'«       ,?»;     ~v    %       \  "..*"'-    /vO-1.     ...    »     -' 

'       1»  /'  *.'»  «  H  -*  "    '  t  -    N  v         V'-.     '          o"V  °  ?     ' •'       <  .  "       '      ' 


(^        «\ 

/'•"••"%*  Vvr".'1    *r 


•        --          •&    - 


Fig.  270.— Organization  following  pneumonia.     Strands  of  connective  tissue  extend 
through  several  alveoli  and  are  in  part  covered  with  epithelium. 

Occasionally,  however,  the  exudate  fails  to  be  removed  promptly,  whether 
because  the  bacteria  persist  or  the  mechanism  of  autolysis  fails,  and  blood- 
vessels and  fibroblasts  do  spring  up  and  invade  the  fibrinous  plugs  in  the 
alveoli,  finally  replacing  them  with  vascularized  tissue.  The  origin  of  this 
vascularized  tissue  is  interesting,  since  it  seems  not  to  arise  from  every  point 
of  the  alveollar  wall.  This  is  partly  because  the  exudate  retracts  and 
remains  m  contact  with  the  walls  at  certain  points  only,  but  even  so,  it 


LOBAR   PNEUMONIA  553 

seems  that  the  new  blood-vessels  fail  to  spring  up  from  all  these  points. 
Instead,  it  may  be  found  by  reconstruction  that  the  connective  tissue 
which  replaces  the  exudate  in  any  given  lobule  of  the  lung  often  springs 
essentially  from  the  wall  of  the  terminal  bronchiole,  or  from  one  of  those 
angles  of  the  alveoli  where  an  arteriole  is  surrounded  by  more  tissue  than 
goes  to  make  up  the  alveolar  wall.  Then  it  follows  the  exudate,  extending 
into  each  alveolus,  and  keeping  clear  of  the  walls  (Fig.  270).  Where  the 
fibrin  extends  through  one  of  the  pores  of  Cohn  the  connective  tissue  follows, 
thickening  itself  into  a  stout  cord  and  stretching  the  pore.  Having  pene- 
trated into  an  alveolus  belonging  to  another  bronchiole,  it  extends  to  replace 
the  exudate  in  that  system.  Consequently  in  the  end  it  seems  that  a  con- 


Fig.  271. — Organizing  pneumonia;  cut  surface  of  lung  as  seen  with  a  lens,  showing 
scar  tissue  extending  through  the  lung,  and  points  of  yellow  opacity  produced  by  fatty 
cells. 

tinuous  network  of  strands  of  fibrous  tissue  stretches  about  in  the  alveoli, 
connected  only  here  and  there  with  their  walls,  so  that  if  the  lung  substance 
could  be  dissolved  away,  the  new  connective  tissue  might  remain  as  a 
sponge-like  mould  of  its  cavities.  When  the  new  connective  tissue  has 
replaced  the  exudate,  or  even  when  it  has  succeeded,  as  it  often  does,  in 
forming  a  sort  of  mantle  about  the  exudate,  epithelial  cells  creep  up  from 
the  alveolar  walls  and  cover  it.  This  whole  process  gives  a  dense  elastic 
consistence  to  the  lung,  and  obviously  impedes  greatly  its  expansion. 
Later,  however,  with  shrinkage  of  the  fibrous  tissue,  there  is  left  much 
more  air-space  in  the  cavity  of  each  alveolus,  although  even  then  the 
function  of  the  lung  must  be  greatly  impaired  (Fig.  271). 


554  TEXT-BOOK   OF   PATHOLOGY 

Gangrene. — Retarded  recovery  in  some  cases  of  pneumonia  is  accom- 
panied by  an  exceedingly  foul  odor  from  the  breath  and  sputum,  which  is 
a  recognized  indication  of  the  existence  of  a  gangrenous  process  in  the  lung. 
This  is  a  commoner  complication  of  lobular  pneumonia,  and  is  the  result  of 
a  secondary  infection  with  organisms  of  a  different  type.  It  has  already 
been  described  in  Chapter  XIV. 

Pneumococcus  Septiccemia. — In  the  course  of  pneumonia  the  pneu- 
mococcus  may  gain  access  to  the  general  blood-stream,  and  be  recogniz- 
able in  cultures  from  the  blood.  Jochmann  leans  to  the  view  that  this  is 
a  very  frequent  occurrence,  since  by  using  large  quantities  of  blood  in 
culture  he  has  succeeded  in  discovering  the  organism  in  a  large  percentage 
of  his  cases.  Cole,  on  the  other  hand,  recognizing  that  occasional  cocci 
may  enter  the  blood-stream,  has  found  that  any  considerable  or  even 
recognizable  bacterisemia  occurs  only  in  the  most  severe  cases,  and  near 
the  fatal  termination  of  the  disease. 

The  accompaniments  of  such  bacterisemia  are  endocarditis,  meningitis, 
and  acute  arthritis,  although  other  rarer  localizations  are  also  recognized. 

Endocarditis  caused  by  the  pneumococcus  resembles  closely  that  pro- 
duced by  the  Streptococcus  hsemolyticus,  or  that  of  the  staphylococcus 
infections.  Large  gray  or  greenish-gray  soft  vegetations  are  formed  on  the 
aortic  or  mitral  or  sometimes  the  tricuspid  valves,  and  are  of  such  friable 
consistence  as  to  be  a  source  of  emboli. 

Meningitis  is  a  fairly  common  accompaniment  of  such  endocarditis  and 
of  pneumococcus  bacteriaemia  in  general.  The  distribution  of  the  exudate 
is  usually  very  general,  involving  the  spinal  cord,  and  extending  into  the 
ventricles. 

Arthritis  may  take  the  form  of  a  serous  exudate  in  the  joint  cavity  in 
which  the  pneumococcus  is  found,  or  in  other  cases  there  is  found  a  purulent 
exudate  with  intense  swelling  and  inflammation  of  the  synovial  membranes, 
erosion  of  the  cartilages,  etc. 

The  pneumonia  itself  is  by  no  means  necessarily  confined  to  one  lobe,  or 
even  to  one  lung.  The  whole  of  one  lung  may  be  involved,  together  with 
the  development  of  patchy  or  lobular  areas  of  pneumonia  in  the  other. 
Or  there  may  be  lobar  involvement  of  both  lungs.  Occasionally  the  spread 
or  extension  of  the  consolidation  may  be  observed  clinically,  and  in  a  recent 
summary  of  the  cases  at  the  Presbyterian  Hospital  it  was  noticed  that 
before  and  during  the  extension  of  an  area  of  consolidation  the  temperature 
and  leucocytosis  frequently  sank  to  low  levels,  indicating  perhaps  a  lower- 
ing of  the  powers  of  resistance  which  allowed  the  infection  to  spread. 

Pleurisy  has  been  mentioned,  and  it  may  be  said  further  that  following 
pneumonia,  or  in  some  cases  without  pneumonia,  the  pneumococcus  gaining 
entrance  into  the  pleura  may  cause  a  suppurative  pleurisy  or  empyema  in 
which  great  quantities  of  purulent  fluid  accumulate,  compressing  the  lung 
and  ultimately  requiring  surgical  intervention. 

Pericarditis  of  serofibrinous  or  fibropurulent  character  may  be  due  to 


LOBAR    PNEUMONIA  555 

extension  through  the  pleuropericardial  membranes,  and  is  a  serious  and 
often  fatal  complication. 

Similarly,  apparently  by  extension  of  the  infection  through  the  dia- 
phragm, a  generalized  peritonitis  may  be  set  up.  Such  pneumococcal  peri- 
tonitis is  described  in  children  and  occurs  sometimes  in  women.  Its  portal 
of  entry  is  not  always  clear,  since  no  lesions  of  the  abdominal  organs  are 
found,  and  it  may  sometimes  occur  without  pneumonia.  The  exudate  is 
greenish  and  soft  and  rich  in  fibrin,  which  is  loosely  attached  to  the  serous 
surfaces. 

Portals  of  entry  for  the  pneumococcus  other  than  the  lungs  should  be 
mentioned.  The  nasal  sinuses  frequently  become  infected  from  the  nose, 
giving  rise  to  a  painful  and  persistent  inflammation.  Extension  of  the 
infection  from  the  nares  and  pharynx  through  the  Eustachian  tube  is  the 
cause  of  those  cases  of  otitis  media  which  are  due  to  the  pneumococcus. 
From  the  frontal  or  ethmoid  sinuses,  as  well  as  from  the  middle  ear,  exten- 
sion may  occur  to  the  cranial  cavity,  with  the  production  of  meningitis. 

LITERATURE 

Cole  and  others:  Jour.  Exp.  Med.,  1912,  xvi,  644-718;  1914,  xx,  346,  363.    Archives  of 

Int.  Med.,  1914,  xiv,  56.    Jour.  Amer.  Med.  Assoc.,  1918,  Ixxi,  635. 
Wadsworth:  Jour.  Exp.  Med.,  1912,  xvi,  54. 
Lamar  and  Meltzer:  Jour.  Exp.  Med.,  1912,  xv,  133. 
Wollstem  and  Meltzer:  Loc.  tit.,  1913,  xviii,  548. 

MacCallum:  Ziegler's  Beitrage,  1902,  xxxi,  440.     (Organizing  pneumonia.) 
Avery,  Chickering,  Cole,  and  Dochez:  Monograph,  Rockefeller  Institute,  No.  7,  1917. 
Kline:  Jour.  Exp.  Med.,  1917,  xxvi,  239. 
Cecil  and  Austin:  Jour.  Exp.  Med.,  1918,  xxviii,  19. 


CHAPTER  XXVIU 
TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued) 

Meningococcus  infections:  Epidemic  cerebrospinal  meningitis.     Endocarditis. 

Gonococcus    infections:  Urethritis    and    sequela.     Salpingitis    and    sequela.     Arthritis, 

ophthalmia,  dermatitis,  endocarditis,  vulvovaginitis  in  children. 

Acute  rheumatism:  Tonsillitis,  arthritis,  endocarditis,  pericarditis,  myocarditis. 

MENINGOCOCCUS  INFECTIONS 

INFECTION  with  the  meningococcus  or  Diplococcus  intracellularis  menin- 
gitidis  of  Weichselbaum  occurs  sporadically  or  in  epidemics,  and  usually 
gives  rise  to  a  febrile  disease  in  which  the  symptoms  are  due  to  the  predom- 
inant affection  of  the  meninges.  In  England  it  is  called  cerebrospinal 
fever.  This  disease  has  been  known  for  a  long  time  and  there  has  always 
been  great  interest  in  its  occurrence  in  epidemics  mysteriously  arising  in 
widely  separated  places.  Much  might  be  written  of  the  history  of  its  va- 
rious appearances,  of  the  terror  which  it  has  always  inspired,  and  of  the 
prolonged  efforts  to  gain  some  insight  into  the  mode  of  transmission  and 
the  life  history  of  the  organism  which  causes  it.  So  much  has  been  accom- 
plished in  recent  years,  especially  through  studies  made  upon  the  great 
numbers  of  cases  which  occurred  among  the  troops  during  the  war,  that 
our  ideas  are  now  much  clearer  than  before,  although  many  obscurities 
remain. 

The  meningococcus  itself  has  been  studied  by  new  methods,  and  especially 
through  the  work  of  Gordon,  Hine,  Flack,  Dopter,  and  Flexner  it  has  been 
learned  that,  as  in  the  case  of  the  pneumococcus,  by  the  application  of  ag- 
glutination tests  and  especially  by  the  absorption  of  agglutinins,  it  is  pos- 
sible to  divide  the  strains  into  several  types.  Dopter  in  1911  distinguished 
as  parameningococcus  one  strain,  which  now  becomes  one  of  the  types.  In 
brief,  Gordon's  Type  I  stands  at  one  end  of  a  series.  His  Type  IV,  which 
corresponds  with  Dopter 's  parameningococcus,  at  the  other  end.  Types 
II  and  III  occupy  places  between  in  the  series,  but  there  are  many  other 
strains  which  are  intermediate.  Indeed,  more  than  fifty  different  subtypes 
have  been  distinguished  approaching  more  or  less  closely  in  their  agglu- 
tinative characters  one  or  other  of  these  main  types.  It  is  stated  in  this 
form  because  there  is,  even  with  this  most  accurate  method  of  recognizing 
a  specific  organism,  a  certain  amount  of  cross  agglutination,  so  that  it  is 
only  an  organism  which  gives  the  maximum  reaction  with  a  serum  produced 
by  the  arbitrary  original  Type  I  and  the  minimum  reaction  with  the  serum 
of  Type  IV  that  is  classed  with  Type  I.  Doubtless  with  further  study 

556 


MENINGOCOCCUS   INFECTIONS  557 

other  differences  may  be  found,  as  in  the  case  of  the  Pfeiffer  bacillus,  which 
will  make  this  differentiation  more  stable. 

No  very  sharp  distinction  can  be  made  between  these  types  as  far  as 
concerns  their  virulence  and  ability  to  produce  disease.  It  is  true,  however, 
that  there  is  a  great  difference  in  the  susceptibility  of  individuals,  since 
many  become  the  healthy  carriers  of  one  or  other  type,  probably  through 
mere  contact  with  infected  persons.  Others  after  surviving  the  disease 
remain  as  carriers  of  the  organisms  which  are  lodged  in  the  nasopharynx. 
It  was  the  problem  of  the  recognition  and  disposition  of  such  carriers 
which  at  first  occupied  so  much  attention  in  the  various  armies.  As  to 
the  mode  of  infection,  there  is  little  doubt  that  transmission  is  by  way  of 
organisms  which  pass  from  the  nasopharyngeal  secretion  of  infected  per- 
sons or  carriers  to  the  nasopharynx  of  others.  The  fact  that  persons  known 
to  carry  these  organisms  in  the  nasopharynx  may  later  develop  meningitis, 
and  the  further  fact  that  persons  exposed  to  contact  with  these  carriers 
become  similar  carriers  or  quickly  develop  the  disease,  support  this. 

From  the  nasopharynx  invasion  may  be  conceived  of  as  occurring  directly 
through  the  ethmoid  plate,  through  the  sphenoid  or  ethmoid  sinuses,  or 
through  the  middle  ear.  Although  Andre  has  shown  that  prolongation  of 
the  subarachnoid  spaces  extend  along  the  olfactory  filaments  into  the  nasal 
fossae,  apparently  offering  an  easy  path,  no  one  has  actually  demonstrated 
organisms  on  their  way  through.  On  the  other  hand,  there  have  been 
many  cases  in  which  an  invasion  of  the  blood-stream  with  the  production 
of  septicaenia  has  preceded  the  appearance  of  any  organisms  in  the  clear 
cerebrospinal  fluid,  but  has  been  followed  later  by  meningitis.  This  has 
been  especially  emphasized  by  Dopter,  many  English  writers,  Worster- 
Drought,  Kennedy,  and  others,  and  in  this  country  by  Herrick.  Indeed, 
Weed  and  his  collaborators,  in  studying  the  infection  of  the  cerebrospinal 
fluid  in  general,  have  shown  that  after  the  experimental  production  of  sep- 
ticaemia the  cerebrospinal  fluid  becomes  infected  easily  when  pressure  is 
reduced  there,  but  only  rarely  if  the  pressure  is  normal  or  heightened.  They 
even  suggest  that  the  removal  of  fluid  by  lumbar  puncture  during  septi- 
caemia may  give  opportunity  for  the  development  of  meningeal  infection. 
On  the  whole,  therefore,  in  spite  of  authoritative  voices  to  the  contrary,  I 
think  the  evidence  is  in  favor  of  the  infection  of  the  meninges  by  the  blood- 
stream, especially  since  the  meningitis  has  nothing  of  the  local  character 
often  seen  when  infection  is  obviously  by  direct  extension  from  a  neighbor- 
ing abscess.  From  this  it  appears  that  we  may  regard  the  disease  as  one 
in  which,  while  various  localizations  of  the  organisms  may  occur  as  in 
heart  valves,  joints,  etc.,  the  usual  local  manifestation  is  in  an  inflamma- 
tion of  the  meninges. 

The  symptoms  most  characteristic  of  this  affection  are  the  sudden  onset, 
Tfiih  chills,  headache,  and  vomiting,  with  rigidity  of  the  neck,  inability  to 
extend  the  leg  while  the  hip  is  flexed  (Kernig's  sign),  petechial  and  pur- 
puric  rash,  herpes,  and  slow  pulse  with  high  fever.  It  may  run  a 


558  TEXT-BOOK    OF    PATHOLOGY 

rapidly  fatal  course,  or  be  more  subacute  in  its  development,  or  finally  be- 
come a  chronic  affection,  in  which  case  various  complications  arise.  Diag- 
nosis is  made  most  certainly  by  the  aspiration  of  the  cerebrospinal  fluid  by 
lumbar  puncture,  with  the  recognition  of  the  meningococcus  by  cultural  and 
morphological  characters,  and  the  treatment  by  injection  of  correspond- 
ing amounts  of  the  antimeningococcal  serum,  which  has  been  developed  by 
Flexner  and  others,  is  going  far  to  reduce  the  mortality  due  to  this  disease. 
The  pathological  alterations  in  the  central  nervous  system  vary  in  their 
character  according  to  the  acuteness  of  the  process.  In  the  acute  forms 
and  sometimes  even  in  the  hyperacute  or  fulminant  cases  there  is  an  ac- 
cumulation of  purulent  exudate  in  the  meshes  of  the  pia-arachnoid  extend- 


Fig.  272.— Cerebrospinal  meningitis. 

ing  widely  over  the  base  of  the  brain  and  over  the  convexity  of  the  cere- 
brum and  down  over  the  spinal  cord,  where  it  tends  to  occupy  the  meninges 
of  the  posterior  aspect.  The  dura  is  smooth,  although  sometimes  hyper- 
aemic,  and  the  surface  of  the  arachnoid,  while  it  may  have  lost  its  gloss,  is 
not  covered  by  any  noticeable  layer  of  pus.  The  exudate  is  collected, 
especially  in  the  sulci  and  in  those  regions  where  the  arachnoid  is  less 
closely  connected  with  the  pia.  The  ventricles  contain  no  great  excess  of 
fluid,  but  this  fluid  is  turbid  or  purulent,  and  there  is  swelling  of  the  choroid 
plexuses,  sometimes  with  minute  hemorrhages.  In  the  less  acute  forms  the 
exudate  is  often  much  more  abundant,  forming  a  thick,  greenish-yellow 
layer,  and  then  fluid  accumulates  in  greater  quantity  in  the  ventricles 
(Fig.  272).  Occasionally  distinct  foci  of  necrosis  are  found  in  the  brain 


MENINGOCOCCUS   INFECTIONS 


559 


substance  bounding  the  ventricles  or  beneath  the  pia,  and  the  blood-vessels 
entering  the  brain  are  surrounded  by  exudate. 

Histologically,  there  are  found  degenerative  changes  in  the  epithelium  of 
the  choroid  plexus,  in  the  more  superficial  cell  layers  of  the  cortex,  and  even 
in  the  nerve  roots.  The  inflammatory  exudate  (Fig.  273)  is  composed  chiefly 
of  polymorphonuclear  leucocytes,  although  a  few  lymphocytes  and  red  cor- 
puscles are  to  be  found.  Councilman  and  his  fellow-workers  have  called 


Fig.  273. Cerebrospinal  meningitis  showing  the  limitation  of  the  exudate  and  the  varied 

character  of  its  cells. 

attention  to  other  much  larger  cells  which  are  present  in  considerable  num- 
bers and  which  are  probably  to  be  regarded  as  large  mononuclear  wander- 
ing cells.  These  have  an  abundant  cytoplasm  and  are  actively  phago- 
cytic,  containing  often  the  fragments  or  whole  bodies  of  several  smaller 
cells.  Meningococci  are  numerous,  and  in  spite  of  the  name,  intracellularis, 
are  often  free.  Fibrin  forms  a  delicate  network  throughout  the  exudate. 
The  walls  of  the  vessels  are  markedly  affected,  being  infiltrated  with  leu- 
cocytes which  accumulate  especially  beneath  the  endothelium.  After 


560  TEXT-BOOK   OF   PATHOLOGY 

their  entry  into  the  brain  their  perivascular  lymph  sheaths  are  often  found 
filled  with  leucocytes. 

In  those  cases  in  which  the  infection  goes  on  to  a  chronic  course  the 
cerebrospinal  fluid  may  become  almost  clear,  and  there  arises  a  chronic 
progressive  hydrocephalus  which  produces  a  train  of  symptoms  and  me- 
chanical effects  resembling  those  seen  in  other  forms  of  hydrocephalus. 
This  is  due  to  the  fact  that  organization  of  the  exudate  gives  rise  to  ad- 
hesions between  the  surface  of  the  brain  and  the  dura,  but  more  particularly 
to  such  as  cover  the  foramina  of  Magendie  and  Luschka,  or  obstruct  the 
communication  of  the  cerebrospinal  space  about  the  cerebellum  and  me- 
dulla with  that  over  the  cerebral  hemispheres.  Drainage  from  the  ven- 
tricles is  interfered  with  and  they  become  distended  with  fluid.  Retraction 
of  the  neck  persists  with  the  various  pareses  which  may  be  found  in  the 
acuter  stages.  Great  emaciation,  persistent  vomiting,  a  stuporous  mental 
state,  with  irritability,  blindness,  and  deafness,  contractures,  and  bed- 
sores end  finally  in  death. 

Lesions  are  produced  in  other  organs  either  by  direct  extension  of  the 
infection  or  as  the  result  of  septicaemia.  The  infections  of  the  eye  may  be 
thought  of  as  the  result  of  the  wandering  of  the  bacteria  along  the  lachrymal 
duct  to  the  conjunctiva,  or  along  the  optic  nerve  with  its  accessory  tissues. 
These  have  not  been  actually  demonstrated,  and  Worster-Drought  and 
Kennedy  think  infection  by  way  of  the  blood-stream  most  probable.  Con- 
junctivitis, keratitis,  iridochoroiditis,  and  even  panophthalmitis  are  ob- 
served. The  latter  processes,  through  organization  of  the  purulent 
exudate  which  accumulates  in  the  chambers  of  the  eye,  lead  to  various 
forms  of  distortion  of  the  eye,  with  blindness.  Blindness  may  also 
follow  hydrocephalus  or  destructive  lesions  in  the  occipital  cerebral 
cortex. 

While  otitis  media  is  uncommon,  permanent  deafness  results  in  many 
cases  of  meningitis  from  direct  involvement  of  the  eighth  nerve  by  exten- 
sion of  the  infection  and  exudate  from  the  meninges.  Its  atrophy  leads 
to  absolute  deafness,  which  is  usually  bilateral,  and  in  young  children  is 
followed  by  mutism. 

Various  more  or  less  transitory  paralyses  may  occur.  Hemiplegia,  pos- 
sibly from  a  destructive  lesion  in  the  internal  capsule,  and  monoplegias, 
more  distinctly  due  to  injuries  in  the  lower  motor  segment  involving  nerve 
roots  or  even  the  spinal  cord,  have  been  observed. 

Arthritis  affecting  any  joint,  but  most  commonly  the  knee-  or  shoulder- 
joint,  is  another  complication,  or  may  occur  in  the  course  of  a  meningococcal 
septicaemia  without  any  meningitis.  The  same  may  be  said  of  endocarditis. 

We  observed  one  case  (Cecil  and  Soper)  in  which  the  meningococcus  was 
present  in  the  crumbling  vegetations  on  the  heart  valves,  and  Fairley  and 
Steward,  Worster-Drought,  and  Kennedy  report  others.  The  other  organs 
show,  as  a  rule,  only  such  changes  as  are  common  to  many  acute  infectious 
processes. 


MENINGOCOCCUS   INFECTIONS  561 

LITERATURE 

Worster-Drought  and  Kennedy:  Cerebrospinal  Fever,  London,  1919. 

Gordon,  Hine,  Flack:   Medical  Research  Committee  Report  on  Cerebrospinal  Fever, 

1916-17,  London. 
Flexner:  Mode  of  Infection,  etc.,  of  Epidemic  Meningitis,  Rockefeller  Institute,  New 

York,  1917. 
Flexner  with  Jobling  and  Amoss:  Jour.  Exp.  Med.,  1907,  ix,  105,  142,  168;  1908,  x,  141, 

690;  1913,  xvii,  553;  1916,  xxiii,  683.     Jour.  Amer.  Med.  Assoc.,  1906,  xlvii,  560; 

1913,  Ix,  1937. 
Councilman,  Mallory  and  Wright:  Report  of  State  Board  of  Health  of  Massachusetts, 

Boston,  1898. 

Weed,  Wegefarth,  Ayer,  and  Felton:  Monograph  No.  12  of  Rockefeller  Institute,  1920. 
Herrick:  Arch.  Int.  Med.,  1918,  xxi,  541. 

GONOCOCCUS  INFECTION 

The  realization  of  the  extent  to  which  gonococci  may  infect  the  body  is  a 
matter  of  very  recent  years.  The  portal  of  entry  is,  in  the  majority  of  cases, 
the  mucosa  of  the  genito-urinary  tract,  since  the  infection  is  commonly 
transmitted  by  coitus.  But  it  may  occasionally  be  transferred  by  infected 
clothing,  towels,  etc.,  in  spite  of  the  ease  with  which  the  organism  is  de- 
stroyed by  drying  and  exposure.  Especially  in  infants  and  children  is 
this  possible,  and  in  orphan  asylums  and  hospitals  epidemics  of  gonorrhceal 
vulvovaginitis  are  of  extremely  common  occurrence.  In  direct  or  indirect 
ways  the  infection  can  also  be  introduced  into  the  mucosa  of  the  mouth, 
nose,  rectum,  conjunctiva,  and  especially  in  the  eye  may  produce  serious 
results. 

Gonococcal  Urethritis  and  its  Sequels  in  the  Male. — There  is,  after 
exposure  to  infection  through  coitus,  during  which  the  organisms  reach  the 
orifice  of  the  urethra,  a  short  period  of  incubation,  averaging  two  to  eight 
days.  Then  there  begins  a  thin,  mucopurulent  exudate  from  the  urethra, 
which  in  a  short  time  becomes  definitely  purulent.  The  orifice,  with  its 
tumefied  edges,  oozes  thick,  greenish  pus,  which  besides  desquamated  epi- 
thelial cells,  contains  abundant  leucocytes,  both  neutrophile  and  eosino- 
phile.  Gonococci  are  found  in  great  numbers,  many  of  them,  if  not  the 
majority,  contained  in  the  bodies  of  the  leucocytes,  where  they  seem  to 
suffer  no  harm.  Ordinarily  this  inflammatory  process  may  affect  only 
the  anterior  portion  of  the  urethra,  where  it  passes  through  a  florid  stage, 
with  profuse  exudate,  gradually  to  recede  after  several  weeks.  In  this 
latter  stage,  which  may  end  in  healing  and  the  disappearance  of  the  cocci, 
the  exudate  becomes  less  abundant  and  mucoid,  gluing  together  the  edges 
of  the  meatus.  But  in  many  cases  there  is  an  extension  to  the  posterior 
urethra,  where  healing  is  more  difficult,  and  from  which  the  important 
complications  in  other  organs  arise. 

There  are,  in  the  course  of  the  urethra,  many  accessory  structures,  some,  such  as  the 
paraurethral  channels,  partaking  of  the  character  of  malformations,  while  others,  the 
lacunae  or  glands  of  Littre  and  the  glands  of  Cowper  and  various  folds  of  mucosa,  are 
37 


562 


TEXT-BOOK    OF    PATHOLOGY 


normally  present.  Directly  communicating  with  the  urethra  there  are,  of  course,  the 
more  developed  accessory  structures— the  prostate  and  seminal  vesicles.  All  of  these 
are  commonly  involved  in  the  more  chronic  or  persistent  gonorrhoeal  infections,  and 
serve  to  maintain  the  infection  in  spite  of  thorough  disinfection  of  the  urethra  itself. 

In  connection  with  the  anterior  urethra 
the  follicles  or  glands  of  Littre  may 
become  converted  into  hard,  inflamed 
nodules. 


The  mucosa  in  the  acute  in- 
flammation is  swollen,  with  des- 
quamation  of  many  epithelial 
cells.  The  gonococci  penetrate 
among  those  which  remain,  and 
extend  even  into  the  subepithelial 
tissues.  Where  there  are  patches 
of  stratified  epithelium,  such  as 
often  occur  normally,  the  cocci 
obtain  an  especially  good  foothold 
and  resist  disinfection.  When  the 
process  has  become  more  chronic, 
especially  in  the  posterior  ure- 
thra, there  appear  ulcerations, 
with  scarring  and  polypoid  ex- 
crescences. The  scarring  results 
in  strictures  or  stenoses  (see  Fig. 
215)  of  the  urethra,  which  cause 
obstruction  to  the  outflow  of 
urine  and  render  catheterization 
necessary.  Not  only  is  cystitis  a 
common  result  of  this,  but  in 
attempts  to  pass  instruments 
through  the  stricture,  wounds  of 
the  adjacent  tissue  are  produced, 
which  may  become  the  origin  of 
intense  infections.  These  may 
assume  a  phlegmonous  character, 
or  there  may  develop  an  abscess 
in  the  perineal  region.  The  ex- 
travasation of  urine  into  such 
wounded  areas  favors  the  devel- 
opment of  the  infection  (Fig.  275). 

Chronic  gonococcal  urethritis  is  commonly  recognized  by  the  presence 
of  shreds  of  filaments  of  mucus  with  leucocytes  and  epithelial  cells  in  the 
urine.  These  may  contain  gonococci,  but  often  the  organisms  are  rare 
and  difficult  to  demonstrate. 


Fig.  275.— Gonorrhceal  stricture  after 
forcing  of  false  passage.  Extensive  de- 
struction and  inflammation.  Hypertrophy 
of  the  bladder;  diphtheritic  cystitis. 


GONOCOCCUS   INFECTION  563 

Cystitis,  while  it  can  be  produced  by  the  gonococcus  alone,  is  rarely 
due  to  that  organism,  but  usually  to  secondary  invaders.  Ureteritis  and 
pyelonephritis  are  reported  as  due  to  ascending  infection  with  the  gono- 
coccus, but  are  rare. 

Prostatitis  and  Vesiculitis. — Various  types  of  infection  of  the  prostate 
by  the  gonococcus  are  described  arising  in  connection  with  posterior  ure- 
thritis.  These  differ  greatly  in  intensity,  for  while  there  may  be  a  sort  of 
catarrhal  inflammation  of  the  ducts  and  acini  of  the  gland,  there  may,  in 
other  cases,  be  far  more  intense  and  destructive  changes  involving  abscess 
formation.  A  chronic  persistent  inflammation  with  a  secretion  containing 
cocci,  and  leading  to  the  enlargement,  or  in  other  cases  to  scarring  and 
atrophy  of  the  gland,  is  most  frequent.  The  seminal  vesicles  may  in  the 
same  way  present  acute  inflammatory  changes  or  more  chronic  altera- 
tions, including  scarring  and  obliteration  of  their  lumina. 

Epididymitis. — A  common  sequel  of  urethritis  is  produced  by  the 
wandering  of  the  gonococci  along  the  vas  deferens  to  the  epididymis, 
where  an  intense  inflammation  involving  the  neighboring  tunica  vaginalis, 
in  many  cases  leads  to  great  swelling  and  induration.  The  gonococci  can 
be  found  in  the  exudate,  even  though  in  some  cases  they  cannot  be  recog- 
nized in  the  vas  deferens  and  have  produced  no  lesions  there.  Scarring 
and  stricture  or  obliteration  of  the  canal  of  the  epididymis  and  of  the  vas 
deferens  may  lead  to  complete  azoospermia  if  the  epididymis  had  been 
affected  on  both  sides. 

Gonococcal  Infection  in  the  Female. — In  the  female  the  urethra,  the 
vagina,  Bartholin's  glands,  and  the  cervix  become  infected  and  react  in  the 
same  way  as  does  the  mucosa  of  the  male  genito-urinary  tract.  The  ure- 
thra, being  shorter  and  without  complicated  accessory  structures,  the  in- 
flammation does  not  lead  to  such  serious  results.  A  swelling  of  the  mucosa, 
with  the  exudation  of  the  characteristic  pus,  occurs.  Bartholin's  glands 
become  greatly  swollen  and  indurated,  and  from  them  there  can  be  ex- 
pressed a  similar  purulent  exudate.  These  things  may  occur  without 
the  extension  of  the  infection  into  the  internal  genitalia,  and,  indeed,  in 
the  vulvovaginitis  of  children,  this  more  external  type  of  inflammation, 
with  reddening  and  swelling  of  the  nymphse,  is  relatively  common.  In  the 
child  the  vagina  is  more  intensely  involved  than  in  the  adult,  where  its 
epithelium  is  much  more  resistant.  Indeed,  in  the  adult,  gonorrhceal 
vaginitis  occurs  practically  only  as  an  acute  process,  and  is  then  relatively 
unimportant.  A  chronic  gonococcal  vaginitis  is  uncommon.  On  the  other 
hand,  the  cocci  readily  pass  into  the  cervical  canal,  and  establish  them- 
selves in  the  mucosa  with  its  glands,  extending  also  to  those  of  the  fundus. 
Slight  erosions,  a  tumefaction  of  the  mucosa,  and  the  secretion  of  a  purulent 
exudate  mark  their  presence  there.  More  important  is  the  effect  of  their 
further  wandering  into  the  Fallopian  tubes. 

Gonococcal  Salpingitis.—In  the  acute  stage  the  tubes  become  swollen, 
hypersemic,  and  cedematous,  the  change  being  especially  striking  in  the 


564 


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fimbriated  extremity.  In  the  mucosa  alterations  due  to  the  presence  of 
the  organisms  among  the  epithelial  cells  of  the  complex  folds  are  in  general 
similar  to  those  in  the  urethra.  Later  chronic  alterations  appear,  de- 
pendent upon  the  deeper  invasion  of  the  cocci  into  the  tissues.  Adhesions 


Fig.  276.— Subacute  gonorrhoeal  salpingitis  with  great  thickening  of  the  folds  of  mucosa 

by  the  cellular  infiltration. 

are  formed  about  the  tube,  and  through  the  organization  of  exudate  there 
is  occlusion  of  its  lumen  at  both  ends  and  the  accumulation  of  a  quantity 
of  pus  in  its  cavity.  Kinking  of  the  tube  may  be  partly  responsible  for 
these  occlusions.  The  progress  of  the  infection  leads  to  great  changes  in 
the  mucosa,  which  in  operative  cases  are  usually  seen  in  their  subacute 


GONOCOCCUS   INFECTION 


565 


stages.  The  folds  of  the  mucosa,  ordinarily  so  delicate  and  complicated, 
become  distended  into  thick  lamellae  (Fig.  276),  which  often  adhere  to  one 
another  and  grow  together  so  that  they  cover  over  the  intervening  spaces, 
which  then,  in  cross-section,  look  like  epithelium-lined  channels  in  the  tube- 
wall  (Fig.  277).  Microscopically,  these  thick  folds  are  found  to  be 


r\ 


Fig.  277. — Pseudofollicular  salpingitis.     The  appearance  of  closed  cavities  is  produced 
by  fusion  of  the  folds  of  the  mucosa. 


stretched  by  great  numbers  of  wandering  cells,  among  which  lymphocytes 
and  plasma  cells  are  very  numerous  and  conspicuous.  Eosinophile  cells  are 
often  very  abundant.  Schridde  and  Amsbacher  claim  that  the  finding  of 
such  an  infiltration  of  lymphocytes  and  plasma  cells  is  sufficient  proof  of 
the  gonococcal  nature  of  the  infection,  but  this  is,  probably  rightly,  con- 
tradicted by  Miiller  and  Menge,  who  state  that  other  organisms,  such  as 


566 


TEXT-BOOK    OF   PATHOLOGY 


the  streptococcus,  may  produce  the  same  lesions  if  time  is  allowed  for 
the  development  of  a  subacute  or  chronic  salpingitis.  The  distension  of 
the  obstructed  tube  with  pus  (pyosalpinx)  may  greatly  separate  and  flatten 
the  folds  of  the  mucosa,  and  the  tube  itself  assumes  then  a  variety  of  forms, 


Fig.  278. — Chronic  gonococcal  salpingitis  or  pyosalpinx. 


Fig.  279.— Hydrosalpinx. 

according  to  the  arrangement  of  the  adhesions  which  may  attach  it  to  the 
uterus,  to  the  ovary,  to  the  rectum,  or  the  pelvic  wall  (Fig.  278).  Most 
often  it  is  roughly  retort  shaped.  Rupture  of  such  a  sac  may  occur  through 
violence  with  discharge  of  the  pus  into  the  peritoneum.  Ordinarily,  there 


GONOCOCCUS   INFECTION  567 

is  not  produced  any  very  severe  peritonitis,  and  this  is  explained  by  the 
fact  that  cultures  from  the  pus  are  usually  sterile.  In  other  cases  the  exu- 
date  may  lose  its  purulent  character  after  the  occlusion  of  the  ends  of  the 
tube  has  occurred  and  become  more  serous.  Such  a  tube  may  develop  into 
a  large,  thin-walled  sac  full  of  clear  fluid  (hydrosalpinx)  (Fig.  279).  Natu- 
rally, either  of  these  results  ends  in  the  complete  loss  of  function  of  the  tube, 
and  if  both  tubes  are  affected,  sterility  follows. 

Gonococcal  infections  of  the  ovary  occur  in  the  form  of  abscesses  or  false 
abscesses,  caused  by  the  invasion  of  the  cocci  into  freshly  ruptured  follicles 
or  corpora  lutea. 

Gonococcal  peritonitis  is  an  outcome  of  the  acute  stage  of  infection  of  the 
uterus  and  Fallopian  tubes,  the  cocci  entering  through  the  fimbriated 
extremities.  It  may  also  be  produced  by  transfer  of  the  organism  by  the 
blood-stream.  The  exudate  is  fibrinous  or  serofibrinous,  and  is  likely  to 
lead  to  extensive  adhesions  among  the  loops  of  intestine.  This  condition 
is  not  of  common  occurrence,  except  in  the  more  localized  form  of  pelvic 
peritonitis,  which  is  extremely  common  in  association  with  salpingitis,  and 
in  its  late  stages  is  found  to  have  bound  the  pelvic  organs  together  by 
firm  or  lax  adhesions. 

Gonococcal  Arthritis. — Somewhat  late  in  the  course  of  an  acute  urethritis, 
that  is,  after  the  inflammation  has  reached  the  posterior  urethra  and  has 
lasted  several  weeks,  there  often  arises  a  painful  involvement  of  a  joint, 
which  is  due  to  the  transportation  of  the  gonococci  by  the  blood-stream  to 
the  synovial  membrane.  This  appears  to  be  commoner  in  men  than  in 
women,  and  usually  only  one  joint  is  involved,  although  others  may  be 
affected  in  succession  later.  The  joint  most  commonly  infected  is  the 
knee,  and  the  inflammation  may  take  several  forms.  The  mildest  is  that 
in  which  there  is  a  mere  accumulation  of  fluid  without  pain  or  marked 
impairment  of  function.  More  frequently  there  is  formed  a  serofibrinous 
or  even  purulent  exudate,  with  infiltration  of  the  surrounding  tissues  and 
extreme  pain,  so  that  the  joint  is  held  flexed.  Erosions  of  the  cartilage 
and  rarefaction  of  the  cancellous  bone  may  occur,  and  fixation  of  the  joint 
with  ankylosis  of  the  bones  sometimes  follows.  Gonococcal  infection  of 
the  bones  themselves  is  reported,  but  is  rare. 

Gonococcal  Ophthalmia. — Infection  of  the  eye  with  this  organism  is 
extremely  serious,  and  often  leads,  even  under  the  most  careful  treatment, 
to  destruction  of  the  eye.  It  occurs  in  infants  from  infection  during  birth 
from  the  inflamed  genitalia  of  the  mother,  and  this  so-called  ophthalmia 
neonatorum,  although  relatively  easy  to  guard  against  or  cut  short  by 
instillation  of  nitrate  of  silver  into  the  infant's  eyes,  is  nevertheless  the  cause 
of  an  enormous  number  of  cases  of  blindness  among  children  everywhere 
in  the  world.  In  older  children— and  this  probably  includes  the  cases  of 
"late  birth  infections,"  which  develop  after  five  days  postpartum— gono- 
coccal  conjunctivitis  is  a  fairly  common  accompaniment  of  the  epidemic 
gonococcal  vulvovaginitis. 


568  TEXT-BOOK   OF    PATHOLOGY 

In  adults  such  conjunctivitis  is  caused  by  the  introduction  of  the  organ- 
ism into  the  eye  with  the  soiled  fingers,  towels,  etc.,  or,  especially  in  phy- 
sicians, by  the  spurting  of  gonorrhceal  pus  into  the  eye.  It  is  said  that  there 
may  also  arise  an  infection  of  the  deeper  parts  of  the  eye  through  trans- 
mission of  the  organism  by  the  blood-stream,  and  in  this  case  there  are  no 
cocci  in  the  conjunctival  sac. 

The  conjunctivitis  begins  with  the  injection  of  the  blood-vessels,  swell- 
ing of  the  lids,  and  the  pouring-out  of  a  thick,  purulent  exudate,  which 
tends  to  glue  the  eyelids  together.  The  conjunctiva  over  the  bulb  swells, 
so  that  the  cornea  is  sunken  beneath  it.  The  slightest  touch  upon  the 
cornea  is  sufficient  to  start  an  erosion  there,  which  progresses  to  ulcera- 
tion  and  often  to  infection  of  the  anterior  chamber,  which  fills  up  with  a 
purulent  exudate.  Healing  of  these  ulcerations  is  likely  to  cause  such  scars 
or  opacities  in  the  cornea  that  the  eye  becomes  useless.  But  there  also 
may  be  produced  extensive  infiltration  of  the  iris  and  neighboring  tissues, 
resulting  in  distorting  adhesions.  Indeed,  the  whole  eye  may  be  invaded 
and  extensively  injured  by  the  infection. 

It  is  conceivable  that  infection  of  the  nasal  sinuses  or  even  meningitis 
might  arise  from  such  a  process,  but  although  deJong  and  others  have 
described  cases  of  gonococcal  meningitis,  the  proof  of  the  identity  of  the 
organism  which  is  so  similar  to  the  meningococcus  is  not  satisfactory  enough 
to  allow  these  cases  to  be  generally  accepted. 

Gonococcal  Dermatitis. — Lesions  of  the  skin  said  to  be  caused  by  the 
gonococcus  assume  many  forms,  among  which  are  erythematous  rashes, 
urticaria,  erythema  nodosum,  haemorrhagic  and  bullous  exanthemata, 
and  hyperkeratoses.  Of  these,  perhaps  the  latter  are  most  character- 
istic. 

Gonococcal  Endocarditis. — It  is  evidence  of  the  transportation  of  the 
cocci  by  the  streaming  blood,  and  therefore  of  the  existence  of  a  general 
gonococcal  septica3inia,  that  endocarditis  may  owe  its  origin  to  this  organ- 
ism. Gonococcal  septicaemia  is  particularly  characterized  by  the  occur- 
rence of  the  arthritis  already  mentioned,  and  of  the  endocarditis,  and  is 
not  an  absolutely  fatal  occurrence.  Cases  have  been  reported  as  recover- 
ing even  after  the  valvular  lesions  were  very  evident,  and  the  cocci  re- 
peatedly demonstrated  in  the  blood. 

The  alterations  of  the  heart-valves  are  rather  characteristic,  in  that  the 
vegetations  are  frequently  extremely  large  and  friable.  They  seem  to 
effect  the  destruction  of  the  valves  with  great  rapidity,  for  in  three  cases 
which  I  have  seen  the  valves  were  reduced  to  ragged  strands,  which  flapped 
in  the  stream,  bearing  on  their  ends  large  crumbling  remnants  of  the  vegeta- 
tions. Apparently  the  aortic  and  the  mitral  valves  are  most  often  affected, 
but  we  were  impressed  with  the  occurrence  of  these  vegetations  in  our  own 
cases  on  the  tricuspid  and  pulmonary  valves.  Pericarditis  and  myo- 
carditis of  focal  or  diffuse  character  often  accompany  the  endocarditis. 
The  organisms  are  found  in  abundance  in  the  vegetations. 


GONOCOCCUS   INFECTION  569 

Vulvovaginitis  in  Children.— With  regard  to  the  infection  itself,  there 
are  some  interesting  features.  It  has  been  pointed  out  that  epidemic 
vulvovaginitis  in  little  children  is  a  very  common  thing,  and  that  in  some 
orphan  asylums  it  is  never  absent,  but  is  known  to  produce  so  little  real 
harm  that  it  is  somewhat  ignored.  Dr.  Northrup  tells  me  that  in  contrast 
to  this  familiar  mild  infection,  the  incomparably  more  serious  effects  of 
infection  from  the  gonococcus  from  urethritis  in  the  adult  impressed  him 
strongly  in  two  cases.  These  were  in  two  young  girls,  who  were  infected 
in  some  way  from  their  mother,  who  had  been  infected  from  the  acute 
urethritis  of  the  father.  They  became  profoundly  ill,  with  circulatory 
collapse  and  symptoms  that  were  thought  to  indicate  appendicitis.  One 
was  operated  upon  and  the  appendix  removed.  Although  it  was  normal, 
the  whole  peritoneum  was  intensely  reddened,  and  there  was  a  slight  serous 
exudate.  There  were  no  other  complications  and  they  recovered.  Re- 
cently, apparently  with  this  idea  in  mind,  Dr.  Pearce  has  investigated  the 
organisms  concerned  in  an  epidemic  in  a  children's  asylum,  and  has  found 
that  they  do  differ  biologically  from  those  isolated  from  urethritis  in  the 
adult.  Her  conclusions  are  in  part  as  follows: 

Two  principal  types  of  gonococci  may  be  recognized  by  the  methods  of 
agglutination  and  complement  fixation,  and  correspond  to  the  adult  and 
infant  types  of  infection  seen  clinically.  The  gonococci  isolated  from  cases 
of  ophthalmia  belong  to  the  adult  type.  It  appears  that  there  may  be 
many  more  varieties,  and  that  these  two  types  are  not  sharply  marked  out, 
but  are  connected  by  intervening  forms. 

LITERATURE 

Jadassohn: 

Ehrmann : 

Scholtz: 

Grosz : 

Elschnig: 

Schlagenhaufer: 

Buschke : 

Menge: 

L.  Pearce:  Jour.  Exp.  Med.,  1915,  xxi,  289. 

C.  Bruck:   Ergeb.  d.  allg.  Path.,  1912,  xvij,  134  (literature). 

Harris,  Dabney,  and  Johnston:   "Endocarditis,"  Johns  Hopkins  Hosp.  Bull.,  1901,  xii. 

68;  1902,  xiii,  236. 

Thayer  and  Blumer:  Ibid.,  1896,  vii,  57;  Jour.  Exp.  Med.,  1899,  iv,  81. 
Thayer:  Amer.  Jour.  Med.  Sci.,  1905,  Ixxx,  751. 
Amersbach:    Ziegler's  Beitrage,  1909,  xlv,  341. 
Watjen:  Ibid.,  1914,  lix,  418. 


ACUTE  RHEUMATISM 

The  disease  affects  young  people  especially,  causing  repeated  attacks  of 
painful  swelling  of  the  joints,  with  fever,  but  usually  without  leaving  any 


Handbuch  der  Geschlechtskrankheiten,  1910,  i;  1912,  ii,  pp.  1-612. 
(These  papers  are  excellent  but  very  prolix.) 


570  TEXT-BOOK    OF    PATHOLOGY 

permanent  disability  of  the  joints.  It  is  usually  preceded  by  tonsillitis, 
and  often  followed  by  chorea,  a  spasmodic  nervous  affection  which  may 
last  a  long  time.  Nearly  always  there  are  serious  changes  in  the  heart, 
involving  the  valves,  the  heart  muscle,  and  the  pericardium.  The  cause  is 
unknown  in  spite  of  the  most  careful  studies,  although  numerous  writers 
have  described  bacteria  for  which  they  claim  an  setiological  role.  Of  these, 
the  majority  are  micrococci  in  pairs  or  in  chains.  Those  described  by 
Singer  and  by  Poynton  and  Paine  are  perhaps  most  discussed,  but  it  is  by 
no  means  proved  that  they  are  the  real  cause  of  the  disease.  In  our  cases 
cultures  from  the  blood  and  joint  fluids,  as  well  as  smears  and  cultures  from 


Fig.  280.— Rheumatic  endocarditis;   verrucose  vegetations  on  mitral  valve.     Chronic 

adhesive  pericarditis. 

the  vegetations  on  the  heart  valves,  have  usually  shown  no  bacteria  unless 
some  terminal  affection,  such  as  pneumonia,  brought  bacteria  to  com- 
plicate the  situation. 

From  the  frequency  of  tonsillitis  in  the  early  stages  it  seems  that  the 
tonsils  form  the  portal  of  entry  for  the  organisms.  Occasionally  there  is 
laryngitis,  rhinitis,  or  otitis  media.  With  the  swelling  of  the  joints  there 
are  high  fever  and  profuse  sweating.  When  the  fever  is  extremely  high, 
death  is  likely  to  ensue. 

The  joints  most  often  affected  are  the  knee,  shoulder,  and  ankle,  although 
nnger-jomts  may  be  involved  in  those  who  work  especially  with  their 


ACUTE   RHEUMATISM 


571 


fingers.  The  swelling  is  very  largely  periarticular,  and  the  excruciating 
pain  is  chiefly  in  the  attachment  of  tendons.  The  joint  fluid  is  usually 
clear,  or  contains  a  few  leucocytes,  although  there  is  sometimes  a  purulent 
exudate.  Purpuric  or  hsemorrhagic  patches  often  appear  in  the  skin,  and 
seem  to  be  due  to  changes  in  the  walls  of  the  blood-vessels,  thought  by  some 
to  be  caused  by  embolic  inflammatory  processes.  There  are  also  nodes 
in  the  skin  and  in  the  periosteum,  which  are  of  inflammatory  character. 


Fig.  281. — Small  homogeneous  hyaline  vegetation,  without  evident  bacteria,  upon  the 
mitral  valve.     Rheumatic  endocarditis. 

• 

The  most  important  lesions  are  undoubtedly  those  in  the  heart,  and  the 
surprising  constancy  of  their  form  and  the  ease  with  which  they  can  be  dis- 
tinguished from  the  other  infectious  diseases  of  the  heart  make  it  seem  more 
likely  that  they  are  caused  by  some  peculiar  infectious  agent. 

There  is  nearly  always  pericarditis,  with  a  sticky  exudate  of  fibrinous 
character,  which  soon  brings  about  the  firm  adhesion  between  the  two 
layers  of  the  pericardium  (Fig.  280).  Since  death  generally  occurs  some 


572  TEXT-BOOK   OF   PATHOLOGY 

time  after  repeated  attacks,  the  pericardium  is  usually  found  densely 
adherent  to  the  heart.  Vegetations  appear  on  the  valves  along  the  line 
of  closure,  and  nearly  always  in  the  form  of  small,  warty,  tough  nodules, 
which  run  like  a  string  of  beads  around  the  whole  valvular  orifice.  They 
are  found  especially  on  the  mitral,  but  also  on  the  tricuspid  and  aortic 
valves,  but  seldom  extend  on  the  heart-wall  or  on  the  chordae  tendinese. 
Healing  of  such  lesions  leads  to  the  thickening  and  scarring  of  the  valves, 
and  often  to  extreme  narrowing  or  stenosis  of  the  orifices.  Doubtless 
renewed  attacks  would  add  a  new  beaded  string  of  vegetations  to  such 
scarred  valves,  and  so  might  the  advent  of  some  other  infection.  While  it 
seems  probable  that  rheumatism  may  well  be  the  original  cause  of  mitral, 


Fig.  282.— Aschoff  body  in  the  heart. 

tricuspid,  and  aortic  stenosis  and  insufficiencies,  it  is  usually  difficult  to 
prove  this,  especially  if  some  other  infection  has  supervened  and  produced 
fresh  vegetations  quite  different  in  character  from  those  of  rheumatism. 
Thus  it  is  common  to  find  the  characteristic  distribution  of  fresh  vegetations 
caused  by  the  Streptococcus  mitior  or  viridans  on  old  scarred  valves,  which 
may  well  have  been  distorted  by  rheumatic  infection  of  years  before.  Most 
interesting  are  the  myocardial  changes,  now  that  their  peculiarities  have 
been  pointed  out  by  Aschoff,  Horder,  Bracht  and  Wachter,  Rothschild  and 
Thalhimer,  and  others.  Focal  collections  of  peculiar  large  cells  in  the 
neighborhood  of  minute  vessels,  or  entirely  surrounding  them,  seem  to  be 
the  reaction  to  focal  injury  to  the  tissue.  These  so-called  Aschoff  bodies 
(Fig.  282)  are  made  up  of  concentrically  arranged  wandering  cells,  most  of 
which  are  conspicuous  from  their  large  size  and  their  large  nuclei,  of  which 
they  often  have  several.  They  are  much  like  the  large  cells  found  in 


ACUTE   KHEUMATISM  573 

Hodgkin's  disease,  although  usually  not  quite  so  large  as  those.  No  bac- 
teria have  been  demonstrated  as  constantly  present  in  these  foci,  but  it  is 
shown  that  in  healing  they  leave  behind  them  scars  which  in  the  end  may 
go  far  toward  producing  the  condition  described  as  chronic  fibrous  myo- 
carditis. These  myocardial  lesions  are  such  constant  accompaniments  of 
the  endocarditis  and  adhesive  pericarditis  that  some  have  spoken  of  the 
rheumatic  lesions  of  the  heart  as  rheumatic  carditis. 

When  the  setiological  factor  is  discovered  and  established,  it  should  be 
easy  to  determine  its  precise  relation  to  these  lesions,  as  well  as  to  the  accom- 
panying purpura,  iritis,  chorea,  tonsillitis,  arthritis,  etc. 

LITERATURE 

Wiesel:  Wien.  med.  Woch.,  1914,  Mv,  661,  746. 
Poynton  and  Paine:   Rheumatism,  London,  1914. 
Singer:  Deut.  med.  Woch.,  1914,  xl,  788. 
Rosenow:  Jour.  Amer.  Med.  Assoc.,  1913,  Ix,  1223. 
Thalhimer  and  Rothschild:   Jour.  Exp.  Med.,  1914,  xix,  417. 
Aschoff:  Verb.  d.  Deut.  Path.  Gesellsch.,  1904,  viii,  46. 
Bracht  and  Wachter:  Deut.  Arch.  f.  klin.  Med.,  1909,  xcvi,  493. 


CHAPTER  XXIX 
TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued) 

Diphtherial  infection:  Diphtheria  of  respiratory  tract.     General  effects  upon  the  heart,  kid- 
neys, etc.     Paralysis. 
Tetanus  infection:  Mode  of  occurrence  and  mechanism  of  distribution  of  the  toxin. 

DIPHTHERIAL  INFECTION 

THE  diphtheria  bacillus  is,  as  is  well  known,  an  organism  which  produces 
its  wide-spread  disturbances  in  the  body  by  the  agency  of  a  soluble  poison. 
In  this  respect  it  is  paralleled  by  the  tetanus  bacillus,  but  by  few,  if  any, 
other  organisms.  It  can,  however,  in  growing  at  the  point  from  which  it 
diffuses  its  toxin,  produce  a  considerable  local  lesion,  a  power  which  is  less 
striking  in  the  case  of  the  tetanus  bacillus. 

Diphtheria  is  commonly  a  disease  of  children  and  young  people,  and  from 
the  readiness  with  which  the  bacteria  are  transferred,  is  likely  to  occur  in 
epidemic  form.  Many  healthy  persons  have  been  found  to  harbor  the 
bacilli  in  their  mouths  and  throats,  and  are  thus  a  menace  to  others. 

The  organisms  may  become  localized  in  the  throat,  producing  character- 
istic lesions  on  the  mucosa  of  the  fauces,  the  uvula,  the  tonsils,  the  pharynx 
or  larynx,  often  extending  into  the  trachea  and  even  deep  into  the  smaller 
bronchi.  Similar  lesions  occur  in  the  nose,  rarely  in  the  ear,  more  often 
in  the  vulva  and  vagina,  and  sometimes  in  the  skin,  especially  in  connec- 
tion with  maceration  of  the  epidermis  or  skin  lesions,  which  prepare  the 
way,  or  with  ulcers  and  wounds.  Since  the  character  of  the  local  lesion  is 
essentially  the  same  everywhere,  a  description  of  the  more  common  form 
in  the  throat  will  suffice. 

A  few  days  after  the  bacteria  lodge  in  the  mucosa,  that  is,  after  the  lapse 
of  enough  time  to  allow  them  to  grow  and  gather  their  forces,  redness  of 
the  whole  lining  of  the  throat  appears,  with  soreness,  difficulty  in  swallow- 
ing, and  evidences  of  an  acute  illness — fever,  leucocytosis,  etc.  White  or 
yellowish-white  flakes  appear  on  the  reddened  surface  at  one  point  or  other, 
and  spread.  It  is  seen  that  the  confluent  patches  thus  form  a  slightly 
elevated,  dull,  opaque,  membrane-like  layer,  which  is  pretty  tenaciously 
adherent  to  the  underlying  tissue.  This  can  be  peeled  off,  but  leaves  a  raw 
surface  which  oozes  blood,  and  upon  which  a  new  false  membrane  quickly 
forms.  In  other  places  the  pseudomembrane  may  be  less  adherent, 
and  this  is  likely  to  be  the  case  within  the  larynx  and  trachea,  where  it 
sometimes  forms  a  complete  lining,  stretching  for  a  long  way  (Fig.  283). 
Evidence  of  this  looser  connection  is  seen  in  the  frequency  with  which 

574 


DIPHTHERIAL   INFECTION 


575 


children  cough  up  the  whole  lining,  or  at  least  large  areas  of  it.  The 
reasons  for  the  closer  adherence  of  the  false  membrane  to  the  mucosa 
of  the  pharynx  and  mouth  than  to  that  of  the  larynx  and  trachea  must  be 
discussed  later. 

While  this  is  the  ordinary  type  of  local  lesion,  the  diphtheria  bacilli 
may  produce  much  milder  inflammation 
of  a  more  catarrhal  character,  or,  on  the 
other  hand,  especially  when  there  is  a 
mixed  infection  and  virulent  streptococci 
add  their  effects,  there  may  be  the  most 
destructive  affection  of  tonsils,  fauces, 
and  larynx,  with  deep  necrosis  and 
sloughing  of  the  tissues,  together  with 
the  most  violent  inflammatory  reaction, 
and  with  great  cedema  of  the  surround- 
ing parts. 

Occlusion  of  the  respiratory  tract, 
either  by  the  great  swelling  produced  as 
just  described,  or  more  commonly  by  the 
accumulation  and  folding  together  of 
the  false  membranes,  can  cause  death  by 
asphyxia.  Indeed,  in  spite  of  trache- 
otomy, deaths  from  this  cause  were  fre- 
quent. O'Dwyer's  method  of  intubation 
went  far  to  save  children  from  this  evil, 
and  the  timely  administration  of  anti- 
toxin has  practically  cleared  away  the 
danger. 

Pathological  Anatomy  of  the  Lesion. — 
The  diphtheria  bacillus  is  one  of  the  many 
agencies  which  can  produce  a  diphther- 
itic inflammation.  It  has  been  remarked 
that  it  may  also  produce  milder  forms, 
but  even  alone  it  is  able  to  produce  this 
most  severe  form. 


Fig.  283. — Diphtheritic  mem- 
brane extending  far  down  into  the 
trachea.  The  tonsils  are  slightly 
swollen. 


It  may  be  repeated,  however,  that  many 
strong  alkalies  or  acids  or  salts  of  heavy  metals, 
such  as  mercury,  can  produce  typical  diphther- 
itic forms  of  inflammation,  just  as  many  bacteria 
can.  In  other  words,  the  term  diphtheritic  is 

used  in  a  purely  anatomical  sense,  to  describe  the  nature  of  the  lesion  and  not  its 
aetiology. 

The  lesion  consists  in  an  effective  destruction  of  some  of  the  superficial 
cells  of  the  mucosa,  which,  under  the  influence  of  these  bacilli,  undergo 
necrosis  and  coagulation.  The  destruction  of  the  overlying  cells  starts 


576 


TEXT-BOOK  OF  PATHOLOGY 


and  favors  the  pouring-out  of  a  coagulable  fluid,  which  permeates  them 
and  spreads  on  the  surface.  The  formation  of  fibrin  through  the 
coagulation  of  this  fluid  not  only  upon  the  surface,  but  everywhere  in 
and  among  the  dead  cells,  establishes  the  false  membrane.  Leucocytes 
appear  in  great  numbers  and  there  is  some  haemorrhage.  Thus  the  first 
false  membrane  to  appear  is  composed  of  the  vaguely  outlined  coagulated 
bodies  of  the  dead  cells,  buried  in  a  feltwork  of  fibrin,  together  with  many 


"'         •-•,: 

•-W^IM^mt^S  '-•.'•^^:- 

;  ^; 

v'''  '       '  '' 


Fig.  284.— Diphtheritic  membrane  in  a  bronchus.     Acute  laryngeal  and  bronchial  diph- 
theria.    The  exudate  has  the  arrangement  in  arcades. 

leucocytes.  If  this  is  torn  off,  the  next  membrane  which  forms  to  replace 
it  will  consist  chiefly  of  fibrin  and  leucocytes,  unless  the  growth  of  bac- 
teria at  the  base  of  this  fresh  ulcer  causes  more  necrotic  tissue  to  become 
incorporated  into  the  new  membrane.  Where  the  necrosis  is  wide-spread, 
the  false  membrane  will  be  found  firmly  attached  by  a  broad  base.  In 
the  trachea  (Fig.  284)  and  bronchi  the  membrane  is  found  to  be  attached 
only  at  the  points  where  the  epithelial  cells  are  necrotic  and  the  base- 


DIPHTHERIAL   INFECTION  577 

ment  membrane  is  destroyed.  Through  such  places  it  exudes  on  the  sur- 
face, becoming  confluent  over  the  intervening  intact  epithelium  in  a  series 
of  arcades.  Beneath  these  arcades  much  of  the  epithelium  may  remain  in- 
tact and  serve  to  regenerate  cells  to  repair  the  gaps  after  the  disease  is  over. 

The  old  discussion  as  to  whether  a  diphtheritic  membrane  was  to  be  regarded  as 
formed  by  a  fibrinoid  degeneration  of  the  superficial  cells  of  the  tissue,  and  not  by  fibrin 
from  the  blood,  raged  violently  for  a  long  time  among  such  men  as  Orth  and  Marchand, 
on  one  side,  and  Neumann  and  his  supporters,  on  the  other.  A  historical  review  is  given  by 
Gaylord  (Jour.  Exp.  Med.,  1898,  iii,  1).  Even  yet  there  are  echoes  of  this  in  the  acri- 
monious paper  of  Dietrich  in  criticism  of  Sudsuki  (Ziegler's  Beitrage,  1901,  xxix,  562; 
xxx,  414).  It  seems  clear  enough  that  most  of  the  fibrin  must  come  from  exuded  plasma, 
but  that  necrotic  cells  embedded  in  it  may  become  indistinguishable  and  add  to  the  bulk 
of  the  mass.  Fibrin  formed  through  and  through  their  dead  bodies  would  still  give  its 
characteristic  staining  reaction. 

Sequelae. — While  the  mechanical  effects  of  such  a  membrane  are  often 
serious,  the  more  remote  sequels  of  the  infection  are  even  more  important. 
Bronchopneumonia  is  a  common  one,  and  is  probably  due  in  most  cases 
to  accompanying  streptococci  which  pass  into  the  bronchi. 

The  other  things  result  from  the  diffusion  of  the  strong  toxin  from  the 
place  where  the  bacilli  are  growing  into  the  circulating  blood. 

Death  may  take  place  in  the  height  of  the  intoxication,  evidently  from 
its  direct  action  upon  the  heart  and  circulatory  system.  In  the  heart 
itself  in  such  cases  no  gross  changes  are  to  be  seen,  and,  indeed,  the  micro- 
scopical changes,  cloudy  swelling,  fat  infiltration,  and  fragmentation  of 
the  heart  muscle  do  not  offer  convincing  evidence  of  the  cause  of  death. 
As  has  been  mentioned  elsewhere,  Passler  and  Romberg  held  the  opinion 
that  the  effect  of  the  poison  was  chiefly  upon  the  vasomotor  control  of  the 
blood-vessels,  allowing  them  to  relax  so  that  circulation  failed.  I  was 
able  to  confirm  this  by  artificially  maintaining  the  blood-pressure  in  the 
brain  and  coronary  arteries,  upon  which  life  was  greatly  prolonged.  But 
it  seemed  clear  that  the  heart  itself  was  also  injured,  since  it  would  not 
beat  quite  so  long  as  a  normal  heart.  It  is  even  more  difficult  to  explain 
the  gradual  or  sudden  weakening  of  the  action  of  the  heart,  with  increased 
pulse-rate  and  altered  rhythm,  which  may  occur  after  or  during  con- 
valescence. It  is  generally  ascribed  to  myocardial  degeneration,  some- 
times to  derangement  of  the  nerves  which  control  the  heart.  Low  des- 
cribes slight  alterations  of  the  conducting  bundle  of  His  in  such  cases, 
but  is  unwilling  to  claim  this  as  the  cause  of  the  heart  failure. 

Albuminuria  is  common  in  diphtheria,  and  the  kidneys  show  acute  and 
subacute  changes  in  most  fatal  cases.  These  rarely  have  the  character  of 
a  glomerulonephritis,  but  are  more  commonly  instances  of  acute  inter- 
stitial nephritis. 

The  lesions  in  other  organs  are  essentially  those  of  any  acute  infection, 
except  that  the  changes  in  the  adrenals  are  likely  to  be  more  intense, 
resulting  in  hemorrhages  and  cellular  degenerations. 

38 


578  TEXT-BOOK   OF   PATHOLOGY 

Paralysis  of  motor  and  to  a  less  extent  of  sensory  nerves  is  dependent 
upon  degenerative  and  destructive  changes  in  the  nerves  themselves,  as 
well  as  in  the  nerve-cells.  The  axones  disintegrate,  and  the  myeline 
sheaths  lose  their  homogeneous  character,  fatty  globules  which  stain  with 
osmic  acid  appearing  in  their  place.  The  nerves  which  supply  the  palate 
and  larynx,  those  of  the  extrinsic  muscles  of  the  eye  and  of  the  muscles 
of  accommodation,  suffer  especially.  Paresis  or  definite  or  temporary 
paralysis  of  the  muscles  of  the  extremities  occur,  but  are  less  common. 

Skin  lesions  in  the  height  of  the  infection  are  usually  in  the  form  of  an 
erythematous  rash,  but  petechise  and  extensive  purpuric  hemorrhages 
sometimes  appear  in  the  severest  cases. 

LITERATURE 
Oertel:   Pathogenese  der  epidemischen  Diphtherie,  Leipzig,  1887.     Deut.  Arch.  f.  klin. 

Med.,  1887-8,  xlii,  511. 

Nuttal  and  Graham  Smith:  Bacteriology  of  Diphtheria,  Cambridge,  1908. 
Behring:  Zeit.  f.  Hygiene  u.  Infektionskr.,  1892,  xii,  1-58. 
Welch:  Johns  Hopkins  Hosp.  Bull.,  1892,  iii,  17;  1895,  vi,  97.    Amer.  Jour.  Med.  Sci., 

1894,  n.  s.,  cviii,  437. 
Low:  Ziegler's  Beitrage,  1910,  xlix,  1. 

TETANUS  INFECTION 

This,  like  diphtheria,  is  essentially  an  intoxication,  since  the  bacteria 
grow  only  at  the  site  of  inoculation,  usually  in  a  wound  into  which  dirt 
has  been  forced,  and  there  produce  a  soluble  toxin,  which  is  diffused 
throughout  the  body.  A  certain  latent  period  elapses  after  the  infection 
before  the  symptoms  appear,  and  the  longer  this  lasts,  the  less  serious 
are  the  effects.  Those  cases  in  .which  the  incubation  .period  is  only  four 
days  are  almost  sure  to  end  fatally.  The  effect  of  the  poison  is  to  produce 
extension  and  extreme  rigidity  of  the  extremities,  often  preceded  by  clench- 
ing of  the  jaw  (hence  lockjaw)  and  stiffness  of  the  neck,  and  followed  by 
violent  contractions  of  the  muscles  of  the  back,  such  as  to  throw  the  body 
into  a  rigid  backward  curve  (opisthotonos) .  When  the  muscles  of  respira- 
tion are  involved,  death  ensues,  or  it  may  result  from  exhaustion.  Reflex 
or  spontaneous  convulsions  of  great  violence  may  occur.  At  autopsy  no 
lesions  are  found  which  are  characteristic  of  the  disease.  It  is  true  that 
Goldscheider  and  Flatau,  Nissl,  and  others,  have  found  swelling  and  frag- 
mentation of  the  tigroid  bodies  of  the  motor  ganglion-cells  and  shrinkage 
with  deep  staining  of  the  nuclei,  but  this  condition  is  found  under  many 
other  circumstances  and  is  by  no  means  specific.  Tetanus  must  then  be 
regarded  as  a  functional  disturbance  produced  by  the  toxin.  Exactly  the 
same  phenomena  can  be  produced  in  animals  by  the  injection  of  the  bac- 
teria-free toxin,  which  is  an  extremely  virulent  poison. 

In  the  pathogenesis  of  tetanus  the  greatest  interest  lies  in  the  point  of 
action  of  the  poison  and  its  mode  of  distribution.  It  is  observed  that 
there  may  be  a  local  rigidity  of  the  muscles  in  the  neighborhood  of  the 
point  of  infection  (local  tetanus),  but  that  while  this  may  sometimes  be  the 


TETANUS    INFECTION  579 

only  symptom,  it  usually  leads  to  a  similar  rigidity  of  the  opposite  extrem- 
ity, and  finally  to  an  involvement  of  the  whole  body  (ascending  tetanus). 
Another  form,  beginning  with  clenching  of  the  jaw  and  stiffness  of  the 
neck,  quickly  spreads  to  all  the  extremities  (universal  or  descending 
tetanus),  while  a  third  form  is  that  in  which  convulsions  form  a  striking 
feature. 

It  was  shown  by  Meyer  and  Ransom  that  the  toxin  travels  from  the 
point  of  inoculation  up  the  nerves  to  the  central  nervous  system,  although 
it  is  also  diffused  to  some  extent  by  the  blood  and  lymphatics.  In  the  case 
of  the  local  tetanus,  which  is  less  striking  in  man  than  in  experimental 
animals,  there  arose  some  question  as  to  the  possibility  of  its  being  due  to 
a  direct  effect  of  the  toxin  upon  the  muscles,  but  the  experiments  of  Permin 
show  clearly  that  if  the  nerve  be  cut  shortly  after  the  injection  of  the  toxin, 
no  such  local  rigidity  appears.  But  the  rigidity  persists  if  the  section  of 
the  nerve  be  performed  after  it  is  well  established,  probably  owing  to  second- 
ary changes  of  unknown  character  in  the  muscles  themselves.  Similarly, 
Meyer  and  Ransom  showed  that  the  injection  of  antitoxin  into  the  nerve 
above  the  point  of  inoculation  would  block  and  neutralize  the  toxin.  Further, 
since  it  might  be  supposed  that  diffusion  by  the  blood-stream  could  bring 
the  poison  to  the  ganglion-cells  of  the  cord,  Permin  has  shown  by  experi- 
ment that  if  antitoxin  be  injected  first,  so  as  to  neutralize  the  poison  carried 
by  the  blood,  a  distinct  local  tetanus  can  be  produced  by  a  small  dose  of 
toxin  injected  into  the  muscles.  The  poison  passes  along  the  nerves 
rapidly,  probably  in  the  axis-cylinders,  since  destruction  of  the  peri- 
neurium  does  not  halt  it,  and  reaches  the  corresponding  ganglion-cells 
of  the  anterior  horn.  If  it  is  limited  in  quantity  so  as  to  affect  only  this 
group,  a  local  tetanus  will  appear.  Otherwise  it  can  spread  to  affect  the 
whole  spinal  cord  and  brain,  and  rigidity  of  the  muscles  over  the  whole 
body  follows. 

In  other  cases  in  which  the  toxin  gains  more  ready  entrance  to  the  blood- 
stream, or  in  which  it  is  injected  into  the  vein  in  an  animal,  the  universal 
or  descending  type  appears. 

The  question  as  to  the  type  of  nerve  which  conducts  the  poison  seems  not 
yet  settled,*  nor  whether  the  anterior  horn  cells  become  spontaneously 
active  in  sending  impulses  to  the  muscles,  or  only  excessively  irritable  and 
responsive  to  sensory  impulses,  to  which  they  act  as  in  reflexes.  Permin 
showed  that,  by  cutting  all  the  posterior  roots  on  one  side  and  injecting 
toxin  into  both  legs,  one  produces  local  tetanus  only  on  the  intact  side, 
while  the  leg,  from  which  no  sensory  impulses  reach  the  cord,  remains 

relaxed. 

In  the  case  of  the  convulsive  attacks  it  seems  that  the  impulses  come  from 

*  Nevertheless,  Meyer  and  Ransom  produced  only  pain  and  greatly  increased  reflex 
excitability  to  pain  by  injecting  the  toxin  into  the  spinal  cord  or  posterior  roots  (tetanus 
dolorosus),  while  injection  into  peripheral  sensory  nerves  was  without  result.  Iney 
therefore  think  the  motor  nerves  the  paths  of  conduction  of  the  poison. 


580  TEXT-BOOK   OF   PATHOLOGY 

the  brain  itself,  which  in  those  cases  has  been  affected  by  the  poison. 
They  can  be  prevented  by  the  removal  of  the  motor  cortex  in  animals, 
and  can  be  produced  in  their  most  extreme  form  in  other  animals  by  inject- 
ing the  toxin  into  the  brain  or  into  the  eye,  whence  it  quickly  passes  into 
the  brain.  Tetanus  is  thus  ordinarily  the  effect  of  the  toxin  upon  the 
spinal  cord,  the  convulsive  features  being  due  to  its  spread  into  the  brain. 
The  enormous  importance  of  this  disease,  especially  in  the  present  war, 
where  wounds  are  contaminated  with  the  highly  manured  soil,  in  which 
the  bacilli  are  abundant,  has  led  to  great  efforts  to  counteract  the  poison. 
Antitoxin,  so  useful  in  guarding  against  the  poison,  and  so  active  in  neu- 
tralizing it  in  the  blood,  cannot  follow  it  from  the  circulation  into  the 
nervous  system.  Therefore,  unless  it  be  injected  into  the  nervous  tissue, 
it  is  relatively  valueless.  As  stated,  it  will  block  the  passage  of  toxin 
along  the  nerve  if  injected  into  the  substance  of  the  nerve,  but  it  must 
remain  difficult  to  diffuse  it  into  the  substance  of  the  cord  and  brain  in 
more  advanced  cases.  The  mortality  remains  high,  although  certain 
narcotics  are  useful  in  stopping  the  flow  of  impulses  from  the  ganglion- 
cells. 

LITERATURE 

Pennin:  Mitth.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1913-14,  xxvii,  1. 
Meyer  and  Ransom:   Arch.  f.  exp.  Pathol.,  1903,  xlix,  369. 
Flatau:  Flatau,  Jacobsohn,  and  Minor:   Path.  Anat.  des  Nervensystems,  Berlin,  1904, 

i,  1290. 
A.  Moschowitz:  Annals  of  Surgery,  1900,  xxxii,  416. 


CHAPTER  XXX 
TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued) 

Asiatic  cholera:  Intestinal  lesions.     General  intoxication. 

Bubonic  plague:   Transmission.     Bubonic  type.     Pneumonic  type. 

Glanders:  Acute  and  chronic  forms. 

Anthrax:    Infection  through  skin,  digestive  tract,  lungs. 

Influenzal  infection.     Relation  to  epidemic  influenza;  pneumonia,  meningitis. 

SEVERAL  other  types  of  bacterial  infection  must  be  considered  here,  some 
of  them  infections  of  enormous  importance  at  certain  times,  when  they  rage 
as  epidemics,  or  in  tropical  countries,  where  they  exist  constantly  as  en- 
demic plagues,  but  described  here  only  in  outline. 

ASIATIC  CHOLERA 

An  epidemic  disease  spreading  with  the  course  of  human  travel,  and  occur- 
ring either  in  groups  of  cases  or  suddenly  affecting  a  whole  community. 
It  is  largely  dependent  upon  infection  of  water  supply  or  of  food,  and  hence 
the  rapidity  of  its  spread  in  cities  where  the  drinking-water  comes  from  an 
infected  source,  as  was  the  case  in  the  Hamburg  epidemic.  It  is  endemic 
in  India,  and  is  the  cause  of  hundreds  of  thousands  of  deaths  every  year 
in  that  country. 

Taken  into  the  stomach  and  intestines,  the  spirillum  of  Koch  requires 
forty-eight  hours  or  more  to  develop  to  a  sufficient  extent  to  cause  the  symp- 
toms. Then  the  disease  proceeds  with  extreme  violence.  There  are  sev- 
eral forms,  in  the  mildest  of  which  there  is  intense  diarrhoea,  which  may 
pass  off  in  a  few  days.  In  the  so-called  cholerine,  there  are  diarrhoea,  vom- 
iting, and  extreme  prostration.  These  conditions  may  pass  into  the  more 
severe  form,  in  which,  with  great  desiccation  of  the  tissues,  there  are  pain- 
ful muscular  cramps,  cold  sweats,  stagnation  of  the  cutaneous  circulation, 
delirium,  and  collapse.  In  others  the  patient  passes  into  coma  and  dies. 

Anuria,  which  may  persist  until  death,  is  in  many  cases  a  most  prominent 
feature,  and  is  accompanied  by  acidosis.  This  is  largely  due  to  the  extreme 
dehydration  of  all  the  tissues  which  leaves  no  water  for  excretion  by  the 
kidneys,  and  a  very  rational  treatment  which  is  in  general  use  consists 
in  the  continuous  infusion  of  salt  solution  in  a  slow  stream  into  a  vein. 

The  following  impressions  of  the  pathological  anatomy  are  copied  from 
notes  made  in  Manila  at  a  time  when  I  had  an  opportunity  to  perform  a 
large  number  of  autopsies  in  cases  of  cholera  during  an  epidemic  of  con- 
siderable severity.  When  the  body  is  brought  warm  to  autopsy,  rigor 
mortis  appears  during  the  autopsy  and  often  draws  the  arms  and  legs  into 

581 


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a  cramped  position.  In  cases  which  have  lain  several  hours  there  is  usually 
the  most  extreme  rigidity.  The  face  is  not  distorted,  but  the  eyelids  are 
drawn  up  so  as  to  expose  the  uprolled  eyes.  The  arms  and  legs  are  like 
iron  and  it  requires  one's  full  strength  to  break  down  such  rigor.  The 
pectoral  muscles  are  hard  and  offer  a  wooden  resistance  to  the  knife.  The 
hands  and  feet  are  blue  and  shrivelled  and  shrunken  in  the  most  curious 
manner.  The  skin  over  the  balls  of  the  fingers  is  wrinkled  and  in  some 
cases  almost  hornlike  and  transparent.  The  same  change  is  visible  over 
the  palms  of  the  hands  and  soles  of  the  feet.  Elsewhere  the  skin  is  very 
inelastic  and  pasty,  and  when  pinched  up  takes  a  long  time  to  smooth  down. 
The  blood  which  oozes  from  the  heart  and  blood-vessels  is  viscid  and  very 
deep  red,  almost  black.  In  this  state  of  extreme  concentration  it  seems 
to  coagulate  less  firmly  than  normal. 

The  organs  in  general  seem  almost  normal,  and  it  is  as  though  one  were 
performing  a  series  of  autopsies  on  the  normal  victims  of  some  railway 
disaster.  The  peritoneum  contains  no  free  fluid;  even  in  the  recesses  and 
fossae  there  is  usually  not  a  drop.  The  peritoneal  surfaces  are  dull  and  dry 
and  are  no  longer  slippery;  when  quickly  pulled  apart  they  sometimes  ad- 
here a  little  and  draw  out  minute  threads  of  viscid  fluid.  The  small  in- 
testines are  usually  distended  with  fluid  and  gas,  and  are  of  a  dull  grayish 
rose  color,  showing  injected  blood-vessels.  They  are  relaxed  and  tend  to 
lie  flat.  The  colon  and  parietal  peritoneum  contrast  rather  sharply  with 
this  on  account  of  their  relatively  normal  pearly  white  color. 

The  pleural  cavities,  like  the  peritoneum,  are  dry,  but  the  pericardium 
contains  a  little  fluid.  The  thymus  is  enlarged  in  nearly  every  case.  In 
children  it  is  especially  bulky,  reaching  10  to  12  grams,  and  extending  down- 
ward as  a  thick  mass.  Even  in  adults  the  organ  lies  over  half  the  pericar- 
dium and  may  measure  10  cm.  in  length.  This  persistence  of  the  thymus 
is  especially  striking  and  probably  accords  with  the  lymphoid  swelling  in 
the  intestine.  The  heart  shows  no  changes  in  anything  except  the  pres- 
ence of  many  ecchymoses  in  the  epicardium  and  in  the  endocardium, 
especially  in  the  papillary  muscles  and  trabeculae  of  the  left  ven- 
tricle. In  marked  contrast  with  the  extreme  rigidity  of  the  body 
muscles  the  myocardium  is  rather  soft,  opaque,  and  grayish  brown, 
and  in  its  inner  layers  more  yellowish.  In  the  lungs  there  was  in 
two  or  three  cases  a  patchy  lobular  pneumonia,  and  in  as  many 
more  distinct  cedema.  But  in  most  instances  there  was  no  character- 
istic alteration.  The  spleen  is  not  enlarged  or,  indeed,  changed  in  any 
particular  from  normal.  In  no  case  was  there  found  anything  which 
could  be  described  as  an  acute  splenic  tumor.  The  liver  too  is  practically 
normal;  the  lobules  are  distinct  and  easily  outlined  and  are  not  dull  or 
cloudy  looking.  There  were  several  cases,  however,  in  which  the  liver  seemed 
drier  than  normal  and  was  very  dark  grayish  red.  The  bile  ducts  seem 
normal  and  the  gall-bladder  is  full  of  green  bile  which  usually  contains  the 
cholera  spirilla.  It  is  said  to  show  a  definite  cholecystitis  at  times,  with 


ASIATIC    CHOLERA  583 

turbid  fluid  and  reddened  mucosa,  but  I  saw  no  such  cases.  The  pancreas 
shows  no  gross  abnormality.  The  stomach  is  usually  empty  and  its  mucosa 
pale.  The  duodenum  begins  at  once  to  show  the  characteristic  lesions  of 
cholera  and  these  continue  throughout  the  small  and  large  intestine. 

The  contents  of  the  small  intestine  vary  greatly;  they  are,  as  a  rule,  fluid, 
but  not  quite  watery,  for  there  is  a  viscidity  due  partly  to  the  admixture 
of  mucus.  The  fluid  is  like  thin  barley  soup,  gray  and  turbid.  When  the 
intestine  is  opened  the  fluid  pours  out  with  radiating  shreds  of  gray  mucus 
which  are  readily  washed  off  the  mucosa.  Toward  the  lower  ileum  it  often 
becomes  tinged  rose  color,  but  this  is  by  no  means  always  so,  and  it  may 
continue  like  thin  gruel  through  the  whole  colon.  "Rice  water"  must  be 
a  poor  descriptive  phrase,  for  the  stools  seem  more  viscid,  turbid,  and  mucoid 
than  that  could  be.  Microscopically  the  contents  of  the  upper  ileum  shows 
myriads  of  bacteria  and  thick  masses  of  desquamated  epithelium  with  few 
or  no  leucocytes.  The  bacteria  are  of  many  kinds,  large  stout  bacilli, 
long  rods  both  coarse  and  thin,  minute  thin  bacilli,  but  rather  few  spirilla. 
They  can  be  found  after  rather  long  search,  but,  of  course,  grow  out  abun- 
dantly on  selective  media.  The  epithelial  cells  seem  to  be  partly  digested 
and  few  of  them  will  take  a  nuclear  stain.  They  are  often  to  be  found  in 
sheets. 

The  mucosa  is  lax,  smooth  and  slippery,  and  spreads  out  easily  as  though 
half  decomposed.  It  is  not  swollen  as  in  oedema,  but  seems  to  be  easily 
permeated  by  the  fluid,  and  not  to  hold  it  back.  When  washed  it  shows 
the  individual  villi  as  tiny  opaque  grayish-white  threads.  The  mucosa  has 
a  certain  opacity,  about  as  intense  as  that  of  wet  white  tissue  paper.  It 
allows  the  red  of  the  injected  submucosa  to  show  through  as  a  rose  color 
veiled  by  the  gauzy  wet  mucosa.  Lower  in  the  intestine  there  may  be  many 
minute  haemorrhages  so  fine  as  to  give  a  pale  red  color  to  the  mucosa  in 
the  neighborhood  of  the  Peyer's  patches  and  solitary  nodules.  In  the  lower 
ileum  these  lymphoid  structures  become  swollen  and  prominent,  not  to 
the  degree  seen  in  typhoid  fever  or  marked  status  lymphaticus,  but  still 
enough  to  make  them  quite  conspicuous.  There  is  no  ulceration,  although 
there  may  be  haemorrhages  of  small  extent.  A  frequent  phenomenon  is  the 
appearance  of  a  grayish-green  opaque  spot  in  the  centre  of  each  solitary 
nodule  and  each  unit  of  the  agminated  patch.  In  a  few  cases  the  haemor- 
rhage is  more  intense,  and  in  one  case  the  whole  mucosa  was  deep  blood  red 
with  only  a  few  patches  of  normal  color.  Occasionally  there  are,  in  pro- 
tracted cases,  patches  of  diphtheritic  exudate. 

The  mucosa  of  the  colon  is  almost  exactly  like  that  of  the  small  intestine. 
It  is  pale,  lax,  moist,  and  rather  white  and  opaque.  In  some  cases  there  are 
many  sharply  outlined  haemorrhages.  The  mucosa  of  the  appendix  is  sim- 
ilarly altered,  although  to  a  slighter  degree.  The  contents  of  the  colon  are 
like  those  of  the  ileum  in  most  cases,  but  it  must  be  remembered  that  there 
are  some  in  which  death  occurs  before  diarrhoea  appears,  and  in  these  cases 
of  cholera  sicca  the  colon  contains  formed  faeces. 


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The  adrenals  show  nothing  abnormal.  The  kidneys  when  not  modified 
by  old  changes  are  practically  normal  in  their  general  appearance.  The 
capsule  strips  off  smoothly,  leaving  a  pale  yellowish-gray  and  rose-colored 
surface.  The  size  and  consistence  are  normal.  On  section  the  striations 
of  the  cortex  and  glomeruli  are  normal  in  arrangement  and  the  only  abnor- 
mality consists  in  a  slight  opacity  and  yellow  hue  in  the  labyrinthine  por- 
tions. Even  in  cases  in  which  there  was  anuria  for  days  before  death  I 
was  able  to  see  little  more  than  this  blotchy  yellow  opacity  in  the  bands 
which  contain  the  convoluted  tubules.  In  other  cases  the  kidney  was  found 
dry  and  dull  looking,  dark  grayish-red,  pasty,  and  inelastic. 

The  urinary  bladder  is  always  empty  or,  at  most,  contains  a  few  drops  of 
thick,  viscid,  turbid  yellow  urine.  The  bone-marrow  is  soft,  fatty,  and 
often  shows  patches  of  dark  red.  The  brain  and  cord  show  no  obvious 
changes. 

Microscopically  examined,  the  wall  of  the  intestine  shows  an  almost 
complete  loss  of  the  epithelium  from  the  mucosa.  Only  in  the  depths  of 
the  crypts  is  any  left,  and  the  villi  project  quite  uncovered.  Their  limit- 
ing membrane  is  still  continuous,  but  the  cells  which  fill  them  at  their  tops 
are  all  necrotic.  The  lymphoid  nodules  are  swollen  and  show  many  frag- 
mented cells  in  their  central  portions,  but  there  is  no  ulceration.  The 
mesenteric  lymph-nodes  nearly  always  present  wide  areas  of  necrosis 
which  occupy  the  position  of  the  sinuses.  The  kidneys,  in  accordance  with 
their  naked-eye  appearance,  are  undisturbed  in  their  anatomical  arrange- 
ment, and  there  is  no  inflammatory  reaction,  but  in  the  severer  cases  there 
are  profound  destructive  changes  in  the  epithelial  cells  of  the  convoluted 
tubules.  Even  in  the  less  advanced,  certain  tubules  are  partly  lined  by 
cells  which  are  swollen  and  contain  large  hyaline  droplets,  but  in  those 
which  have  passed  through  several  days  of  anuria  the  convoluted  tubules 
are  choked  throughout  their  whole  course  with  masses  of  necrotic  cells. 
No  constant  changes  can  be  made  out  in  the  spleen  and  liver  in  this  series 
of  cases,  although,  as  stated,  some  authors  have  observed,  apparently  in 
cases  which  survive  for  some  time,  an  acute  cholecystitis  and  even  an  ex- 
tensive cholangitis. 

Great  differences  of  opinion  prevail  as  to  the  exact  nature  of  the  infection 
in  cholera,  especially  with  regard  to  the  distribution  of  the  organisms  in 
the  body.  I  found  difficulty  in  distinguishing  the  spirilla  in  the  mass  of 
miscellaneous  bacteria  in  the  intestinal  contents,  while  Schobl  and  others 
speak  of  that  fluid  as  a  pure  culture  of  cholera  vibrios.  Most  authors  state 
that  the  specific  organisms  are  confined  to  the  intestinal  tract,  and  that 
the  violent  symptoms  are  due  to  the  absorption  of  toxic  materials,  but  Col- 
onel Greig  has  found  patches  of  bronchopneumonia  loaded  with  the  spirilla 
and  has  cultivated  them  also  from  the  spleen.  He  therefore  naturally 
regards  the  cholecystitis  and  cholangitis,  and  even  the  mere  infection  of 
the  bile  of  the  gall-bladder,  as  due  to  circulation  of  the  bacteria  in  the 
blood,  rather  than  to  wandering  from  the  intestine  by  way  of  the  gall-duct. 


BUBONIC    PLAGUE  585 

The  necrosis  of  the  mesenteric  glands  which  occurred  so  often  in  our  series 
would  suggest  an  escape  of  the  organisms  by  way  of  the  lymphatics.  The 
necrosis  of  the  renal  epithelium  has  the  appearance  of  a  toxic  process,  es- 
pecially since  the  cholera  vibrios  have  been  so  rarely  found  in  the  urine, 
although  so  carefully  searched  for.  But  so  far  cultures  from  the  circulat- 
ing blood  have  been  negative. 

The  great  frequency  of  infection  of  the  bile  is  of  much  importance,  since 
it  is  the  basis  of  the  persistence  of  the  organisms  in  the  excreta  of  convales- 
cents, just  as  in  typhoid  fever,  although  probably  these  persons  do  not 
remain  infected  for  nearly  so  long  a  time.  The  stools  have  been  found  to 
contain  the  spirilla  for  forty  to  ninety  days  after  recovery,  but  Kulescha 
had  one  case  in  whose  bile-ducts  they  were  found  ten  months  after  the 
onset  of  the  disease. 

LITERATURE 

Krause  and  Rumpf :  Handb.  d.  Tropenkrankheiten,  Mense,  1914,  iii,  242. 
Koch,  R.:  Arb.  a.  d.  Kais.  Gesundheitsamte,  1887,  iii. 
Crowell:  Philippine  Jour.  Science,  1914,  ix,  361. 
Th.  Fahr:  Ergebn.  d.  allg.  Path.,  1909,  xiiii,  1. 
Schobl:  Philippine  Jour.  Science.  1915,  x,  11. 

Heiser  and  Ernst:  Wood's  Ref.  Handb.  Med.  Sci.,  New  York,  1917,  viii,  552. 
Greig:  Indian  Jour.  Med.  Research,  1914,  i,  67. 

BUBONIC  PLAGUE 

The  plague  is  another  affection  endemic  in  certain  countries,  where  it  is 
essentially  a  disease  of  rats  and  other  rodents,  but  spreading  with  the  trans- 
portation of  infected  materials  or  rats  to  other  countries.  It  has  occurred 
with  the  same  virulence  in  winter  weather  in  Manchuria  as  in  the  heat  of 
India  or  Africa. 

Plague  is  caused  by  the  Bacillus  pestis,  discovered  by  Yersin  and 
Kitasato,  an  organism  of  extraordinary  virulence,  capable  of  causing  infec- 
tion from  the  slightest  inoculation,  and  producing  a  highly  mortal  disease, 
in  which  it  becomes  distributed  in  enormous  quantities  through  the 
body.  Infection  can  occur  through  the  skin,  through  the  respiratory  tract, 
and,  possibly,  though  this  is  unimportant,  through  the  digestive  tract. 
By  far  the  most  common  are  infections  through  the  skin,  either  through 
wounds  (Durck  describes  infection  from  a  rat-bite)  or  through  the  bites  of 
infected  fleas.  The  rather  rare  cases  of  primary  plague  pneumonia  are  often 
caused  by  the  inhalation  of  bacilli  carried  in  fine  droplets  of  sputum  ex- 
haled by  another  person  with  plague  pneumonia.  In  the  great  Manchurian 
epidemic  of  1910-11  Strong  tells  me  the  cases  were  nearly  a1!  of  the  pneu- 
monic type  and  were  uniformly  fatal.  He  and  his  assistant  escaped  infec- 
tion by  wearing  thick  masks  of  cotton. 

By  far  the  greater  number  of  the  cases  in  ordinary  plague  are  not  of  the 
pneumonic  type,  but  are  characterized  by  buboes  or  suppurations  of  the 
inguinal,  axillary,  and  other  lymph-glands.  In  these  the  infection  is  prob- 


586 


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ably  caused  by  the  bites  of  fleas  which  have  infected  themselves  from  plague- 
stricken  rats.  C.  J.  Martin  has  shown  me  the  plugs  of  plague  bacilli  which 
form  in  the  proventriculus  of  the  flea,  preventing  the  access  of  any  blood 
to  its  stomach.  Such  a  flea,  constantly  hungry,  will  bite  again  and 
again,  each  time  transferring  plague  bacilli  to  its  victims. 


Fig.  285. — Pneumonic  plague.  The  exudate  and  congestion  are  such  as  are  described 
for  the  stage  of  engorgement  in  ordinary  pneumonia.  Great  quantities  of  bacteria  in 
the  tissues,  especially  in  the  lymphatics  of  the  bronchial  walls. 

Bubonic  Type. — After  a  short  incubation  period,  painful  swellings  appear 
in  the  groin.  In  the  early  stage  these  glands  are  swollen  and  sprinkled  with 
haemorrhages.  The  lymph  sinuses  are  packed  with  phagocytic  cells  which 
contain  the  bacilli  in  numbers.  Necrosis  follows  quickly  and  becomes 
extensive,  and  is  associated  with  much  haemorrhage  and  outpouring  of 
leucocytes.  Diirck  thinks  it  largely  due  to  circulatory  obstruction.  The 
whole  centre  of  the  gland  breaks  down  into  an  abscess  cavity  and  may  be 


BUBONIC    PLAGUE  587 

discharged.  Metastases  of  the  bacilli  occur  to  the  next  glands,  and 
shortly  to  the  lungs  and  other  organs.  In  the  lungs  foci  of  necrosis  of  the 
tissue  with  suppuration  are  produced  by  this  embolism,  and  the  same  is 
true  for  the  liver.  There  is  a  great  swelling  and  softening  of  the  spleen 
with  grayish  opacity,  caused  by  the  new  formation  of  cells,  which  Durck 
thinks  are  endothelial  cells  from  the  sinuses.  Abscesses  occur  there  also. 
In  the  kidneys  there  may  be  definite  focal  necroses,  abscess  like  in 
appearance,  with  many  bacilli,  or  more  commonly  an  acute  hsemorrhagic 
nephritis  with  necrosis  and  desquamation  of  the  epithelial  cells,  both  in 
the  glomerular  capsules  and  tubules. 

On  the  whole,  the  appearance  is  that  of  a  fulminant  general  septicsemia, 
with  the  lodgment  of  enormous  numbers  of  bacilli  in  any  or  all  of  the  organs, 
and  their  transportation  in  quantities  in  the  lymph  and  circulating  blood. 

Pneumonic  Form. — In  the  bubonic  form  there  may  be  found,  in  some 
cases,  lobular  consolidation  of  the  lung,  sometimes  discrete,  more  often 
confluent.  This  is,  in  fact,  the  commoner  type  of  pneumonia  found  in 
such  epidemics  as  that  of  Manchuria,  but  Strong  emphasizes  the  fact  that 
the  somewhat  hypothetical  stage  of  engorgement,  always  described  for  the 
pneumococcus  pneumonia,  is  really  the  commonest  phenomenon  in  these 
cases,  since  the  affected  persons  die  before  actual  hepatization  can  be  pro- 
duced (Fig.  285).  He  describes  lobar  consolidation  also,  in  which,  how- 
ever, only  a  small  part  of  the  lung  was  ever  found  in  the  'stage  of  gray 
hepatization,  another  part  in  that  of  red  hepatization,  while  the  greater 
part  was  in  the  stage  of  engorgement.  Even  in  the  gray  stage  there  is 
little  fibrin,  while  in  the  more  usual  stage  of  engorgement  there  are  hardly 
any  leucocytes,  although  the  alveoli  are  filled  with  bacteria  and  fluid  and 
desquamated  epithelium,  and  the  capillaries  are  greatly  distended. 

In  the  other  organs  there  were  found  evidences  of  an  intense  general 
septicsemia,  with  cloudy  swelling  and  hemorrhages,  but  usually  no  such 
embolic  lesions  as  described  for  the  more  slowly  advancing  bubonic  form. 

LITERATURE 

Durck:    Ziegler's  Beitrage,  1904,  Suppl.  vi. 

Albrecht  and  Ghon :  Beulenpest  im  Bombay,  Wien,  1898-1900. 

Strong  and  Teague:  Philippine  Journal  of  Science,  1912,  vii,  129,  137. 

GLANDERS 

Primarily  a  disease  of  horses,  mules,  etc.,  infection  with  the  Bacillus  mallei 
may  occur  in  those  who  handle  horses  or  who  are  exposed  in  some  way  to 
contagion  from  them.  In  a  few  cases  fatal  infections  have  occurred  in 
persons  working  in  laboratories  with  cultures  of  the  organism. 

In  horses  the  disease  is  largely  an  affection  of  the  nasal  and  respiratory 
tracts,  and  frequently  assumes  a  chronic  course.  Nodules  appear  in  the 
nasal  mucosa,  especially  upon  the  septum,  which  are  quite  firm  at  first, 
but  later  present  a  necrotic  centre  and  develop  into  ulcers,  which  heal  with 


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extensive  scar  formation,  recognizable  by  its  curious  stellate  arrangement. 
Affections  of  the  trachea  and  lungs,  of  the  intestines,  lymph-glands,  spleen, 
etc  ,  are  also  found  in  these  animals  (Kitt). 

In  man  the  formation  of  necrotizing  or  pustular  eruptions  in  the  nose  has 
been  described,  and  in  such  cases  the  destructive  action  of  the  bacilli  leads 
before  long  to  the  ulceration  and  perforation  of  the  septum  of  the  nose, 
partial  destruction  of  the  turbinate  bones,  or  even  of  the  palate.  More 


Fig.  286. — Glanders.     Focus   of  lobular  pneumonia  with  abscess-like   destruction  of 
tissue  and  organization  of  adjacent  exudate. 

common  are  infections  through  the  skin,  which  give  rise  to  deep  indurated 
swellings  which  persist  until  incised,  or  until  they  burst  spontaneously, 
setting  free  a  thick,  stringy  pus.  Such  abscesses  heal  very  slowly,  and 
usually  a  sinus  persists  for  a  long  time.  In  other  cases  serpiginous  ulcers 
are  formed  in  the  skin  which  extend  in  one  or  other  direction,  leaving 
behind  a  partly  healed  or  scarred  area.  Most  of  the  cases  have  presented 
deep  muscular  abscesses  which  evacuate  the  same  thick  pus  and  are  slow  to 


ANTHRAX  589 

heal.  At  times  the  bone  is  attacked,  and  in  many  instances  there  have  been 
necrosis  and  final  perforation  of  the  bones  of  the  skull.  Multiple  embolic 
lesions  in  which  necrotic  or  caseous  material  is  formed  and  surrounded  by  a 
dense  granulation  tissue  are  found  in  various  situations  in  the  body.  Pul- 
monary lesions  are  especially  frequent,  and  assume  various  forms.  In  one 
case  which  I  studied  in  Professor  Marchand's  laboratory  the  man  had  been 
accidentally  infected  by  thrusting  the  needle  of  a  syringe  full  of  a  culture  of 
Bacillus  mallei  into  his  thumb.  Two  months  later  he  died  with  what 
appeared  to  be  a  diffuse  tuberculous  pneumonia.  In  these  lesions,  however, 
there  were  found  the  bacilli  in  pure  culture,  and  microscopically  the  changes 
were  quite  unlike  those  of  tuberculosis.  Instead  (Fig.  286),  there  were 
foci  of  necrosis  with  debris  of  cells  and  tissue  closely  coagulated  together, 
but  without  nuclear  stain,  surrounded  by  a  zone  of  fragmented  nuclei, 
and  this  in  turn  by  a  thick  infiltration  of  leucocytes.  The  adjacent  lung 
tissue  was  the  seat  of  an  organizing  pneumonia,  and  there  was  extensive 
filling  of  alveoli  with  large  mononuclear  cells,  as  in  caseous  pneumonia. 
In  this  case  there  was  nothing  of  the  formation  of  nodules  with  giant-cells 
which  has  been  so  generally  described  in  the  lesions  of  glanders.  Especially 
in  the  foci  in  the  nasal  mucosa,  but  also  in  glanders  lesions  elsewhere,  there 
is  said  to  be  an  extensive  new  formation  of  epithelioid  cells  and  even  of 
giant-cells  which  gives  the  lesions  something  of  the  character  of  a  tubercle. 
As  Duval  points  out,  this  occurs  only  with  bacilli  of  relatively  low  virulence 
and  in  the  more  chronic  cases.  Otherwise  the  necrosis  of  the  tissue  is 
quickly  produced  and  the  surrounding  granulation  tissue  is  less  characteristic. 

LITERATURE 

G.  D.  Robins:  Studies  from  the  Royal  Victoria  Hosp.,  Montreal,  1906,  ii,  No.  1. 
J.  H.  Wright:  Jour.  Exp.  Med.,  1896,  i,  577. 
Th.  Kitt:  Path.  Anat.  d.  Hausthiere,  1901,  ii,  138,  etc. 
MacCallum:  Ziegler's  Beitrage,  1902,  xxxi,  440. 

ANTHRAX 

A  disease  which  affects  cows,  sheep,  and  other  herbivorous  animals  is  caused 
by  infection  with  the  well-known  Bacillus  anthracis,  and  is  transmitted  to 
man  through  contact  with  the  sick  animals,  or  through  handling  their 
infected  hides.  In  certain  industries  which  have  to  do  with  hides  (tanning, 
etc.)  or  with  hair  or  wool  in  the  making  of  mattresses,  paper,  etc.,  infection 
may  occur,  sometimes  almost  in  epidemic  form  (wool-sorter's  disease, 
Hadernkrankheit) . 

Cattle  are  infected  especially  in  pastures  which  are  subject  to  inundation, 
but  a  field  once  infected  may  remain  so  for  a  long  time,  and  the  infection  be 
added  to  by  the  secretions  of  the  cattle  themselves,  or  by  the  soiling  of  the 
ground  with  the  remains  of  cattle  which  have  died  or  been  slaughtered 
and  buried  there.  Naturally,  chances  for  infection  occur  in  the  stalls 
where  such  cattle  are  kept. 


590  TEXT-BOOK    OF    PATHOLOGY 

In  these  animals  the  disease  may  be  very  acute,  killing  within  a  few  hours, 
or  there  may  develop  definite  carbuncles  or  more  diffuse  oedema  in  the  skin 
or  in  the  intestinal  tract.  At  autopsy  there  is  found  a  general  septi- 
caemia— the  blood-vessels  are  full  of  the  bacilli,  and  the  internal  lesions  in 
general  are  ecchymoses,  acute  splenic  tumor,  cloudy  swelling  of  liver  and 
kidneys,  etc.,  such  as  might  be  found  in  other  acute  infections. 

In  man  the  portal  of  entry  may  be  through  the  skin,  the  digestive  tract, 
or  the  lungs.  In  the  case  of  the  skin  some  slight  abrasion  is  usually  the 
point  of  entrance,  although  it  has  been  shown  experimentally  that  anthrax 
bacilli  rubbed  on  the  intact  skin  can  pass  through  the  hair-follicles.  During 
the  war  there  were  several  cases  in  which  the  infection  was  traced  to  the 
use  of  shaving  brushes  made  of  hair  from  infected  animals.  A  small  pain- 
ful red  nodule  appears,  resembling  a  flea-bite,  and  rapidly  enlarges 
and  shows  a  greenish,  necrotic  centre,  induration  and  reddening  of  the 
surrounding  tissue,  with  blisters  filled  with  yellowish  or  bluish  fluid. 
This  phlegmonous  infiltration  of  the  skin  and  subcutaneous  tissue  spreads 
quickly,  and  the  central  part  dries  up  into  a  leather-like  crust  under  which 
the  tissue  is  necrotic  and  loaded  with  anthrax  bacilli.  Such  a  carbuncle 
is  at  least  evidence  of  a  certain  resistance,  although  from  it  the  bacilli 
may  spread  in  quantities  into  the  blood.  There  is  another  type  in 
which,  instead  of  a  localized  carbuncle,  a  wide-spread  oedema  of  the  skin 
and  underlying  tissue  appears,  with  myriads  of  bacilli.  This  indicates  a 
poorer  ability  to  resist,  and  passes  on  to  a  more  surely  fatal  outcome.  In 
the  more  resistant  cases  the  leucocytosis  is  high  and  phagocytosis  is  active, 
but  in  some  the  bacilli  surround  themselves  with  thick  capsules,  and  are 
then  not  readily  taken  up  by  the  leucocytes.  It  is  thought  that  the  forma- 
tion of  such  capsules  is  an  indication  that  the  bacilli  are  gaining  the  upper 
hand  in  the  struggle,  and  the  prognosis  is  correspondingly  bad.  The 
neighboring  lymph-glands  become  swollen  and  haBmorrhagic,  and  thence 
the  infection  becomes  generalized. 

In  the  persons  who  work  with  hair,  hides,  and  wool,  inhalation  of  the 
dust  which  bears  the  anthrax  spores  produces  a  singularly  fatal  form  of  the 
disease,  which  is  primarily  a  lobular  or  lobar  pneumonia,  distinguishable  only 
by  the  recognition  of  the  bacilli  from  other  types  of  pneumonia.  Eppinger 
has  described  many  cases  in  which  he  found  lesions  chiefly  in  the  thoracic 
viscera;  the  pleural  and  pericardial  surfaces  were  covered  with  a  fibrino- 
purulent  or  hsemorrhagic  exudate,  and  the  lungs  were  partly  consolidated. 
A  lobular  or  confluent  hepatization  of  the  lungs  with  exudate  of  a  soft  or 
haemorrhagic  character  was  found,  and  microscopically  the  alveoli,  as  well 
as  the  lymphatics  and  tissue  crevices,  were  loaded  with  bacilli.  Neighbor- 
ing lymph-glands  were  greatly  enlarged  and  hsemorrhagic,  and  elsewhere 
there  were  the  changes  of  a  general  septicaBmia.  Risel  described  in  this 
connection  great  haBmorrhagic  infiltration  of  the  mediastinal  tissues,  as  well 
as  of  the  bronchial  lymph-glands.  In  persons  who  have  swallowed  infected 
meat  or  milk  there  arise  intestinal  carbuncles,  just  as  in  cattle.  These  are 


ANTHRAX 


591 


usually  single,  but  may  be  multiple,  and  occur  most  commonly  in  the 
jejunum.  The  lesion  seems  to  begin  in  the  depths  of  the  mucosa,  or  in  the 
submucosa,  and  appears  as  a  red,  pea-sized  to  plum-sized  swelling,  which  is 
made  up  of  cedematous  tissue  loaded  with  bacilli  and  leucocytes  The 
whole  adjacent  mucosa  and  submucosa  become  infiltrated,  and  the  car- 
buncle itself  ulcerates  deeply.  The  mesenteric  glands  swell  and  are 
hsemorrhagic. 

In  all  these  cases  there  are  evidences  of  the  most  intense  acute  general 
infection.  Probably  in  no  other  disease  do  such  quantities  of  bacteria 
appear  in  the  circulating  blood.  So  extensively  do  they  fill  the  capillaries 


Fig.  286A. — Anthrax  meningitis. 

that  it  has  even  been  suggested  that  in  this  disease  the  symptoms  may  be 
due  to  that  obstruction.  The  bacilli  can  be  recognized  by  staining  a  single 
drop  of  the  circulating  blood.  The  spleen  becomes  greatly  swollen  and 
soft  and  turgid  with  dark  blood.  Indeed,  it  is  from  this  dark  color  and 
incoagulability  of  the  blood,  which  give  the  spleen  such  a  peculiar  appear- 
ance, that  the  disease  derives  its  various  names  (Milzbrand,  charbon,  an- 
thrax). Cloudy  swelling  of  the  liver  and  kidneys  is  constant,  but  there 
may  also  be  necrosis  and  disintegration  of  the  cells  in  these  organs. 

Hsemorrhagic  meningitis  appears  to  be  not  uncommon,  and  in  one  of 
RisePs  cases  it  formed  the  most  striking  feature  (Fig.  286A).  There  were  in 
the  nasal  mucosa  ulcerated  nodules  extending  into  the  submucosa,  and  from 


592  TEXT-BOOK   OF   PATHOLOGY 

these  a  hsemorrhagic  cellular  exudate  rich  in  bacilli  could  be  traced  along  the 
lymphatic  sheaths  of  the  olfactory  nerves  to  the  brain. 

LITERATURE 

Risel:  Zeit.  f.  Hygiene,  1903,  xlii,  381. 
Eppinger:  Die  Hadernkrankheit,  Jena,  1894. 
Koranyi:  Nothnagel's  Handb.,  1897,  Bd.  v,  Th.  v,  Abt.  i. 

Salmon  and  Smith:  United  States  Department  of  Agriculture,  Bureau  Animal  In- 
dustry, Circular  71,  1904. 
W.  Koch:  Deutsche  Chirurgie,  1881,  Lief  9. 
Herzog:  Ziegler's  Beitrage,  1915,  Ix,  513. 

INFLUENZA 

From  remote  antiquity  the  disease  which  is  now  called  influenza  or  la 
grippe  has  been  known  on  account  of  its  extraordinary  power  of  spreading 
with  great  rapidity  over  whole  countries,  or  even  over  the  whole  world. 
The  history  of  the  disease,  which  may  be  read  in  Hirsch's  Geographical 
and  Historical  Pathology,  or  in  the  monographs  of  Ripperger  and  of 
Leichtenstern,  is  truly  remarkable,  since  the  records  of  the  epidemics  go 
back  to  the  tenth  century  and  show  that  in  some  way  not  yet  understood 
the  peoples  of  all  countries  have  been  visited  periodically.  There  is  no 
definite  regularity  about  the  appearance  of  the  great  epidemics,  although 
it  has  been  thought  that  they  come  about  every  thirty  years.  Then  the 
disease  sweeps  round  the  whole  world,  progressing  westward  in  a  general 
way,  although  this  too  is  questioned.  The  last  pandemic  outbreak  was 
in  1889,  after  which  vague  local  epidemics  occurred  without  attracting 
special  attention  until  1918,  when  the  more  familiar  recent  world  visita- 
tion occurred. 

The  name  influenza,  which  merely  means  "influence"  in  Italian,  is  de- 
rived from  the  mistake  of  someone,  who,  in  attempting  to  read  an  Italian 
treatise,  thought  it  the  name  proposed  for  the  disease.  It  has  long  been 
recognized  as  a  specific  infectious  disease,  and  from  the  general  uniformity 
of  the  symptoms  when  occurring  in  epidemic  distribution  it  has  been  easy 
to  identify  it  in  each  new  outbreak.  Isolated  cases  at  other  times  are, 
however,  not  so  certainly  diagnosed. 

This  affection  is  described  at  this  point  not  because  there  is  anything 
to  show  that  it  is  a  bacterial  disease,  but  because  there  is  no  sufficient 
proof  that  it  should  be  classed  otherwise.  It  has,  however,  the  general 
characters  of  the  exanthematic  diseases,  such  as  measles  and  scarlet 
fever,  which  we  do  not  think  of  as  caused  by  bacteria.  Indeed,  Bloom- 
field  and  Harrop  have  described  a  rash  and  an  eruption  in  the  mouth  as 
quite  characteristic. 

The  symptoms  are  much  like  those  of  a  cold,  with  fever,  catarrhal  in- 
flammation of  the  mucosse  of  the  nose  and  throat,  general  aching  and  pros- 
tration. There  is  no  leucocytosis,  but  a  marked  decrease  in  the  number  of 
leucocytes  (leucopenia),  and  in  association  with  this  the  resistance  to 


INFLUENZA  593 

bacterial  invasion  is  greatly  lowered — more,  indeed,  than  in  any  other 
disease.  No  one  as  far  as  we  know  has  died  of  influenza,  and  we  are 
practically  entirely  uninformed  as  to  the  nature  of  any  changes  in  the 
internal  organs  which  may  result  from  it.  It  passes  off  after  a  few  days 
and  apparently  confers  an  immunity,  although  it  is  difficult  to  make  this 
statement  with  any  assurance.  It  seemed  nevertheless  that  those  who 
had  lived  through  the  epidemic  of  1889-91  were  seldom  affected  in  the 
recent  epidemic,  while  young,  strong  persons  were  attacked.  In  remote 
islands  of  the  Pacific  and  elsewhere  this  did  not  come  out  clearly,  and  it 
seemed  to  be  the  old  and  weak  who  suffered.  Experiments  conducted 
by  Prof.  M.  J.  Rosenau  for  the  purpose  of  inoculating  volunteer  non- 
immunes  failed  completely.  Every  conceivable  mode  of  transmitting  the 
disease  from  patients  in  every  stage  of  the  illness  was  tried,  but  in  no  way 
could  he  provoke  the  appearance  of  influenza  in  his  volunteers.  Similar 
experiments  were  carried  out  in  California  with  yeung  volunteers  who  had 
never  been  exposed  to  the  disease,  and  these  also  gave  negative  results. 
Sputum,  blood,  and  other  fluids  were  inoculated,  without  the  slightest 
effect.  Nevertheless  the  disease  spreads  with  the  most  astounding 
rapidity,  and  appears,  as  it  seems,  explosively  in  all  quarters  of  a  city  or 
of  a  country  at  once.  It  seems  incredible  that  anything  but  human 
intercourse  could  be  responsible,  but  all  sorts  of  other  explanations  have 
been  proposed  without  much  solid  foundation.  Much  has  been  made  of 
the  fact  that  in  several  instances  epidemics  of  influenza  have  appeared 
on  ships  while  coasting  along  the  shore  of  a  country  where  the  disease 
raged,  although  the  ship  never  touched  land. 

Although  no  one  has  died  of  influenza  directly,  the  predisposition  of 
those  affected  to  secondary  infection  with  all  sorts  of  bacteria  is  such 
that  hundreds  of  thousands  and  even  millions  of  persons  have  died  in 
the  course  of  the  present  epidemic  (for  a  recrudescence  seems  to  be  in  prog- 
ress) from  the  pneumonia  produced  by  the  secondary  invaders.  Almost 
all  the  bacteriologists  and  pathologists  in  the  world  have  seized  the  op- 
portunity to  investigate  the  disease,  and  the  results  up  to  the  present  have 
been  most  confusing.  After  the  last  pandemic  appearance  of  the  influenza 
R.  Pfeiffer  studied  the  bacteria  in  the  bronchial  secretion  of  sporadic 
cases  of  bronchitis  and  pneumonia,  and  discovered  a  minute  bacillus 
which  was  Gram  negative  and  required  haemoglobin  for  its  growth.  Al- 
though the  epidemic  had  been  over  for  two  years,  he  announced  without 
any  proof  whatever  that  this  bacillus  was  the  cause  of  influenza,  and  it 
took  the  name  Bacillus  influenza.  Nothing  could  have  been  the  source 
of  more  confusion,  for  this  organism  or  one  of  its  varieties  is  extremely 
widely  distributed  and  common  at  all  times  and  can  be  found  in  the 
throats  of  many  healthy  people,  as  well  as  in  the  bronchi  of  those  with 
tuberculous  and  other  pulmonary  diseases.  Rivers  has  found  that 
there  are  pathogenic  and  non-pathogenic  forms  readily  separable  by  cul- 
tural and  agglutination  characters.  The  pathogenic  group  is  a  serious 
39 


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cause  of  disease  and  is  prominent  among  the  secondary  bacterial  invaders 
in  producing  pneumonia  after  influenza. 

There  are  still  some  investigators  who  think  this  bacillus  of  Pfeiffer 
is  the  cause  of  the  epidemic  disease  influenza,  and  Blake  and  Cecil  think 
they  have  reproduced  the  epidemic  disease  in  monkeys  by  intratracheal 
inoculations  of  the  bacillus  of  Pfeiffer.  I  myself  do  not  think  the  epidemic 
disease  influenza  is  caused  by  this  bacillus,  because  the  forms  of  pneu- 
monia which  follow  influenza 
are  not  all  alike,  and  there  is 
one  perfectly  characteristic 
group  which  is  caused  by  the 
Pfeiffer  bacillus  in  pure  cul- 
ture. Further,  there  are  many 
cases  in  which  I  have  been 
unable  to  find  the  bacillus  at 
all,  although  other  organisms, 
such  as  the  pneumococcus  or 
streptococcus,  were  present 
and  produced  pneumonia.  It 
is,  of  course,  possible  that 
some  bacterium  might  cause 
the  epidemic  disease  and  then 
be  overgrown  and  obliterated 
by  another,  which  produces 
the  secondary  pneumonia. 
But  it  is  especially  because  of 
the  phenomenal  rapidity  of  the 
spread  of  the  infection,  which 
is  so  unlike  that  of  any  bacte- 
rial disease,  that  it  seems  im- 
probable that  it  should  be  due 
to  the  bacillus  mentioned.  In 
Camp  Meade,  where  the  ad- 
vent of  the  epidemic  was 
awaited,  since  it  had  pro- 
gressed from  the  north  to  New 
Jersey,  3  cases  appeared  in  one 
day  and  3000  next  day. 

Sequelae  of  Influenza. — In  many  cases  pneumonia  follows  quickly 
upon  influenza  and  is  accompanied  if  untreated,  by  an  intense  inflammation 
of  the  larynx  and  trachea.  The  pneumonia  is  caused  by  pneumococci  of 
all  types — by  a  hsemolytic  streptococcus,  by  the  Staphylococcus  aureus, 
Friedlander's  bacillus,  the  bacillus  of  Pfeiffer,  or  by  a  mixture  of  two  or 
more  of  these  and  various  other  organisms.  The  anatomical  character 
of  the  pneumonia  varies  with  the  resistance  offered,  as  in  the  case  of  the 


Fig.  286B. — Pneumonia  caused  by  the  pneu- 
mococcus during  the  epidemic  of  influenza  in  a 
person  still  suffering  from  that  disease. 


INFLUENZA 


595 


post-measles  pneumonias  described  under  the  heading  Streptococcal  In- 
fections, but  for  some  of  the  organisms  there  are  more  or  less  typical 
forms,  since  in  all  the  patients  the  resistance  is  greatly  lowered. 

The  pneumococci  produce  a  confluent  lobular  consolidation  (Fig. 
286B)  which  begins  in  very  sharply  outlined  blocks  of  elastic  cedemat- 
ous  ha3morrhagic  tissue  in  which  the  ductuli  alveolares  are  lined  with  a 
hyaline  membrane  and  are  filled  with  fluid,  while  the  alveoli  contain  a 


Fig.  286C.— Pneumococcal  pneumonia  in  influenza.  The  ductuli  alveolares  are  dis- 
tended with  fluid  and  lined  with  a  peculiar  hyaline  material.  The  alveoli  contain  an  ex- 
tremely fresh  exudate. 

fresh  red  clot  of  exudate  made  up  of  a  loose  fibrinous  exudate  with  well- 
preserved  red  corpuscles  and  leucocytes  and  myriads  of  organisms  (Fig. 
286C).  This  hyaline  lining  membrane  runs  from  the  bronchioles  down 
into  the  alveoli,  but  keeps  the  form  of  a  thin  layer.  It  does  not  give  the 
reactions  for  fibrin.  It  is  a  substance  which  we  have  not  seen  in  other 
cases  of  pneumonia  than  those  following  influenza,  although  it  is  said  to 
appear  in  the  lungs  of  those  who  have  been  killed  by  war  gases.  Good- 


596 


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pasture  has  published  a  paper  stating  that  this  membrane  is  one  at  least 
of  the  specific  lesions  due  to  the  influenza  itself.  Staphylococci  may  be 
associated  with  a  similar  consolidation,  but  tend  to  produce  discrete  ab- 
scesses. Friedlander's  bacillus  causes  an  analogous  consolidation,  but 
with  a  viscid  glutinous  exudate.  The  hsemolytic  streptococci  bring 
about  a  wide-spread  and  extreme  oedema  with  extensive  confluent  consoli- 
dation. The  tissue  is  loaded  with  organisms,  and  necrotic  where  they 
are  most  abundant.  We  found  no  cases  in  which  the  patient's  tissues 

were   resistant   enough  to  produce 
the    interstitial    form    seen    after 
;'£."':£  measles. 

^£  The  influenza  bacillus  of  Pfeiffer 

when  present  in  pure  culture  causes 
in  those  persons  who  appear  to  be 
least  resistant  an  intensely  haemor- 
rhagic  consolidation  in  which  the 
lobular  areas  run  together.  The 
leucocytic  exudate  is  not  very  con- 
spicuous, but  is  especially  dense 
about  the  bronchioles.  In  other 
cases  which  appear  to  be  more  re- 
sistant the  Pfeiffer  bacillus  alone 
produces  numbers  of  yellowish- 
white,  firm,  nodular  areas  of  con- 
solidation about  terminal  bron- 
chioles (Fig.  286D).  These  project 
from  the  cut  surface  almost  like 
tubercles,  but  are  found  on  micro- 
scopical examination  to  be  due  to 
the  great  thickening  of  the  wall  of 
the  bronchiole  and  of  the  walls  of 
the  neighboring  alveoli,  partly  by  a 
new  growth  of  connective  tissue  and 
partly  by  infiltration  with  wander- 


Fig.  286D.— Interstitial  bronchopneu- 
monia  caused  by  the  bacillus  of  Pfeiffer 
in  a  person  who  began  with  influenza. 


ing  cells.  The  alveoli  and  the 
bronchiole  are  filled  with  leucocytes. 
This  is  a  form  of  interstitial  bron- 

chopneumonia  somewhat  different  from  that  caused  by  the  hsemolytic 
streptococcus.  The  bacilli  are  not  strictly  limited  to  the  bronchiole,  the 
exudate  is  composed  of  polynuclear  leucocytes  with  little  or  no  hsemor- 
rhage,  the  lymphatics  of  the  interlobular  spaces  and  vessel  walls  are  not 
specially  involved,  and  there  is  no  great  pleural  effusion.  Usually  these 
lungs  are  dry  and  pale  and  adherent  to  the  parietal  pleura. 

Healing  processes  end  in  extensive  organization  of  exudate,  bronchiec- 
tasis,  and  a  most  remarkable  hyperplasia  of  epithelium  in  the  alveoli 


INFLUENZA 


597 


which  produces  epithelial  masses  which  sometimes  look  like  giant  cells, 
sometimes  like  an  invading  tumor. 

The  anatomical  picture  in  each  type  of  Pfeiffer  bacillus  pneumonia, 
fresh  and  late,  is  so  frequently  repeated  that  it  seems  to  be  characteristic 
enough  to  afford  a  very  good  indication  of  the  bacterium  concerned. 

The  bacillus  of  Pfeiffer  has  been  found  several  times  as  the  cause  of 
acute  endocarditis.  It  is  also  found  not  infrequently  and  especially  in 
children  as  the  cause  of  acute  fibrinopurulent  meningitis  in  the  exudate 


Fig.  286E. — Interstitial  bronchopneumonia  caused  by  the  bacillus  of  Pfeiffer. 

of  which  it  is  abundant.  Dr.  Rowland  has  had  21  cases  of  this  affection 
and  they  appear  to  be  wholly  independent  of  any  epidemic.  In  one  of 
these  cases  I  found  at  autopsy  not  only  the  acute  meningitis,  but  an  acute 
peritonitis  in  which  the  same  organism  was  present  alone  in  the  exudate. 
It  is  probably  in  the  upper  air  passages  that  it  is  most  frequently  to 
be  found.  Crowe  and  Neville  found  it  often  infecting  the  antrum  of  the 
upper  maxilla.  In  the  lung  it  appears  to  accentuate  the  development  of 
tuberculosis,  and  in  the  cavities  and  in  bronchiectatic  spaces  it  persists 
for  a  very  long  time. 


598  TEXT-BOOK    OF    PATHOLOGY 

Whether  the  lethargic  encephalitis  which  has  prevailed  since  the  in- 
fluenza epidemic  of  1918  is  associated  with  epidemic  influenza  and  due  to 
the  same  cause  remains  to  be  determined. 

LITERATURE 

Hirsch:  Handbook  of  Geographical  and  Historical  Pathology,  New  Sydenham  Society, 

1883,  vol.  i,  7. 

Leichtenstern :  Influenza,  Wien,  1912,  A.  Holder. 

Ripperger:  Influenza,  Miinchen,  1892,  Munch.  Med.  Woch.,  1893,  xl,  775. 
Davis,  D.  J.:  Jour.  Infect.  Dis.,  1912,  x,  259.     Amer.  Jour.  Dis.  Child.,  1911,  i,  249. 
Chickering  and  Park:  Jour.  Amer.  Med.  Assoc.,  1919,  Ixxii,  617. 
Opie  and  others:  Ibid.,  p.  556 
Goodpasture:  Ibid.,  p.  724.    U.  S.  Naval  Med.  Bulletin,  1919,  xiii,  No.  2;  Amer.  Jour. 

Med.  Sci.,  1919,  clviii,  863. 

MacCallum:  Jour.  Amer.  Med.  Assoc.,  1919,  Ixxii,  720.    Medical  Record,  May  10, 1919. 
Bloomfield  and  Harrop:  Johns  Hopkins  Hosp.  Bulletin,  1919,  xxx,  1. 
Nolf,  Spehl,  Colard  et  Firket:  Archives  Med.  Beiges,  1919,  Ixxii,  1. 


CHAPTER  XXXI 
TYPES  OF  INJURY.— BACTERIAL  DISEASE   (Continued) 

Typhoid  infection:     General  relations.     Intestinal,  lymphatic,  splenic,  and  other  lesions. 
Necroses  in  various  organs.     Affections  of  circulatory,  respiratory,  and  nervous  system. 
Paratyphoid  infection:   Relation  to  typhoid  and  enteritis  infection.     Acute  gastro-enteritis, 
accessory  lesions. 
Dysentery:    Various  organisms  concerned.     Intestinal  lesions. 

TYPHOID  INFECTIONS 

INFECTION  with  the  Bacillus  typhosus  ordinarily  produces  characteristic 
lesions  only  in  man,  although  Greenbaum  has  succeeded  experimentally 
in  setting  up  similar  effects  in  the  organs  of  chimpanzees  by  inoculation. 
In  the  smaller  laboratory  animals  a  general  septicaemia  may  follow  infec- 
tion, but  there  are  none  of  the  destructive  anatomical  changes  observed 
in  man. 

In  man,  although  attention  has  long  been  concentrated  upon  the  more 
local  manifestations,  there  occurs  a  general  septicaemia  in  which  the  bacilli 
are  readily  demonstrated  in  the  blood  in  the  earlier  days  of  the  disease,  less 
readily  or  not  at  all  in  the  later  stages.  While  in  most  cases  the  local  altera- 
tions of  the  intestines  are  most  striking,  they  may  be  completely  absent, 
so  that  it  seems  that  the  less  conspicuous  changes  due  to  the  general  dis- 
tribution of  the  bacilli  are  more  constant  ,and  characteristic  features. 

The  bacilli  gain  entrance  by  way  of  the  digestive  tract,  being  introduced 
with  drinking-water,  vegetables  grown  on  infected  ground  or  watered  with 
infected  water,  and  infected  milk  and  other  food  into  which  the  bacilli 
may  have  been  introduced  in  the  process  of  preparation.  Even  ice  and 
oysters  seem  to  have  been  the  source  of  infection  in  epidemics.  Flies 
may  carry  the  bacilli  from  exposed  faeces,  etc.,  to  food.  Since  persons 
who  have  recovered  from  typhoid  fever  may  harbor  the  bacteria  in  bile, 
urine,  and  faeces  for  many  years,  they  become  a  menace  to  others,  and 
especially  when  they  act  as  cooks  the  danger  of  their  transferring  the  bacilli 
to  food  is  very  great.  Thus  a  recent  epidemic  in  the  Sloan  Hospital  was 
traced  to  a  cook  who  was  a  typhoid-bacillus  carrier.  Another,  reported 
in  the  Journal  of  the  American  Medical  Association  in  1915,  was  traced  in 
the  same  way  to  the  cook  who  prepared  a  large  panful  of  spaghetti,  even 
though  it  was  cooked  in  another  place  and  not  again  touched  by  her.  It 
was  shown  that  in  the  spaghetti,  which  had  stood  overnight,  there  had  been 
a  great  growth  of  the  bacilli,  which  in  the  cooking  were  scarcely  warmed  in 
the  centre  of  the  mass. 

Typhoid  fever  is  essentially  a  disease  of  unsanitary  conditions  of  life, 

599 


600 


TEXT-BOOK   OF    PATHOLOGY 


and  disappears  in  proportion  as  the  food  and  water  supplies  are  kept 
clean.  But  the  introduction  and  perfection  of  the  method  of  vaccination 
against  typhoid  infection  by  Wright  and  Russell  has  gone  far  toward  ob- 
literating the  disease  altogether.  When  the  troops  were  called  together 
in  the  camps  during  the  war,  some  such  plague  of  typhoid  fever  as  occurred 
at  the  time  of  the  Spanish  War  might  have  been  expected.  But  vac- 
cination of  every  recruit  was  compulsory, 
and  there  was  no  typhoid.  It  is  one  of 
the  few  great  triumphs  of  preventive 
medicine,  but  it  is  not  all  powerful,  for 
overwhelming  doses  of  bacilli  will  still 
produce  the  disease.  Although  the  wards 
of  the  hospital  used  to  be  filled  with  these 
cases,  they  are  rare  now,  and  the  only 
autopsy  we  have  seen  in  the  last  year  was 
in  the  case  of  a  cleaner  in  a  laboratory 
who  must  have  swallowed  a  culture. 

Infection  with  the  Bacillus  typhosus 
produces  in  man  a  protracted  febrile  dis- 
ease, which  begins  usually  one  or  two 
weeks  after  infection  and  lasts  for  five  or 
six  weeks  or  more.  There  are  localized 
changes  in  the  intestines,  especially  in  the 
lymphoid  structures,  in  the  abdominal 
lymph-glands,  the  spleen,  and  bone-mar- 
row. There  is  a  general  cloudy  swelling 
of  the  organs,  with  wide-spread  focal  ne- 
croses, and  other  less  constant  lesions. 

Intestinal  Lesions. — In  the  first  week 
of  the  disease  the  lymphoid  nodules  of 
the  intestines,  including,  of  course,  the 
Peyer  patches,  become  swollen  and  stand 
up  above  the  surrounding  mucosa  (Fig. 
287).  This  may  be  caused  partly  by  hy- 
persemia,  but  is  chiefly  due  to  an  increase 
in  the  numbers  of  lymphoid  and  other 
cells.  The  change  is  most  evident  in  those 
Peyer's  patches  and  solitary  nodules  in 

the  lower  part  of  the  ileum,  becoming  less  marked,  and  finally  fading  away 
toward  the  upper  part  of  the  intestine.  In  the  colon  the  degree  of  swelling 
varies  greatly— sometimes  it  is  imperceptible;  in  other  cases  it  is  extreme 
and  overshadows  the  slighter  changes  in  the  ileum.  On  gross  inspection 
it  appears  that  this  swelling  is  sharply  limited  to  the  lymphoid  structure, 
which  thus  becpme  very  conspicuous  and  prominent,  but  it  may  be  con- 
cluded, both  from  the  microscopical  examination  in  this  stage  and  from 


i 

Fig.  287.— Typhoid  fever  with 
swelling  and  beginning  ulceration 
of  Peyer's  patches. 


TYPHOID    INFECTIONS 


601 


the  later  ulceration,  that  the  alteration  in  the  tissue  extends  beyond 
their  limits.  There  is  a  catarrhal  inflammation  of  the  rest  of  the  mucosa, 
which  may  be  evident  as  a  moderate  hypersemia,  but  is  often  incon- 
spicuous. 

Later,  in  the  second  week  in  most  cases,  the  superficial  parts  of  the  swollen 
Peyer's  patches  and  nodules  lose  their  reddish-gray  color  and  the  velvety 
smoothness  of  their  surface,  and  in  smaller  or  larger  areas  become  opaque 
and  dry  looking,. and  in  these  areas  become  stained  a  brownish-green  from 
the  intestinal  contents.     This  is  the  formation  of  the  slough,  which  is  an 
expression  of  the  partial  necrosis  of  the  swollen  patch.     Sometimes  the 
change  progresses  rapidly  and  goes 
deep,  involving  all  but  the  margin 
of  the  patch.     In  the  nodules  the 
necrotic  slough  appears  as  a  little, 
rough,  greenish  plug  embedded  in 
the  top,  and  surrounded  by  the  hy- 
persemic  margin.    From  the  outside 
the  Peyer's  patches  can  be  recog- 
nized,  as  a  rule,   by  their  darker 
color  and  by  the  injection  of  the 
subserous  blood-vessels,  but,  as  a 
rule,  the  solitary  nodules  scarcely 
show  through  at  this  stage. 

Not  all  the  swollen  Peyer's 
patches  or  solitary  nodules  advance 
to  this  stage.  Indeed,  in  every  case 
at  autopsy  it  is  usual  to  find  some, 
perhaps  even  the  majority,  which 
have  proceeded  no  further  than  the 
swelling,  as  far  as  the  unaided  eye 
can  see.  It  is  quite  common  to  find 
the  advanced  change  only  in  those 
situated  rather  low  in  the  intestine, 
near  the  ileocsecal  valve,  although 
it  is  quite  true  that  there  are  other 

cases  in  which  all  the  lymphoid  areas  throughout  the  greater  part  of  the 
ileum  have  run  the  whole  gamut  of  changes.  In  persons  who  recover 
and  in  whom  these  swollen  lymphoid  structures  which  have  not  pro- 
gressed to  necrosis  return  to  normal,  there  must  be  a  process  of  resolu- 
tion somewhat  analogous  to  that  in  pneumonia.  Still  later  other 
changes  occur  in  those  Peyer's  patches  which  present  necrotic  areas. 
The  greenish  mass  retracts  a  little  from  the  edge  and  loosens  all 
around  its  margin.  The  crevice  goes  deeper  toward  the  middle 
288)  and  soon  the  whole  slough  is  dislodged  and  falls  into  the  lumen 
of  the  intestines,  leaving  an  excavation  or  ulcer  of  corresponding  depth 


Fig.  288.— Typhoid  fever.  Swollen 
Peyer's  patches  with  beginning  separa- 
tion of  the  slough. 


602 


TEXT-BOOK    OF    PATHOLOGY 


(Fig.  289).  If  the  slough  is  completely  removed,  it  leaves  a  clean  ulcer, 
the  bottom  of  which  is  usually  formed  by  the  muscular  layers  of  the 
wall,  which  show  plainly  the  parallel  arrangement  of  their  fibers.  Some- 
times the  ulcer  is  more  shallow,  and  then  its  floor  is  part  of  the  infiltrated 
submucosa — at  other  times  it  is  deeper  and  may  even  extend  quite  through 


•"VHMMmnMHBHHHL   _          ,4 

Fig.  289.-Typhoid  ulcers  after  the  discharge  of  most  of  the  necrotic  tissue. 


occur     On  T    fi*T'  '"  f^  C^e  ComPlete  Per«°n  is  likely  to 

M ^  easUy  CfilmofTh  t™  **  ^  °f  ^^^  with  ™*  a 

film  of  the  necrotic  wall  remaining.    From  the  outside  this 

rhagTc  LTe  "'  ^^^^  Patch  surrounded  by  a  dark  haemor- 

It  has  already  been  said  that  the  ulcer  need  not  excavate  the  whole  of 


TYPHOID    INFECTIONS  603 

the  swollen  patch.  One  frequently  finds  several  small  and  rather  deep 
ulcers  in  one  Peyer's  patch,  separated  from  one  another  by  partitions  of 
still  living  tissue.  On  the  other  hand,  the  ulceration  may  extend  quite 
beyond  the  margin  of  the  lymphoid  tissue,  so  as  to  correspond  no  longer 
with  the  original  form,  and  in  the  neighborhood  of  the  ileocsecal  valve 
it  is  common  to  find  neighboring  ulcers  confluent  to  such  a  degree  that 
only  small  islands  of  mucosa  are  left.  Higher  up  it  is  usual  to  find  the 
ulcers  more  limited  to  the  outlines  of  the  Peyer's  patches  and  solitary  nod- 
ules. Quite  similar  processes  take  place  in  the  colon  and  in  the  vermiform 
appendix,  and  it  is  not  uncommon  to  have  a  perforation  in  the  base  of  an 
ulcer  in  the  latter  situation.  Since  these  perforations  occur  rapidly  with- 
out time  for  any  adhesions  to  form  between  the  intestinal  loop  and  other 
tissues,  a  general  peritonitis  is  the  common  result.  Naturally,  in  this 
respect  perforations  in  the  free  moving  ileum  are  more  serious  and  likely 
to  be  fatal  than  those  in  the  appendix,  where  localizing  agencies  are  more 
available. 

In  many  cases  there  is  bleeding  from  the  ulcerated  intestinal  wall,  the 
blood  escaping  with  the  stools  sometimes  in  such  quantities  that  the 
patient  dies  from  its  loss.  It  is  rare  that  one  can  find  any  vessel  which  can 
be  shown  to  have  been  the  source  of  the  haemorrhage. 

After  the  ulcer  is  cleaned  of  its  slough,  healing  begins  by  the  formation 
of  a  layer  of  granulation  tissue  in  the  base,  soon  followed  by  the  growth 
of  a  single  smooth  layer  of  epithelium  across  its  surface.  The  depression 
into  which  this  epithelium  must  grow  is  before  long  made  up  to  its  original 
level  by  the  new  formation  of  lymphoid  tissue,  and  it  becomes  impossible 
to  tell  where  the  ulcer  had  been.  No  great  scar  formation  occurs,  and 
there  seems  never  to  be  a  stricture  of  the  intestine  due  to  the  healing  of  a 
typhoid  ulcer. 

The  nature  of  these  lesions  is  rather  different  from  any  of  the  effects  of 
bacterial  invasion  met  with  so  far,  and  is  to  be  understood  only  in  the  light 
of  the  general  effect  of  the  typhoid  bacillus  upon  the  body.  The  bacteria 
hitherto  studied  have  been  found  to  produce  a  reaction  on  the  part  of  the 
bone-marrow,  which  liberates  into  the  circulating  blood  great  numbers  of 
polymorphonuclear  leucocytes.  Such  a  leucocytosis  fitted  well  with  the 
mechanism  of  ordinary  inflammation,  and  even  though  we  recognized  the 
presence  of  many  mononuclear  wandering  cells  in  all  stages,  and  especially 
in  the  more  chronic  forms  of  inflammation,  the  polynuclear  neutrophiles 
dominated  the  scene  in  fresh  inflammations.  In  typhoid  fever  there 
is  no  such  leucocytosis — the  total  number  of  leucocytes  per  cubic  milli- 
metre is  rather  decreased,  and  the  lymphocytes  become  relatively  numer- 
ous. Even  in  the  presence  of  secondary  infections,  which  in  normal 
persons  produce  a  leucocytosis,  the  bone-marrow  seems  incapable  of 
responding  actively,  and  there  is  only  a  halting  leucocytosis. 

In  the  typhoid  lesions  the  bacilli  are  found— indeed,  they  are  carried 
everywhere  in  the  circulating  blood,  but  their  presence  rather  repels  the 


TEXT-BOOK   OF   PATHOLOGY 

polymorphonuclears.  Nor  is  it  possible,  as  in  the  case  of  the  staphylo- 
coccus,  to  demonstrate  the  bacilli  as  the  central  point  about  which  the 
lesion  is  concentrated.  Instead,  one  finds  clumps  of  bacilli  in  the  tissues 
without  any  striking  reaction  about  them,  and  elsewhere  foci  of  coagula- 
tive  necrosis,  with  few  or  no  bacilli. 

In  the  earliest  stages  of  medullary  swelling  (Fig.  290)  the  Peyer's  patches 
and  solitary  nodules  show  an  increase  of  the  lymphoid  cells,  which  become 
scattered  into  the  adjacent  mucosa  and  into  the  submucosa  underneath. 
But  the  lymphocytes,  many  of  which  seem  to  have  emigrated  from  the 
blood-vessels,  are  soon  rendered  less  conspicuous,  and  separated  by  the 
appearance  of  great  numbers  of  large  pale  cells  with  rather  pale  vesicular 
nuclei.  It  is  about  these  cells,  which  occur  in  all  typhoid  lesions,  that 
violent  discussion  has  raged,  especially  with  regard  to  their  origin.  They 
are  most  actively  phagocytic,  and  engulf  the  injured  lymphocytes  until 
soon  the  latter  are  found  only  in  groups,  while  the  large  cells,  each  of  which 
may  contain  two  or  three  bodies  of  lymphocytes,  occupy  most  of  the  field. 


Fig.  290. — Typhoid  fever.     Beginning  swelling  of  a  lymph-nodule  in  small  intestine. 


Hoffmann  and  Billroth  described  these  cells  and  noted  their  phagocytic  capacity. 
Mallory  decides  that,  since  they  behave  like  endothelial  cells,  they  are  endothelial  cells, 
and  without  further  ado  calls  them  endothelial  cells  throughout.  Marchand,  more 
cautious,  thinks  that  they  may  be  partly  derived  from  the  reticulum  cells,  partly  from 
the  endothelium  of  the  lymphatics.  Saltykow  thinks  that  he  can  trace  them  from  the 
endothelial  cells  of  the  lymph  sinuses,  but  finds  them  mixed  in  the  sinuses  with  lymphoid 
cells  of  various  types.  It  is  a  matter  most  difficult  to  decide  by  the  fallible  methods 
of  tracing  transitions,  and  especially  difficult  in  this  case,  since  it  is  so  rare  a  piece  of 
fortune  to  be  able  to  study  the  typhoid  lesions  in  their  earliest  stages. 

The  cells  seem  to  be  mobile  not  only  because  they  are  phagocytic,  but  because  they 
are  found  in  abundance  far  in  the  tissue  of  the  submucosa,  away  from  the  reticulum 
of  the  lymphoid  tissue  and  from  the  lymphatic  channels.  They  are  not  peculiar  to 
typhoid  fever,  but  occur  in  identical  form  in  tuberculosis  and  other  affections. 

It  seems,  indeed,  that  they  are  indistinguishable  from  other  large  mononuclear  wander- 
ing cells,  and  that  the  conception  of  the  lesions  in  typhoid  fever  becomes  far  simpler 
if  we  look  upon  them  as  a  form  of  reaction  in  which  the  wandering  cells  which  come 
into  the  neighborhood  of  the  bacilli  are  the  various  types  of  wandering  mononuclear 
cells  instead  of  polynuclear  leucocytes.  That  some  endothelial  cells  can  act  as  phagocytes 
is  unquestionable,  but  that  the  whole  reaction  to  the  presence  of  the  typhoid  bacilli  should 


TYPHOID    INFECTIONS 


605 


be  ascribed  to  endothelial  cells  makes  typhoid  fever  a  disease  without  an  analogue. 
While  it  is  perfectly  clear  that  in  the  spleen  the  endothelial  cells  of  the  venous  sinuses 
are  in  typhoid  fever,  as  in  other  conditions,  actively  engaged  in  phagocytosis,  it  is  not 


Fig.  291.— Edge  of  swoUen  patch  in  early  stage  of  typhoid  fever.  The  large  phago- 
-cytic  cells  are  accumulated  in  the  submucosa,  and  there  are  two  lymphatic  channels  dis- 
tended with  them.  In  the  detail  some  of  these  phagocytes  are  shown  with  their  content 
of  injured  lymphocytes. 


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so  clear  in  other  situations,  such  as  the  substance  of  the  lymphoid  tissue  or  the  submucosa 
of  the  intestine,  that  the  phagocytic  cells  are  derived  from  the  endothelium.  Confusion 
arises  perhaps  from  the  persistence  of  the  idea  that  all  crevices  in  the  tissues  are  lined, 
if  only  incompletely,  with  endothelial  cells.  It  is  my  belief,  on  the  contrary,  that  endo- 
thelial  cells  are  not  thus  scattered  everywhere,  but  that  they  form  the  specialized 
lining  of  closed  blood-channels  and  lymphatic  channels.  The  lymph-sinuses  of  the 
lymph-gland  in  connection  with  the  lymphatic  trunk  are  lined  with  continuous  endo- 


S9S 


:',   .:.-••    -~    '.      • 

•  .-  v:--,;v::  ,-..:-•; --^:>-     — .'   "    *  . 

Fig.  291A.— Typhoid  fever.     Margin  of  swollen  and  slightly  ulcerated  Peyer's  patch. 

thelium,  but  these  cells  are  not  scattered  everywhere  among  the  elements  of  the  lym- 
phoid tissue.  This  specific  position,  as  the  lining  tissue  of  channels,  is  even  more  clearly 
seen  in  such  tissue  as  the  submucosa,  where  it  is  not  confused  by  the  great  mass  of 
lymphoid  cells.  How  such  lining  cells  could  scatter  themselves  in  such  quantities  and 
wander  everywhere  through  the  tissue  without  completely  disorganizing  the  blood-  and 
lymph-channels  is  not  clear.  On  the  other  hand,  one  finds  lymphocytes  emigrating 
actively  through  the  vessel-walls  in  typhoid  fever,  and  in  the  tissue  assuming,  exactly 
as  Maximow  described  for  his  polyblasts,  larger  and  larger  forms.  They  do  exactly 


TYPHOID    INFECTIONS  607 

the  same  thing  in  other  more  chronic  inflammation,  and  there  we  believe  that  the 
whole  group  of  cells,  from  the  lymphocyte  to  the  largest  macrophage,  may  arise  as  mem- 
bers of  one  group  of  mononuclear  wandering  cells,  recognizing  that  many  of  them  may 
have  led  this  wandering  life  for  a  long  time  instead  of  having  recently  emigrated  from 
the  blood-stream.  Instead,  therefore,  of  calling  them  endothelial  cells,  I  prefer  to  speak 
of  the  large  phagocytic  cells  briefly  as  macrophages,  and  to  regard  them  as  members 
of  the  familiar,  if  much  misunderstood,  group  of  mononuclear  wandering  cells  which  are 
present  in  some  stage  of  their  development  and  wandering  career  everywhere  through 
the  tissues,  and  are  especially  ready  to  swallow  up  injured  cells  and  fragments  of  cellular 
debris. 

The  accumulation  of  the  wandering  cells,  and  especially  of  the  pale 
macrophages,  goes  far  to  obliterate  the  architecture  of  the  Peyer's  patch 
and  convert  it  into  a  continuous  mass  of  cells.  On  the  surface  various  bac- 
teria are  found.  Some  of  these  may  invade  the  interior,  but  this  is  es- 


"  •' 

Fig.  292. — Typhoid  fever.     Later  stage,  with  superficial  slough  and  beginning  ulceration. 

pecially  true  of  the  typhoid  bacilli,  which  are  found  in  clumps  in  the  tissue. 
Foci  of  coagulative  necrosis  appear  irregularly,  and  not  in  any  especial 
relation  with  the  bacilli,  and  becoming  confluent,  form  the  slough  (Fig. 
292).  There  is  no  leucocytic  reaction  to  the  presence  of  these  patches  of 
dead  tissue — a  zone  of  fragmented  nuclei  may  mark  them  out.  Some 
authors  have  thought  them  due  to  the  diffusion  of  a  poison  produced  by  the 
bacilli;  others  ascribe  them  to  anaemia  produced  (Orth)  by  compression 
of  the  blood-vessels  or  (Mallory)  by  thrombosis  of  the  small  arterioles  and 
venules.  Mallory  describes  many  such  thrombosed  vessels,  the  thrombus 
being  caused  sometimes  by  the  clumping  of  injured  endothelial  cells  within 
the  vessel,  at  other  times  by  the  lifting-up  of  the  lining  endothelium  by 
cells  and  fibrin  accumulated  beneath  it. 

At  this  stage,  when  the  necrosis  becomes  confluent,  nearly  all  the  cells 
of  the  compact  mass,  even  at  a  distance  from  the  necrosis,  show  signs  of 
degeneration  and  disintegration.  Doubtless  many  macrophages  burdened 
with  lymphocytes  and  other  materials  fall  into  fragments,  which  are 
swallowed  in  their  turn  by  other  phagocytic  cells. 

The  lymphatic  channels  are  often  packed  with  cells,  which  they  trans- 
port to  the  sinuses  of  the  nearest  lymph-gland.  The  stroma  of  the  neigh- 


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boring  mucosa  presents  changes  almost  exactly  like  those  in  the  lymphoid 
nodules  and  in  the  submucosa,  through  the  muscle,  and  in  the  subserous 
tissue  one  finds  the  fixed  tissue  elements  spread  apart  by  the  abundant 
wandering  cells. 

Lymphatic  Glands.— The  mesenteric  lymph-glands  become  greatly 
swollen,  soft,  and  often  hsemorrhagic.  The  retroperitoneal  glands  take 
some  slight  part  in  this,  but  the  glands  most  affected  are  those  which 


Fig.  293. — Mesenteric  lymph-node  in  typhoid  fever.     The  sinuses  are  filled  with  large 
mononuclear  cells,  among  which  are  necrotic  clumps. 

drain  the  most  involved  part  of  the  intestine  (Fig.  293).  Bacilli  are  scat- 
tered in  their  sinuses  and  tissues.  The  lymph-cords  show  exactly  the 
same  changes  as  are  seen  in  the  Peyer's  patches.  The  sinuses  are  enor- 
mously widened  and  packed  with  cells,  which  are  mostly  macrophages, 
although  there  are  many  lymphocytes.  Probably  most  of  these  cells  are 
swept  into  this  situation  from  the  intestinal  lesions,  but  some  may  appear 
in  the  gland  itself.  Necroses  quite  like  those  described  are  found  begin- 
ning in  the  mass  of  cells  which  fills  the  sinus,  and  extending  thence  to 


TYPHOID   INFECTIONS 


609 


the  lymph-cords.  Sometimes  nearly  the  whole  gland  becomes  necrotic. 
From  the  glands  great  quantities  of  the  large  cells  and  others  can  be  swept 
on  into  the  thoracic  duct,  and  thus  into  the  subclavian  vein.  In  one  in- 
stance (Verh.  Dtsch.  Path.  Gesellsch.,  1903,  ix)  I  found  them  transported 
in  this  way  in  such  quantities  as  to  plug  many  branches  of  the  pulmonary 
artery. 

The  Spleen. — The  acute  splenic  tumor,  which  is  very  constant  in  typhoid 
fever,  differs  from  that  found  in  other  infections  in  the  extreme  abundance 


Fig.  294. — Acute  splenic  tumor  in  typhoid  fever.     The  splenic  pulp  shows  great  accumu- 
lations of  blood  with  phagocytic  cells  containing  red  corpuscles. 

of  red  corpuscles,  both  loose  in  the  splenic  pulp  and  engulfed  in  numbers 
by  large  phagocytic  cells  (Fig.  294).  The  presence  of  these  "red-corpuscle- 
carrying  cells"  is,  of  course,  the  result  of  the  profuse  scattering  of  red  cor- 
puscles out  of  the  venules  into  the  pulp.  Many  of  them  are  clearly  the 
endothelial  cells  of  the  splenic  venules.  Others  correspond  to  the  macro- 
phages  seen  elsewhere.  There  are  relatively  few  nucleated  cells  in  such  a 
pulp,  and  if  the  haemoglobin  is  washed  out  by  fixation  of  the  piece  of  spleen 
in  alcohol,  the  tissue  looks  rarefied  under  the  microscope.  Necroses  occur 
in  the  splenic  pulp,  exactly  as  they  do  in  the  lymph-glands  and  Peyer's 
40 


61Q  TEXT-BOOK   OF   PATHOLOGY 

patches.  The  result  of  these  changes  is  the  great  enlargement  of  the 
spleen,  which  sometimes  weighs  900  grams.  The  organ  becomes  extremely 
soft,  and  may  rupture  during  life,  with  alarming  or  fatal  haemorrhage.  At 
autopsy  it  is  usually  like  a  semifluid  mass  of  deep-red  color,  and  on  section 
the  relatively  unchanged  Malpighian  bodies  are  scarcely  to  be  seen  through 
the  overflowing  splenic  pulp.  In  other  cases  the  splenic  pulp  may  con- 
tain many  more  macrophages  than  are  shown  in  the  drawing. 

Blood  and  Bone-marrow. — The  blood  contains  bacilli  through  most  of 
the  course  of  the  disease.  The  leucocytes  are  low,  with  usually  a  relative 
increase  of  the  mononuclear  cells.  Platelets  are  decreased  in  number. 
In  the  course  of  the  disease,  especially  in  its  later  stages,  there  may  arise  a 
severe  anaemia.  The  bone-marrow  responds  to  the  infection  by  the  pro- 
duction of  abundant  lymphoid  cells  and  others  resembling  plasma  cells,  but 
the  formation  of  granulated  myelocytes,  the  forerunners  of  the  neutro- 
phile  leucocytes,  appears  to  be  in  abeyance.  Everywhere  through  the 
marrow  there  are  found  the  macrophages,  which  show  here,  as  in  the 
Peyer's  patches,  a  great  avidity  for  the  injured  bodies  of  other  cells. 
Necroses  occur,  just  as  they  do  in  the  spleen  and  the  lymphoid  apparatus 
(Longcope). 

Liver  and  Gall-bladder. — The  liver  is  always  swollen,  and  on  section 
appears  dull,  opaque,  and  inelastic.  It  forms  a  typical  example  of  cloudy 
swelling,  and  microscopically  the  cells  present  the  changes  characteristic 
of  that  condition.  Occasionally  in  the  fresh-cut  surface,  or  through  the 
capsule,  one  can  see  minute,  opaque,  yellowish  spots,  which  sometimes 
reach  a  diameter  of  1  to  2  mm.  These  are  focal  necroses,  which  are  con- 
stantly present  in  the  liver  in  this  disease,  although  they  are  usually  so 
small  as  to  be  scarcely  made  out  with  certainty  with  the  naked  eye.  Mai- 
lory  describes  two  types — one  produced  in  the  lymphoid  tissue,  which 
occurs  in  the  so-called  portal  spaces,  and  which  shows  changes  identical 
with  those  in  the  Peyer's  patches;  the  other  occurring  anywhere  within  the 
lobule,  and  involving  the  destruction  of  a  group  of  liver-cells.  The  first 
type  must  be  uncommon  or  very  inconspicuous.  The  second  is  the  type 
found  in  every  typhoid  liver.  The  foci  consist  of  compact  masses  of  dis- 
torted and  fragmented  cells,  bound  together  with  fibrin,  and  pretty  sharply 
marked  out  from  the  surrounding  tissue.  Mallory  regards  these  foci  as 
anaemic  areas  caused  by  the  plugging  of  the  capillaries  of  the  liver  by  macro- 
phages which  have  been  swept  in  with  the  portal  blood.  These  large  cells, 
lodging  in  the  capillaries,  soon  become  surrounded  by  thrombi,  which 
continue  the  occlusion.  Frankel  and  others  have  thought  the  necroses  due 
rather  to  the  direct  action  of  the  toxin  upon  the  liver-cells,  with  secondary 
invasion  of  wandering  cells. 

It  has  always  been  difficult  to  believe  that  the  occlusion  of  the  capillaries, 
even  if  it  occur  on  all  sides  of  such  a  minute  mass  of  tissue,  should  cause  the 
death  of  the  liver-cells  in  these  tiny  areas,  since  they  might  receive  enough 
nutrition  from  the  adjacent  capillaries.  In  a  series  of  dogs  we  have  injected 


TYPHOID    INFECTIONS 


611 


© 


© 


*C 


-e> 


'" 


.© 


© 


corn-starch  in  suspension  so  as  to  plug  a  great  many  capillaries,  but  with- 
out producing  necroses,  except  perhaps  in  one  case,  where  the  capillaries 
became  distended  into  great  spaces  filled  with  the  granules  and  the  liver- 
cells  were  compressed  and  displaced.  Even  then  it  was  scarcely  possible 
to  demonstrate  actual  necrosis  of  the  cells. 

Something  analogous  to  this  seems  to  occur  in  the  typhoid  liver,  in  which, 
in  the  necrotic  and  coagulated  patches,  one  does  not  find  many  actual 
necrotic  liver-cells.  We 
have  had  an  opportunity 
to  study  the  beginning 
of  the  lesions  in  the  liver 
of  a  man  who  had  been 
ill  only  a  few  days,  and 
in  whom  the  autopsy  was 
performed  one  hour  after 
death,  and  it  becomes 
perfectly  clear  that  these 
foci  are  not  primarily 
areas  of  necrosis  of  the 
liver-cells  at  all,  but  ac- 
cumulations of  the  large 
mononuclear  cells  swept 
in  by  the  portal  stream, 
which  distend  the  capil- 
laries to  a  huge  size  and 
push  aside  the  liver-cells 
(Fig.  295).  Even  in  the 
middle  of  such  a  mass, 
that  is,  between  two  such 
distended  capillaries,  the 
liver-cells  are  found  to  be 
alive.  It  is  possible  that 
they  may  be  so  included 

as  to  be  involved  in  the  necrosis,  but  most  of  them  are  pushed  aside,  and 
the  necrosis,  when  it  appears,  is  essentially  the  degeneration  and  disinte- 
gration of  a  mass  of  macrophages  which  has  packed  itself  into  the  widened 
capillaries  at  a  point  in  the  liver  tissue  from  which  the  liver-cells  have 
been  for  the  most  part  dislodged,  and  has  there  become  matted  together 
by  fibrin.  When  the  areas  become  larger  by  the  constant  accumulation 
of  the  cells  floating  in  the  blood,  it  is  no  longer  possible  to  determine  how 
they  were  formed,  but  from  the  early  stages  one  many  convince  oneself 
that  the  coagulative  necrosis  is  primarily  an  affair  of  the  wandering  cells, 
and  that  the  liver-cells  are  only  accidentally  involved  in  the  mass. 

Rarely  large  necroses  or  abscess-like  foci  occur  in  the  liver. 

The  gall-bladder  may  become  infected  with  the  bacilli,  probably  by  way 
of  the  bile-ducts,  either  from  the  intestines  or  from  the  liver,  although  it  is 


Fig.  295. — Typhoid  fever.  Beginning  focal  necrosis 
in  liver;  accumulation  of  wandering  cells  with  little 
evident  injury  of  liver-cells. 


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perfectly  possible  that  they  might  arrive  there  by  the  blood-stream.  They 
may  cause  no  trouble,  but  may  remain  and  multiply  there  for  many  years. 
Such  persons  are  among  the  typhoid  carriers  mentioned  above.  Occa- 
sionally there  are  attacks  of  pain  in  the  region  of  the  gall-bladder  during 
the  fever,  but  more  frequent  are  the  cases  of  acute  or  chronic  cholecystitis 
occurring  some  time  after  recovery.  In  Hunner's  case,  eighteen  years  had 
elapsed  since  the  attack  of  typhoid  fever.  The  exudate  is  sometimes  puru- 
lent, but  more  commonly  mucoid,  and  is  usually  associated  with  gall-stones. 


,  .    e,    «   T 


Fig.  296.  —  Typhoid  fever.     Larger  focus  in  liver  in  which  the  area  is  occupied  by  pha- 
gocytic  cells,  the  liver-cells  having  been  displaced  or  destroyed. 

Gushing  was  able  to  cultivate  the  Bacillus  typhosus  from  the  centres  of  the 
gall-stones,  as  well  as  from  the  bile,  and  thought  that  agglutinated  bacilli 
might  constitute  the  nucleus  upon  which  gall-stones  could  form.  The 
evidence  in  this  question  has  been  discussed  elsewhere  (Chapter  XX). 

Kidneys  and  Bladder.—  The  kidneys  show  a  cloudy  swelling  of  the  cor- 
tex comparable  to  that  of  the  liver.  (Edema  with  great  pallor  is  some- 
times observed.  Actual  acute  nephritis  with  exudative  changes  is,  in  my 
experience,  rare.  The  bacilli  pass  through  the  kidney  evidently  through 


TYPHOID    INFECTIONS  613 

lesions  of  some  sort,  and  appear  in  the  urine.  Although  the  bladder  and 
ureters  are  not  commonly  affected,  catarrhal  or  diphtheritic  cystitis  may 
occur.  The  urine  continues  to  show  the  presence  of  bacilli  for  a  long  time 
in  some  cases. 

Respiratory  Organs. — Lobar  and  lobular  pneumonia  may  accompany 
typhoid  fever,  the  former  rarely,  the  latter  as  a  common  terminal  affection. 
Lobar  pneumonia  caused  by  the  Bacillus  typhosus  is  of  a  peculiarly  haemor- 
rhagic  character.  Usually  the  pneumococcus  is  the  causative  agent  when 
this  complication  occurs,  and  there  may  be  a  combined  septicaemia  with 
both  organisms  (Robinson).  In  the  bronchopneumonia  the  typhoid 
bacillus  may  cause  the  lesions,  and  appear  in  the  sputum,  but  probably 
in  most  cases  other  organisms  are  concerned. 

In  the  pharynx  and  larynx  there  is  sometimes  an  extensive  diphtheritic 
and  hsemorrhagic  inflammation  in  a  late  stage  of  the  disease. 

Circulatory  Apparatus. — The  heart  muscle  is  soft  and  flabby  and  opaque, 
and  may  contain  a  little  fat.  Endocarditis  is  uncommon,  but  has  been 
described,  the  vegetations  containing  the  bacilli.  There  are  instances  in 
which  the  peripheral  arteries,  especially  the  arteries  of  the  brain,  have  been 
occluded  by  thrombi.  In  other  cases  thrombosis  of  brachial  or  femoral 
arteries  has  led  to  gangrene.  Thayer  has  examined  the  arteries  in  many 
cases  after  typhoid  fever,  and  finds,  in  rather  a  high  percentage,  evidences 
of  beginning  arteriosclerosis.  This  is,  however,  not  peculiar  to  this  infec- 
tion. 

Thrombosis  of  the  veins  is  far  more  common  than  that  of  the  arteries. 
It  occurs  usually  in  the  left  femoral  and  saphenous  veins,  and  causes  the 
extremely  painful  swelling  of  the  leg  which  has  long  been  known  as  ''milk- 
leg,"  or  phlegmasia  alba  dolens.  With  the  organization  of  the  clot  and 
its  recanalization,  together  with  the  development  of  collateral  channels, 
the  oedema  disappears  and  the  leg  can  again  be  used.  Other  veins  may 
also  be  affected. 

Muscles. — A  wide-spread  hyaline  degeneration  of  the  substance  of  the 
muscle-fibres,  first  described  by  Zenker,  is  often  found,  especially  in  the 
abdominal  muscles  and  in  the  muscles  of  the  thigh.  (See  Fig.  39.)  The 
muscle-fibres  lose  their  striations,  and  are  divided  into  irregular,  formless 
clumps  within  the  sarcolemma.  Rupture  of  such  injured  muscles  gives 
rise  to  gross  hemorrhages,  and  if  one  observes  a  great  haemorrhage  within 
the  sheath  of  the  rectus  abdominis,  suspicion  is  at  once  directed  to  a 
typhoid  infection,  although  the  condition  is  not  peculiar  to  typhoid. 

Bones  and  Joints.— After  convalescence,  or  even  many  years  later,  there 
sometimes  arise  painful,  abscess-like  swellings  over  the  ribs  or  the  tibiae, 
or,  indeed,  over  any  bone.  Incision  allows  the  escape  of  a  thick,  stringy, 
purulent  fluid,  and  it  is  found  that  an  abscess  cavity  extends  down  through 
the  periosteum  or  into  the  bone.  The  periosteum  is  greatly  thickened 
and  uplifted  from  the  bone,  and  there  may  be  necrosis  and  sequestration 
of  part  of  the  bone.  Mixed  infections  occur,  but  the  typhoid  bacillus  is 
found  and  may  cause  these  changes  alone.  Such  infections  are  very  per- 


614  TEXT-BOOK    OF    PATHOLOGY 

sistent,  and  unless  thoroughly  cleaned  out,  fail  to  heal.  Typhoid  arthritis 
occurs,  but  is  very  rare. 

Skin. — Prominent  among  the  changes  in  the  skin  is  the  roseola  or  typhoid 
rash.  Slightly  raised,  flat,  rose-colored  spots  appear  early  in  the  disease, 
and  are  an  evidence  of  the  diffuse  septicsemic  character  of  the  disease. 
The  bacilli  have  been  cultivated  from  these  rose  spots,  and  Frankel,  in 
sections,  found  branched  colonies  of  the  bacilli  in  what  he  thought  were 
the  lymph-vessels  of  the  papillae.  Purpuric  spots,  diffuse  erythema,  etc., 
may  also  occur.  Furunculosis,  so  common  in  the  later  stages,  is  due  to  a 
secondary  staphylococcus  infection. 

Nervous  System. — The  disease  has  its  name  from  the  stuporous  con- 
ditions produced  by  the  infection.  Nevertheless,  actual  cerebral  changes, 
recognizable  anatomically,  are  rare.  I  have  described  one  case  of  purulent 
leptomeningitis  due  to  the  Bacillus  typhosus  alone,  and  Cole  has  collected 
many  others  from  the  literature.  The  exudate  resembles  that  in  the  epi- 
demic cerebrospinal  form,  but  is  richer  still  in  macrophages  which  contain 
the  debris  of  cells.  Here  it  seemed  especially  clear  that  these  large  cells 
are  to  be  regarded  as  part  of  the  army  of  mononuclear  wandering  phago- 
cytes. Local  and  multiple  neuritis  occurs,  but  is  not  serious,  and  quickly 
disappears  in  convalescence. 

Genital  Organs. — Typhoid  bacilli  have  been  cultivated  from  the  uterus 
in  cases  in  which  typhoid  fever  occurred  during  pregnancy.  Lesions  of  the 
placenta  of  hsemorrhagic  type  give  one  explanation  for  the  transmission  of 
the  bacilli  to  the  foetus,  but  it  seems  that  this  may  occur  without  obvious 
placental  changes.  Lynch  shows  that  the  effect  is  a  fcetal  septicaBmia,  and 
that  the  child  dies  in  utero  or  soon  after  birth.  Mastitis  is  a  rare  sequel 
of  typhoid  fever.  McCrae  has  recorded  three  cases. 

In  rare  cases  orchitis  follows  convalescence  and  may  lead  to  indurative 
atrophy  or  abscess  formation. 

Parotitis. — Owing  to  the  prolonged  illness  and  the  stuporous  condition, 
the  mouths  of  these  patients  become  foul  unless  continually  cleansed.  Paro- 
titis may  arise  by  extension  of  infection  along  the  duct,  or  by  lodgment  of 
bacilli  carried  there  by  the  blood.  Suppuration  may  destroy  much  of  the 
gland  and  extend  into  the  adjacent  tissue  or  into  the  neck.  In  these  cases 
there  is  commonly  a  mixed  infection. 

LITERATURE 
General— Osier:   Principles  and  Practice  of  Medicine,  New  York,  Sixth  Edition,  1905. 

"Studies  in   Typhoid   Fever,"  Johns   Hopkins  Hosp.  Reports,    1895,  v; 

1902,  x. 

Curschmann:    Nothnagel,  Spec.  Path.  u.  Ther.,  1902,  Bd.  iii,  Th.  1. 
Hoffmann:    Veranderungen  der  Organe  beim  abdominal  Typhus,  Leipzig, 

1869. 

Brouardel  and  Thoinot:   La  Fievre  Typhoide,  Paris,  1905. 
Mallory:   Jour.  Exp.  Med.,  1898,  iii,  611. 
Posselt:  Ergebn.  d.  allg.  Path.,  1912,  xvi^  184. 
Gay:  Typhoid  Fever,  New  York,  1918. 


PARATYPHOID    INFECTIONS  615 

Typhoid  Septicaemia.—  Rudiger:  Trans.  Chicago  Path.  Society,  1903,  v,  187. 
Cole:  Johns  Hopkins  Hosp.  Bull.,  1901,  xii,  203. 
Lartigau:   New  York  Med.  Jour.,  1900,  Ixxi,  944. 
Roseola.— E.  Frankel:  Zeit.  f.  Hygiene,  1900,  xxxiv,  482. 
Typhoid  Cholecystitis.— Gushing:   Johns  Hopkins  Hosp.  Bull.,  1898,  ix,  91,  257. 

Hunner:    Ibid.,  1899,  x,  163. 

Placental  Transmission.— Lynch:  Johns  Hopkins  Hosp.  Reports,  x,  283. 
Typhoid  Meningitis.— Cole  and  MacCallum:   Johns  Hopkins  Hosp.  Reports,  1904,  xii, 

411. 

Bone  Lesions.— Parsons:   Johns  Hopkins  Hosp.  Reports,  1895,  v,  417. 
Miscellaneous. — McCrae:    Ibid.,  1902,  xiii,  20. 

A.  L.  Mason:  Boston  Med.  and  Surg.  Jour.,  1897,  cxxxvi,  449,  468. 
Longcope:   Centralbl.  f.  Bakt.  u.  Paras.,  Abt.  i,  1905,  xxxvii,  Ref.  23. 
Robinson:   Bull.  Ayer  Clinical  Labt.,  1906,  iii,  96. 
Vaccination. — Russell:  Mil.  Surgeon,  1909,  xxiv,  479. 


PARATYPHOID  INFECTIONS 

In  discussing  the  effects  of  poisons  upon  the  tissues  reference  was  made  to 
the  outbreaks  of  severe  gastro-intestinal  disturbances  produced  by  the 
eating  of  infected  or  partly  decomposed  meat,  and  it  was  then  shown  that 
such  epidemics  of  what  seems  to  be  a  form  of  poisoning  are  really  commonly 
due  to  infection  with  some  member  of  that  group  of  bacilli,  of  which  the 
Bacillus  enteritidis  of  Gartner  is  the  type.  These  are  somewhat  allied  to 
the  Bacillus  typhosus,  and  it  has  been  more  recently  recognized  that  there 
are  at  least  two  types  of  bacilli  which  are  not  only  members  of  this  family, 
but  produce  at  times  a  disease  practically  indistinguishable  from  a  mild 
attack  of  typhoid  fever.  These  are  the  paratyphoid  bacilli  A  and  B,  of 
which  A  is  an  acid  producer,  B  an  alkali  producer.  Of  these,  the  latter 
occurs  far  more  frequently  and  is  so  like  the  Bacillus  enteritidis  of  Gartner 
as  to  be  most  easily  distinguished  by  the  agglutination  reactions.  They 
were  first  described  in  America  by  Gwyn. 

The  infection  occurs  by  the  gastro-intestinal  tract,  probably  from  eating 
from  an  animal  infected  before  slaughtering,  meat  which,  upon  standing, 
has  become  far  richer  in  bacilli.  Two  chief  types  of  infection  occur — 
the  acute  gastro-enteritis  and  the  typhoid  form.  The  acute  gastro- 
enteritis represents  at  least  a  part  of  the  cases  of  cholera  nostras,  and  is  dis- 
tinguishable from  true  cholera  by  bacteriological  study  only,  although, 
of  course,  the  attendant  circumstances  may  make  the  diagnosis  easy. 
There  is  intense  diarrhoea  with  desiccation  of  all  the  tissues  and  collapse, 
sometimes  leading  to  death.  At  autopsy  no  changes  are  found  except 
some  general  swelling  and  reddening  of  the  gastro-intestinal  mucosa. 

The  second  type,  probably  long  mistaken  for  typhoid  fever,  is,  in  fact, 
almost  precisely  like  that  disease  in  its  clinical  symptoms,  details  such  as 
the  roseola,  laryngitis,  etc.,  being  exactly  repeated.  There  are  also  quite 
similar  complications,  such  as  paratyphoid  meningitis,  cholecystitis,  cystitis, 
pyelitis,  etc.  Few  cases  have  been  studied  at  autopsy,  and  these  are  re- 
viewed by  Burckhardt.  In  a  large  proportion  of  them  there  were  found 


615  TEXT-BOOK   OF   PATHOLOGY 

swelling  in  the  lymphoid  structures  of  the  intestines,  and  ulceration  resem- 
bling, even  in  histological  detail,  the  lesions  of  typhoid  fever.  Others  showed 
no  affection  of  the  intestine  whatever  (Longcope).  In  the  cases  with  ulcer- 
ation there  was  swelling  of  the  mesenteric  glands,  whose  sinuses  were  filled 
with  phagocytic  cells  and  presented  necroses  here  and  there.  The  spleen 
showed  no  characteristic  alterations,  but  necroses  (so-called  lymphomata) 
were  found  in  the  liver.  From  these  cases  the  Bacillus  paratyphosus 
B  was  isolated  in  pure  culture  from  the  organs,  the  bile,  and  the  circulating 
blood,  and  recognized  by  its  cultural  characteristics  and  by  its  agglutina- 
tion properties.  Two  cases  studied  at  autopsy  in  which  there  was  infec- 
tion with  paratyphoid  A  showed  in  one  case  ulcers  in  the  intestine,  in  the 
other  case  none. 

In  most  cases  the  course  is  mild  and  brief,  but  the  complications,  espe- 
cially cystitis  and  pyelonephritis  or  pyelitis,  may  persist  a  very  long  time, 
with  constant  discharge  of  the  bacilli,  which  are  far  more  destructive  in 
those  situations  than  the  typhoid  bacillus. 

It  is  evident  that  much  more  light  will  be  shed  on  these  infections  shortly, 
and  already  the  literature  concerning  them  is  abundant,  if  somewhat  unsat- 
isfactory. 

LITERATURE 

J.  L.  Burckhardt:  Centralbl.  f.  allg.  Path.,  1912,  xxiii,  49. 
Johnston,  Hewlett,  Longcope:   Amer.  Jour.  Med.  Sci.,  1902,  cxxiv,  187. 
Gwyn:  Johns  Hopkins  Hosp.  Bull.,  1898,  ix,  54. 
Pratt:    Boston  Med.  and  Surg.  Jour.,  1903,  cxlviii,  137. 
Schottmuller:  Mohr  and  Staehelin,  1911,  i,  519.     Zeitschr.  f.  Hygiene,  1901,  xxxvi,  368. 

The  literature  since  1916  is  voluminous,  but  adds  little  exact  information. 
Huebschmann:  Ziegler's  Beitr.,  1913,  Ivi,  514. 
Saltykow:  Virch.  Arch.,  1913,  ccxi,  467. 
Loele:  Ergebn.  Allg.  Path.,  1915,  xviii,  i.  546. 
Rathery:  Les  fievres  paratyphoides  B,  Paris,  1916. 
Vincent  and  Muratet:  Typhoid  and  Paratyphoid  Fever,  London,  1917. 
Dawson:  Proc.  Roy.  Soc.  Med.,  1915,  ix.     Quart.  Jour.  Med.,  1915-16,  ix,  98. 
Mallie:  Infection  paratyphique,  Paris,  1916. 
Sacquepee,  Burnet,  and  Weissembach:  Reunion  med.  de  la  4me  Armee,  1915. 

DYSENTERY  INFECTIONS 

The  bacilli  responsible  for  the  causation  of  the  endemic  and  epidemic  dys- 
entery which  prevails  so  widely  in  the  tropics  and  in  occasional  epidemics 
in,  temperate  zones  were  recognized  by  the  aid  of  the  agglutination  reaction 
with  the  patient's  serum.  Four  types,  differing  in  this  agglutination  and 
in  certain  biological  characters,  are  recognized,  and  known  as  the  Shiga, 
Flexner,  Y  type  of  His  and  Russel,  and  the  type  of  Strong.  Of  these,  the 
Shiga  type  seems  to  be  most  widely  disseminated,  and  produces  a  distinct 
toxin.  The  Flexner  type  has  only  a  very  slight  power  of  toxin  production. 
Epidemics  arise  in  the  rainy  season,  especially  where  there  are  sudden 
variations  of  temperature,  and  in  the  hot  seasons  in  more  temperate  zones. 
The  bacilli  are  disseminated  by  people  who  have  partially  or  completely 


DYSENTERY   INFECTIONS 


617 


recovered  from  a  previous  attack,  but  still  carry  and  discharge  the  organ- 
ism. They  are  distributed  in  drinking-water,  in  food,  by  direct  and  indi- 
rect contact,  by  flies,  dust,  etc.  The  unsanitary  mode  of  life  in  many  parts 
of  the  tropics  and  in  many  cities  favors  their  rapid  spread. 

The  disease  is  chiefly  an  infection  of  the  colon,  although  the  lower  part 
of  the  ileum  may  also  be  involved.  It  begins  with  hypersemia  of  the  mucosa 
and  the  secretion  of  abundant  slimy,  clear,  mucoid  fluid,  which  is  later 


*  \  If  '"4*      **         «i       *V«  S'X«  '       '       &<,*<       •         •  "^  '  > :       f'' 

i^\:H--l|^fcS?r$S^  ^it 


Fig.  297. — Dysentery.  Diphtheritic  and  hsemorrhagic  inflammation  of  the  intestine 
involving  the  crests  of  the  folds  of  the  mucosa.  The  pseudomembrane  is  still  adherent, 
and  there  is  extensive  haemorrhage  beneath  it. 

streaked  with  blood.  The  swollen  mucosa  shows  points  and  streaks  of 
haemorrhage,  and  soon  there  appear  chaff-like,  opaque  flecks  on  the  crests 
of  the  folds  (Fig.  297).  Even  at  this  stage,  when  these  flecks  indicate 
the  death  of  the  surface  of  the  mucosa,  resolution  or  healing  may  take 
place,  but  usually  the  diphtheritic  character  of  the  lesion  becomes  more 
evident  and  progresses  to  ulceration.  The  more  prominent  parts  of  all 
the  folds  become  covered  with  a  thick,  dull  layer  of  exudate,  which  con- 


618 


TEXT-BOOK    OF    PATHOLOGY 


stitutes  a  false  membrane  and  is  continuous  with  the  densely  coagulated 
dead  layer  of  mucosa  (Fig.  298).  All  around,  haemorrhage  and  an  intense 
inflammatory  reaction  with  oedema  appear.  With  the  sloughing  off  of  this 
layer  irregular  ulcers  are  left.  These  vary  in  size  and  depth,  and  while 

sometimes  quite  large  sheets 
of  dead  and  coagulated  mucosa 
and  exudate  escape  with  the 
stools,  at  other  times  the  ulcers 
are  more  localized,  but  pene- 
trate deeper  into  the  submu- 
cosa,  the  musculature,  or  even 
the  subserous  tissues  (Fig.  299). 
Perforations  occur,  but  are  rare. 
The  presence  of  this  process  ex- 
cites the  most  violent  diarrhoea, 
with  tenesmus  and  the  passage 
of  liquid,  mucoid,  and  blood- 
tinged  stools.  So  constant  is 
the  passage  of  fluid  stools,  and 
so  violent  the  continual  strain- 
ing, that  the  patient  becomes 
exhausted.  Vomiting  may  be- 
gin; the  skin  is  covered  with 
sweat;  the  voice  hoarse  and  eyes 
sunken,  and  the  whole  condi- 
tion cholera  like.  Such  patients 
may  die  in  collapse.  If  the  at- 
tack is  not  fatal,  there  may 
be  relapses  from  time  to  time, 
lasting  over  a  long  period,  and 
finally  the  disease  settles  into 
a  milder  chronic  process.  The 
ulcers  heal  by  the  formation  of 
granulation  tissue,  over  which 
a  smooth  layer  of  epithelium 
grows  without  the  new  forma- 
tion of  glands.  Much  scar  tis- 
sue develops  in  the  gut  wall  in 
the  base  of  such  ulcers,  and 
contracts  so  as  to  constrict  or 
kink  the  intestine.  Very  nar- 
,  row  strictures  may  be  formed 

tnus      The  ulcers  are  irregular  in  extent  and  outline,  and  are  often  conl 
lent,  leaving  islands  of  mucosa  which  stand  out  above  the  new  epithe- 
lium as  pedunculated  polypoid  masses.     In  one  case  which  I  saw  there 
long  bridges  of  nmcosa  which  had  been  undermined  and  which,  in 


Fig.  298.— Acute  diphtheritic  and  haemor- 
rhagic  dysentery.  Colon  of  a  child,  showing 
abundant  pseudomembrane  on  the  crests  of  the 
folds  of  the  mucosa. 


DYSENTERY   INFECTIONS 


619 


some  places,  having  broken  away  at  one  end,  hung  in  the  intestine  like 
long  pendulous  polypi. 

Even  in  the  acute  disease  the  other  organs  are  not  much  changed;  there 
is  no  septicaemia,  and  therefore  there  are  no  cutaneous  changes.  There  is 
no  acute  splenic  tumor  and  no  pronounced  cloudy  swelling  of  the  viscera. 
The  bacilli  are  found  in  the  swollen  mesenteric  glands  and  also  in  the 


Fig.  299. — Dysentery  in  a  child.     Extensive  ulceration  of  the  colon,  which  involved 
also  the  ileum  to  a  less  extent. 

spleen  and  liver,  but  not  elsewhere.  Painful  joint  changes  are  not  uncom- 
mon, consisting  in  effusions  into  the  joints,  especially  those  of  the  foot, 
knee,  and  hip.  When  the  pain  and  swelling  subside  in  one  joint,  another 
may  become  affected,  and  with  each  there  is  a  rise  in  temperature.  They 
recover  their  normal  condition  without  any  inflammatory  residue.  Tran- 
sient paralyses,  which  sometimes  involve  muscular  atrophy,  also  occur. 


520  TEXT-BOOK   OF   PATHOLOGY 

In  children  in  summer  epidemics  it  has  been  shown  by  Basset  and  Duval, 
Knox  and  Wollstein,  that  the  Shiga  bacillus  is  the  causative  agent  of  the 
dysentery,  which  is  practically  identical  with  that  of  adults,  and  in  which 
the  mortality  is  high.  It  has  long  been  known  that  in  asylums  and  prisons 
outbreaks  of  dysentery  were  due  to  some  such  infection,  doubtless  in- 
troduced, as  we  now  appreciate,  by  a  bacillus  carrier.  Kruse  spoke  of 
this  as  pseudodysentery,  which  was  unfortunate,  since  it  has  been  shown 
that  these  cases  were  due  to  the  Shiga  bacillus  (Vedder  and  Duval). 

As  stated,  the  blood  of  dysentery  patients  acquires,  after  eight  to  ten 
days,  the  power  of  agglutinating  bacilli  of  the  same  type.  But  the  serum 
of  those  infected  with  the  Shiga  type  agglutinates  only  the  Shiga  bacillus 
except  in  very  concentrated  form,  while  the  serum  of  those  suffering  from 
infection  with  the  Flexner  type  will  agglutinate  both  in  considerable  dilu- 
tion. The  Shiga  bacillus  produces  a  strong  toxine  which  has  long  been 
known  to  cause  in  rabbits  not  only  a  severe  intestinal  lesion  with  haem- 
orrhages but  also  paralysis.  This  is  well  described  and  illustrated  by 
Doerr  in  his  monograph  on  the  toxine.  Clinicians  have  recognized  the  oc- 
currence of  postdysenteric  paralyses  in  human  beings,  and  have  ascribed 
them  to  some  form  of  neuritis,  but  Dopter  has  shown  that  in  rabbits 
at  least  the  paralyses  are  due  to  definite  lesions  in  the  gray  matter  of  the 
central  nervous  system.  Olitzky  and  Kligler  have  recently  restudied  the 
toxine,  and  have  found  that  there  may  be  distinguished  an  exotoxin  which 
is  heat  labile,  and  which  attacks  the  nervous  tissues,  and  an  endotoxin 
which  is  more  stable  and  which  is  responsible  for  the  intestinal  lesions. 
Antitoxins  can  be  produced  for  each  of  these,  and  are  specific. 

LITERATURE 

Shiga:  Centralbl.  f.  Bakt.  u.  Paras.,  1898,  Abt.  1,  xxiii,  599.    Ibid.,  1898,  xxiv,   817. 

Osier  and  McCrae,  Modern  Medicine,  1913,  i,  766. 
Flexner:  Univ.  of  Penn.  Med.  Bull.,  1901,  xiv,  190.      Trans.  Cong.  Amer.  Phys.  and 

Surg.,  1900,  v,  61.    Studies  of  Diarrhceal  Diseases  of  Infancy,  New  York,  1904. 
Duval  and  Bassett:  American  Medicine,  1902,  iv,  417. 
Whitmore:  Philippine  Jour,  of  Science,  1911,  vi,  215. 
Vedder  and  Duval:  Jour.  Exp.  Med.,  1901-05,  vi,  181. 
Kruse:  Deut.  med.  Woch.,  1900,  xxvi,  637. 
Lentz:  Kolle  and  Wassermann,  1909,  2  Ergnzbd.,  391. 
Ruge,  Mense:  Hand.  d.  Tropenkrankheiten,  1914,  iii,  158. 
Kossel,  Singer:  Munch,  med.  Woch.,  1915,  Ixiii,  85,  183. 
Doerr:  Das  Dysenterietoxin,  Jena,  1907. 
Olitsky  and  Kligler:  Jour.  Exp.  Med.,  1920,  xxxi,  19. 


CHAPTER  XXXII 
TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued) 

Leprosy:  Nodular  and  anesthetic  forms.  The  bacillus  and  transmission.  Lesions  of  the 
internal  organs.  Affections  of  nerves  and  their  sequelce. 

Actinomycosis:  General  character  of  the  disease  and  organism.  Related  organisms.  Mode 
of  infection.  The  destructive  lesions. 

LEPROSY 

KNOWN  in  detail  in  ancient  times  as  a  contagious  disease  of  destructive 
character  and  quite  incurable,  leprosy  has  spread  over  practically  all  the 
countries  of  the  world,  and  lepers  are  now,  as  in  the  time  of  Moses,  objects 
of  horror  and  aversion. 

The  disease  is  the  result  of  infection  with  the  Bacillus  leprse,  discovered 
by  Hansen  in  1874,  and  is  a  slowly  developing  affection,  of  extreme  chron- 
icity,  in  which  nearly  all  the  tissues  become  invaded  by  the  bacilli.  It 
occurs  in  at  least  two  main  forms,  although  there  are  many  combinations 
and  modifications  of  these  types.  One  is  the  tubercular  or  nodular  leprosy, 
in  which  the  skin,  especially  in  the  exposed  parts,  is  lifted  up  over  firm 
nodules,  which  in  time  break  through  and  ulcerate.  The  other  is  the  so- 
called  anaesthetic  leprosy,  in  which,  without  much  change  in  the  skin,  dis- 
ease of  the  nerves  leads  to  a  loss  of  sensation,  which  is  followed  by  trophic 
changes  in  the  extremities  and  by  mutilations  from  unnoticed  injuries. 
The  lepers  live  for  a  long  time  and  become  fearfully  deformed,  dying 
finally  from  the  disease  itself,  or  from  some  in tercurrent  affection. 

Since  writing  this  chapter  the  first  time  I  have  had  the  opportunity  of 
visiting  many  leper  colonies  in  the  South  Sea  Islands,  the  East  Indies,  the 
West  Indies,  and  in  South  America,  and  have  had  occasion  to  perform 
some  autopsies  in  advanced  cases.  The  affection  is  far  more  prevalent 
than  we  are  accustomed  to  think  it,  and  on  account  of  its  disabling  char- 
acter and  the  isolation  it  enforces  is  one  of  the  most  tragic  of  all  diseases. 

The  mode  of  transmission  is  not  really  known,  although  various  state- 
ments are  made  with  an  air  of  authority.  Mere  contact  with  those  suf- 
fering from  the  disease  is  probably  sufficient  if  prolonged  enough  because 
so  many  bacilli  are  discharged  from  the  nose  and  from  open  ulcerations, 
but  we  must  hasten  to  add  that  the  Catholic  Sisters  and  others  who  spend 
their  lives  in  nursing  and  caring  for  these  patients,  are  practically  never 
infected.  No  doubt  they  are  well  aware  of  the  risk  and  are  very  careful, 
but  they  do  not  avoid  contact  with  the  sick.  There  is  no  good  evidence 
that  leprosy  is  inherited,  even  when  both  parents  are  lepers,  and  there 
are  many  examples  of  the  contrary.  But  when  the  children  are  left  to 

621 


622 


TEXT-BOOK    OF    PATHOLOGY 


live  with  their  mothers  in  the  leper  colony  they  frequently  develop  the 
disease.  Of  four  such  children  in  a  colony  visited  last  summer,  three 
showed  large  circinate  skin  lesions,  while  the  other  was  clean.  Some 
statistics  seem  to  show  that  transmission  is  not  so  frequent  between 
husband  and  wife  as  might  reasonably  be  expected,  and  that  among  rela- 
tives cases  are  found  most  often  in  brothers  and  sisters.  Nevertheless 
it  has  always  been  thought  that  sexual  intercourse  plays  a  very  great  part 
in  the  spread  of  the  infection.  Every  sort  of  biting  insect  has  been  in- 
vestigated in  the  hope  that  one  of  them  might  be  found  responsible  for  the 


Fig.  300.  —  Tubercular  or  nodular  leprosy,  showing  lesions  on  face  and  body. 
carrying  of  the  bacilli,  but  so  far  with  negative  results.     It  is,  of  course, 
largely  on  account  of  the  fact  that  the  incubation  period  of  the  disease 
may  last  over  months  or  years  that  the  difficulty  of  determining  the  manner 
of  transmission  is  so  great. 

The  two  forms  mentioned  above  are  seldom  quite  distinct,  and  it  is 
only  recently,  in  Jamaica,  that  I  have  seen  a  considerable  number  of  cases 
of  the  pure  anaesthetic  form,  with  practically  no  changes  in  the  skin,  but 
with  mutilation  of  the  hands  and  feet  from  which  fingers  and  toes  had  dis- 


by 


°f 


'  ManUa'  and 


sent  to 


LEPROSY 


623 


appeared  so  that  only  stumps  were  left.     The  tuberculous  form  is  almost 
always  found  to  show  anaesthesias  and  the  nerves  are  thickened  into  cords 


Fig.  300A — Tubercular  leprosy,  showing  advanced  lesions  of  face  and  hands  (Kuala 

Lumpur). 


Fig.  300B. — Tubercular  leprosy  with  extreme  destructive  changes  in  hands  and  face 

(Kuala  Lumpur). 

and  are  found  at  autopsy  to  be  densely  embedded  in  the  peculiar  tissue 
which  is  so  characteristic  of  all  the  lesions. 

It  would  be  difficult  to  describe  all  the  atypical  forms  of  skin  lesion 


624  TEXT-BOOK   OF   PATHOLOGY 

found  in  leprosy,  and  yet  the  average  advanced  case  presents  an  almost 
monotonously  uniform  appearance  (Figs.  300,  300A,  300B,  300C).  The 
disease  begins  insidiously,  sometimes  with  a  febrile  illness  which  passes  off, 
to  be  followed  some  time  later  by  the  appearance  of  a  reddened  elevated 
patch  somewhere  upon  the  body,  or  by  the  partial  depigmentation  of 
patches  of  the  skin.  There  is  really  no  basis,  however,  for  the  expression 
" white  as  a  leper,"  for  they  show  no  patches  or  scars  which  would  im- 
press one  as  white.  Leucoderma  from  other  causes  is  common  though, 
and  has,  no  doubt,  given  rise  to  this  idea.  The  nodules  or  elevated  patches 
become  more  numerous  and  affect  especially  the  face,  hands,  and  feet, 
although  they  are  also  frequently  enough  found  on  the  trunk  when 


Fig.  300C.— Anaesthetic  leprosy.     Mutilation  of  hands  and  feet  without  lesions  of  face 

(Bali). 

not  covered  with  clothing.  The  eyebrows  and  eyelashes  fall  out,  and 
there  appears  a  diffuse  thickening  of  the  brows,  the  upper  parts  of 
the  cheeks,  the  alae  of  the  nostrils,  and  the  edges  of  the  ears.  The  lobes 
of  the  ears  are  often  especially  enlarged  and  are  soft  so  that  they  swing 
about  as  the  man  walks.  Later  in  all  these  positions  the  thickening  takes 
the  form  of  rough  nodules  which  throw  the  skin  up  into  great  folds  and 
eminences.  Tumor-like  masses  form  especially  on  the  alae  of  the  nose  and 
spread  out  laterally.  The  cartilage  of  the  nose  often  becomes  destroyed 
so  that  the  nose  is  telescoped  into  itself  in  such  a  way  that  the  nostrils 
open  forward.  By  this  time  the  lesions  elsewhere  are  also  far  advanced 
and  usually  several  fingers  have  been  lost. 

Even  early  in  the  disease  there  are  ulcerative  changes  in  the  mucosa  of 


LEPROSY  625 

the  nose,  and  diagnosis  often  rests  upon  finding  the  bacilli  in  scrapings 
from  this  ulcerated  mucosa.  Later  many  of  the  nodules  in  the  skin  break 
open  and  fail  thereafter  to  heal  for  a  long  time,  discharging  quantities  of 
bacilli  with  the  exudate  from  the  ulcer.  The  most  disfiguring  losses  of 
substance  may  occur  in  this  way  in  the  tissues  of  the  face  and  even  in  the 
bones  underneath,  so  that  sometimes  no  recognizable  face  is  left.  In  the 
case  of  the  fingers  it  is  not  always  the  advance  of  the  strictly  leprous 
lesions  that  produces  the  mutilation,  for  secondary  infections  are  very 
common.  They  begin  in  the  form  of  a  panaritium  or  felon,  and  in- 
fection extends  rapidly  along  the  tendon  sheaths  so  that  amputation 
must  be  performed,  if  at  all,  at  a  point  far  above  that  which  is  obviously 
diseased. 

The  conjunctive  and  cornese  are  frequently  the  seat  of  leprous  lesions 
which  spread  across  and  produce  opacity,  and  with  healing  leave  the 
eye  quite  blind. 

The  bacilli,  which  are  acid  fast  and  resemble  closely  the  tubercle  bacillus, 
are  present  in  the  lesions  in  enormous  numbers.  They  are  in  such  relation 
to  the  pathological  changes  that  there  can  be  little  doubt  that  they  are  the 
actual  cause  of  the  disease,  although  the  other  postulates  for  the  proof 
of  the  setiological  relation  of  an  organism  to  a  disease  have  net  been  very 
satisfactorily  carried  out. 

The  lesions  are  all  based  on  the  formation  of  a  specific  sort  of  granulation 
tissue  which  is  composed  of  a  loose  network  of  branching  connective- 
tissue  cells,  rich  in  blood-vessels  and  especially  in  wide  lymphatics.  It  is 
infiltrated  with  mononuclear  wandering  cells  of  many  forms  and  sizes, 
all  of  which  appear,  however,  to  belong  to  one  series.  Many  of  these 
attain  the  size  of  giant  cells  and  are  provided  with  several  nuclei.  All 
of  the  wandering  cells  are  loaded  with  globules  of  fat.  Such  tissue  occurs 
in  discrete  lobules  beneath  the  skin  or  in  the  internal  organs,  which  when 
stained  with  Sudan,  appear  as  solid  red  masses.  Some  of  the  cells  become 
so  swollen  with  fat  as  to  lose  all  recognizable  cell  structure,  and  in  these 
large  fat  globules  which  are  sometimes  surrounded  by  several  cells  there 
is  a  mass  of  bluish  staining  granules  which  become  apparent  after  the  fat 
has  been  dissolved  out.  It  does  not  appear  that  bacilli  accumulate  in 
such  globules.  All  the  cells  are  thus  vacuolated,  as  seen  in  preparations 
from  which  the  fat  has  been  dissolved  out,  and  much  has  been  written  on 
the  foamy  cell,  characteristic  of  leprosy.  All  of  these  cells  are  phagocytic, 
and  may  contain  bacilli,  but  it  is  chiefly  in  the  swollen  endothelial  cells 
of  the  lymphatics  and  blood-vessels  that  they  are  heaped  up  in  red 
staining  masses.  In  other  cases  we  have  found  the  bacilli  so  numerous 
that  almost  every  wandering  cell  contained  them.  Leucocytes  play 
very  little  part  in  the  infiltration,  but  necrosis  of  the  tissue  occurs 
frequently,  and  in  those  areas  there  are  many  fragmented  nuclei  and 
some  leucocytes. 

In  the  nodules  on  the  body  surface  the  overlying  epithelium  is  stretched 


626 


TEXT-BOOK    OF    PATHOLOGY 


out  in  a  smooth  layer  so  that  the  papillae  are  obliterated  (Fig.  301),  and 
the  tissue  beneath  is  hyaline  and  almost  devoid  of  nuclei  for  a  short  dis- 
tance. After  it  breaks  down  the  ulcer  persists  for  a  long  time,  but  is 
usually  filled  up  at  length  by  a  dense  scar.  The  mucosae  of  the  nose  and 
nasal  sinuses  are  affected  in  exactly  the  same  way,  and  ulcerations  on  a 


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^fe/^^i^j 

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Fig.  301.— Leprosy.  The  section  through  a  leprous  nodule  of  the  skin  shows  the 
obliteration  of  papillae  and  the  accumulation  of  giant-cells,  which  are  loaded  with  bacilli, 
in  the  deeper  tissues. 

basis  of  the  same  sort  of  tissue  are  found  throughout  the  pharynx  larynx, 
and  trachea.  Some  authors  have  described  leprous  lesions  of  the  lungs 
which  were  hardly  distinguishable  from  tuberculosis,  but  in  the  cases 
which  I  have  studied  it  was  really  tuberculosis,  which  seems  to  be  a  com- 
mon secondary  infection  in  leprosy. 


LEPROSY 


627 


Fig.  302. — Leprosy.     Focal  accumulation  of  lepra  cells  in  the  liver.     These  cells  contain 

many  bacilli. 


/ 

'/&—^^^-^-^'-'^--:;'^/'     i-  .    '.',,-.  "'*?&*&*•   •A-.    . 


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Fig.  303. — Leprous  neuritis  with  much  scar  formation  about  the  nerve-bundles. 


628 


TEXT-BOOK   OF    PATHOLOGY 


In  the  liver  and  spleen  there  are  scattered  everywhere  minute  foci  of 
tissue  made  up  of  the  same  network  with  vacuolated  or  fat-holding  cells 
as  seen  elsewhere.  These  miliary  lepromata  (Fig.  302)  which  contain 
bacilli  are  quite  conspicuous  in  a  microscopical  section,  although  they 
cannot  be  seen  with  the  naked  eye.  *Lesions  of  the  intestines  have  been 
described,  but  must  be  rare.  In  the  lymph-nodes  the  leprous  granula- 
tion tissue  is  found  to  occupy  the  margins  of  the  lymph  cords,  leaving  the 

sinuses  fairly  free.  In  the  testicle  the 
tubules  are  spread  apart  by  the  same 
tissue,  loaded  with  bacilli,  and  the 
tubules  are  reduced  to  hyaline  strands. 
In  the  bones  there  may  exist  a  kind 
of  leprous  osteomyelitis,  with  lesions 
analogous  to  those  of.  the  skin,  but 
this  is  much  less  important  than  the 
changes  in  the  bones  associated  with 
the  affection  of  the  nerves  and  with 
the  secondary  infections. 

Leprous  neuritis  or  perineuritis  is 
one  of  the  most  constant  features  cf 
the  disease,  and  the  disturbances  of 
sensation  which  result  are  often  the 
first  to  rouse  suspicion  of  its  exist- 
ence. It  is  by  no  means  limited  to 
tl  o  anaesthetic  form,  but  is  found  in 
tlu  tuberculous  and  mixed  forms.  The 
nerves  of  the  arm  and  the  more  super- 
ficial ones  in  the  leg  may  be  felt  through 
the  skin  as  thick  stiff  cords,  which  at 
autopsy  are  found  to  show  the  nerve 
bundles  spread  apart  and  embedded 
in  tissue  of  the  type  described  above 
(Fig.  303).  Bacilli  are  scattered  in 
this  tissue,  but  also  make  their  way 
into  the  medullary  sheaths  of  the  indi- 
vidual fibres.  The  fibres  degenerate 
and  sensation  is  lost  long  before  any 
motor  disturbances  appear.  The  lesion 

of  the  nerve  is  usually  only  in  patches  along  the  course,  but  the  bacilli  may 
be  found  not  only  there,  but  sometimes  in  the  ganglion  cells  of  the  root 
ganglia  and  in  the  spinal  cord  and  brain. 

Most  striking  are  the  atrophies  of  the  bones  of  the  extremities  which 
result  from  this  interruption  of  the  nerves  which  causes  the  phalanges  to 
shrink  and  the  bones  to  fuse  into  thin,  pointed  remnants  of  bone,  attached 
to  the  metacarpals  or  metatarsals.  These  in  their  turn  may  atrophy  and 


Fig.  304.— Atrophy  and  distortion 
of  the  bones  of  the  foot  in  leprosy 
(Harbitz). 


ACTINOMYCOSIS  629 

become  disarranged,  so  that  finally  the  hand  or  foot,  further  cramped 
by  contractures,  assumes  the  most  distorted,  claw-like  appearance  (Fig. 
304).  Harbitz,  in  describing  these,  has  pointed  out  the  fact  that  this  is 
a  process  of  mutilation  not  necessarily  associated  with  ulceration  and  in- 
flammation. Indeed,  the  most  disfiguring  mutilations  arise  from  the  insen- 
sibility of  the  hands  and  feet,  which  makes  it  possible  for  these  patients 
to  suffer  from  burns  or  other  injuries  without  drawing  away  or  protecting 
themselves.  Nevertheless,  it  seems  probable,  from  Harbitz's  pictures, 
that  most  of  these  deformed  extremities  are  the  more  direct  result  of  loss 
of  nerve  impulses. 

LITERATURE 

Sokolowsky:  Virch.  Arch.,  1900,  clix,  521. 
Babes:    Histologie  der  Lepra,  Berlin,  1898. 
Kedrowski:   Arch.  f.  Derm.  u.  Syphilis,  1914,  cxx,  267. 
Sticker:    Handb.  d.  Tropenkrankheiten,  Mense,  1914,  iii,  1. 
Uhlenhuth  and  Westphal:  Centralbl.  f.  Bakt.  u.  Paras.,  1901.  xxix,  Abt.  i,  233. 
Sakurane:   Ziegler's  Beitrage,  1902,  xxxii,  563. 
Harbitz:  Archives  of  Int.  Med.,  1910,  vi,  147. 
Duval:   Jour.  Infectious  Diseases,  1912,  xi,  116. 

ACTINOMYCOSIS 

This  disease,  common  in  cattle,  and  recognized  as  an  infectious  process  by 
Bollinger,  was  later  described  by  J.  Israel  for  man.  The  cattle  present  a 
tumor-like  swelling,  usually  of  the  jaw,  with  sinuses  and  purulent  dis- 
charge in  which  peculiar  yellow  granules  or  sulphur  grains  are  found.  In 
human  beings  the  affection  is  quite  commonly  also  a  swelling  of  the  j  aw, 
but  there  are  several  other  typical  localizations,  namely,  in  the  thoracic  or- 
gans, in  the  intestines,  or  in  the  skin.  Ponfick  recognized  the  identity  of 
the  disease  in  man  and  animals.  Examination  of  the  pus  or  of  sections  of 
the  granulation  tissue  lining  the  sinuses  shows  the  causative  agent  to  be  a 
branched  organism  which  grows  in  tangled  mycelia.  Numerous  broken 
portions  resembling  bacilli  or  cocci  occur.  The  sulphur  grains  are  knots  of 
the  mycelium  with  radially  projecting  tips,  which  form  a  layer  covering 
the  central  tangle.  Each  of  these  tips  is  surrounded  by  a  club-shaped  or 
bulbous  covering,  of  homogeneous,  refractive  material.  The  micro- 
scopical section  through  such  a  granule,  therefore,  shows  a  curved  or  scal- 
loped margin  of  such  clubs,  arranged  parallel  or  at  least  radially.  It  was 
from  this  arrangement  that  the  name  actinomyces  or  "Strahlenpilz"  was 
derived. 

There  are  many  other  closely  allied  organisms,  which  are  commonly  spoken  of  under 
the  name  streptothrix,  and  most  writers  make  a  point  of  applying  the  name  actinomyces 
to  that  organism  which  produces  the  disease  in  man  and  cattle,  saying  that  the  strepto- 
thrices  differ  from  it  in  not  being  able  to  produce  the  radiate,  club-like  growths.  So 
often  has  this  been  repeated  that  the  distinction  will  doubtless  persist  for  a  long  time'. 
The  truth  of  the  matter  is,  however,  very  different.  Such  club-bearing  knots  of  myce- 
lium are  not  formed  by  the  organisms  in  culture,  but  only  in  the  tissues  of  an  animal 


630  TEXT-BOOK    OF    PATHOLOGY 

(exceptionally  in  cultures  in  serum  or  animal  tissue).  So  far  from  their  being  unable  to 
form  such  clubs,  those  of  the  streptothrix  group  which  can  infect  animals  produce  the 
most  beautiful  clubs  under  the  proper  conditions.  One,  commonly  known  as  the 
Streptothrix  asteroides,  if  injected  into  the  peritoneum  of  a  rabbit  so  that  the  infection 
meets  with  more  resistance  than  if  injected  directly  into  the  blood,  will  form  everywhere 
in  the  organs  graceful,  plume-like  masses  of  clubs  in  every  respect  similar  to  those  of 
Actinomyces  bovis.*  Indeed,  there  is  no  valid  reason  for  separating  these  organisms 
into  two  groups,  and  since  the  name  streptothrix  has  long  been  preempted  for  an  alga, 
it  is  necessary,  according  to  all  rules  of  nomenclature,  to  call  them  all  actinomyces,  that 
being  the  first  name  applied  to  any  of  the  group. 

It  is  perfectly  true  that  not  all  this  group  have  the  same  pathogenic  powers.  Some, 
indeed,  are  entirely  saprophytic,  while  others,  such  as  the  Actinomyces  asteroides,  have 
been  found  in  subacute  abscesses  in  the  brain,  in  generalized  peritonitis,  etc. 

The  Actinomyces  bovis,  described  by  Wolff,  Israel,  Wright,  and  others, 
is  an  anaerobic  organism,  and  is  recognized  as  the  cause  of  the  disease  in 
both  cattle  and  man.  It  has  not  been  found  in  the  outside  world  in  spite 
of  the  existence  of  so  many  allied  forms,  and  probably  lives  on  the  mucosa3 
of  the  mouth  and  digestive  tract.  It  has  always  been  thought  to  be  intro- 
duced into  the  tissues  by  straws  or  splinters,  but  it  begins  to  seem  more 
probable  that  it  merely  takes  advantage  of  the  presence  of  such  a  foreign 
body  to  display  its  pathogenic  properties.  Details  of  the  morphology  of 
these  remarkable  organisms  must  be  read  in  the  papers  cited. 

Having  reached  the  tissue,  the  presence  of  the  mycelium  is  quickly  re- 
sponded to  by  necrosis  of  the  cells  and  by  the  abundant  accumulation  of 
leucocytes.     The  process  advances  slowly  though,  and  there  is  a  most  pro- 
fuse formation  of  granulation  tissue  round  about  such  an  area  after  weeks 
or  months;   while  the  central  part  of  the  lesion  is  made  up  of  liquid  pus 
full  of  the  branching  organisms,  the  outer  zones  are  composed  of  such 
dense  fibrous  tissue  as  to  form  a  tumor-like  mass.     Lining  the  cavity  is 
still  fresher  granulation  tissue,  which  is  now  loaded  with  large  mononuclear 
wandering  phagocytic  cells,  which  are  themselves  so  full  of  fat-granules 
as  to  give  this  layer  an  opaque  yellow  color.     Frequently,  lying  loose  in  the 
pus  in  the  centre,  there  is  one  of  the  sulphur  grains  with  its  clubs  (Fig.  305). 
No  giant-cells  are  found,  as  a  rule,  nor  any  distinctly  tubercle-like  nodules. 
The  mycelium  grows  and  advances  into  the  tissues,  destroying  and  lique- 
fying it  slowly  with  the  aid  of  the  abundant  leucocytic  reaction,  and  is 
attended  constantly  by  the  most  tremendous  formation  of  encapsulating 
connective  tissue.     Given  such  a  process,  it  is  not  surprising  that  this 
becomes  one  of  the  most  destructive  of  all  diseases.     The  infection  bur- 
rows through  the  tissues  for  great  distances,  completely  distorting  what- 
ever it  traverses,  and  it  stops  for  nothing — bones  are  penetrated  as  easily 
as  muscles,  and  from  the  lung  such  a  mine-like  advance  may  push  through 
the  pericardium  and  heart -wall  into  the  interior  of  the  heart. 


*  For  that  matter  many  bacilli— the  diphtheria  bacillus,  Moller's  grass  bacillus  and 
others— can  do  the  same  thing  under  favorable  circumstances. 


ACTINOMYCOSIS 


631 


More  than  half  of  the  infections  are  in  connection  with  the  mouth  and 
pharynx,  and  seem  to  begin  in  the  gums  about  the  teeth,  although  some- 
times the  tongue  or  cheek  is  first  affected.  The  abscess-like  lesion,  with 
its  bulwark  of  connective  tissue,  usually  appears  in  the  parotid  or  sub- 
maxillary  region,  extending  thence,  with  destruction  of  the  jaw,  into  the 
neck.  Another  group  begins  in  the  thorax,  probably  in  the  bronchi  or  in 


Fig.  305. — Actinomycosis.  The  peculiar  lobulated  masses  of  mycelium,  edged  with 
a  row  of  clubs,  are  surrounded  by  leucocytes,  outside  which  is  a  layer  of  granulation 
tissue  rich  in  large,  fat-laden  phagocytic  cells.  Outside  this  is  dense  fibrous  tissue. 

~the  substance  of  the  lung,  and  extends  thence,  sometimes  to  appear  in 
a  sinus  or  series  of  sinuses  perforating  the  skin.  Naturally,  the  pleura 
approached  by  this  process  becomes  enormously  thickened.  A  third  site 
of  predilection  is  in  the  intestines,  and  especially  in  the  ileocsecal  region, 
where  a  submucous  abscess  soon  forms  a  mass  which  progresses  with 
adhesions  to  adjacent  abdominal  organs  and  to  the  abdominal  wall,  often 
forming  long,  burrowing  sinuses  between  the  muscles  or  reaching  bones 


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or  joints.  At  times  one  finds  great  masses  of  dense  fibrous  tissue  riddled 
everywhere  with  cavities  full  of  pus,  which  represent  the  ramifying  and 
anastomosing  suppurating  centres.  Actinomycosis  of  the  ovary  and  tubes 
has  been  observed  in  many  cases.  The  fourth  group  of  cases,  which  is 
much  smaller,  is  thought  to  be  due  to  infection  through  the  skin.  Here 


ft 


Fig.  306.— Actinomycotic  abscess  in  liver.     The  figure  shows  the  extraordinary  scarring 
about  the  abscesses,  which  are  merely  loculi  in  a  dense  fibrous  mass. 

again  the  deeper  tissues,  including  the  fasciae,  bones,  and  joints,  may  be 
penetrated  and  destroyed. 

In  the  course  of  such  a  chronic  infection  metastases  into  the  internal 
organs  may  occur,  and  we  find  abscesses  in  the  spleen  or  liver  (Fig  306) 
or  elsewhere  which  may  become  evacuated  or  may,  in  their  turn,  burrow 
and  wall  themselves  off.  Usually,  however,  if  the  disease  has  progressed 


ACTINOMYCOSIS  633 

to  that  point,  life  is  cut  short  by  an  intercurrent  affection.    Amyloid  is 
often  found  in  the  organs  at  autopsy. 

LITERATURE 

Bostroem:    Ziegler's  Beit.,  1891,  ix,  1. 
Ponfick:  Die  Actinomykose  d.  Menschen,  Berlin,  1882. 
Israel:  Virch.  Arch.,  1879,  Ixxiv,  15;  1879,  Ixxviii,  421. 
Wright:  Jour,  of  Med.  Research,  1905,  xiii,  349. 
Shiota:   Dtsh.  Zeit.  f.  Chir.,  1909,  ci,  289. 
Kohler:    Frankfurter  Zeit.  f.  Path.,  1914,  xv,  146. 

Harbitz  and  Grondahl:    Amer.  Jour.  Med.  Sci.,  September,  1911,  cxlii,  386. 
Dresel:   Ziegler's  Beit.,  1915,  Ix,  185. 

MacCallum:  Centralbl.  f.  Bakt.  u.  Paras.,  Abth.  i,  Orig.,  1902,  xxxi,  529. 
Abbott  and  Gildersleeve:  Ibid.,  547. 


CHAPTER  XXXIII 

TYPES  OF  INJURY.— BACTERIAL  DISEASE  (Continued).— TUBER- 

CULOSIS 

Tuberculosis:  Etiology.  Distribution  and  transportation  of  bacilli.  Modes  of  infection. 
Immunity  and  hypersensitization.  The  tubercle,  tuberculous  granulation  tissue,  acute 
tuberculous  inflammation,  distribution  of  the  bacilli  in  the  body.  Acute  miliary  tuberculosis. 
Tuberculosis  of  respiratory  organs,  digestive  tract,  serous  surfaces,  lymph-glands,  genito- 
urinary tract,  nervous  system,  skin,  bones,  and  joints. 

TUBERCULOSIS 

^Etiology. — The  disease  tuberculosis  was  known  in  practically  all  its 
forms  long  before  its  cause  was  discovered.  Since  it  is  of  universal  dis- 
tribution and  causes  the  death  of  more  persons  than  any  other  disease, 
it  has  always  been  earnestly  studied  as  far  as  was  possible  with  the  avail- 
able means.  Several  epochs  stand  out  in  this  study,  although  it  must  be 
confessed  that  we  are  still  far  from  a  complete  understanding  of  the 
disease,  and  other  epochs  are  still  to  come.  Laennec  knew  that  pulmonary 
consumption  was  in  some  way  the  same  disease  as  that  in  which  the  organs 
were  sprinkled  with  small  gray  tubercles;  Villemin  proved  it  by  inoculat- 
ing caseous  material  into  animals  and  producing  tubercles,  but  it  was  not 
until  1882  that  R.  Koch  discovered  the  bacillus.  Then,  since  it  was 
shown  to  be  the  common  cause  of  all  the  different  manifestations  of  the 
disease,  there  should  have  been  no  further  dispute  between  the  supporters 
of  the  duality  or  of  the  unity  of  tuberculosis.  Nevertheless,  this  went 
on  for  years.  Koch  made  the  further  discovery  that  a  toxic  material 
which  he  called  tuberculin  could  be  extracted  from  the  bacilli.  For  a 
time  he  maintained  that  this  could  be  used  as  a  curative  or,  at  least,  as  a 
protective  therapeutic  agent  and,  of  course,  the  whole  world  was  stirred 
by  this.  But  it  proved  a  vain  hope,  and  tuberculin  became  known  only 
as  a  material  which  could  be  used  for  diagnosis,  since  it  is  harmless  when 
injected  into  normal  persons,  but  stirs  up  a  febrile  reaction  in  those  already 
infected  with  tuberculosis.  Koch  also  observed  that  injection  of  tuber- 
culin caused  a  flare  up  of  activity  in  the  tuberculous  lesions  already 
present,  and,  what  was  more  important,  that  injection  of  live  bacilli  in 
an  animal  already  tuberculous  had  something  of  the  same  effect.  He  saw 
that  the  course  of  infection  by  these  live  bacilli  themselves  was  quite 
different  in  an  animal  already  tuberculous  from  what  it  would  be  in  an 
animal  which  had  never  been  infected,  but  he  made  no  further  use  of 
this  observation. 

In  1898  Theobald  Smith  proved  that  all  tubercle  bacilli  were  not  alike 
and  that  there  were  easily  recognizable  differences  between  the  bovine 

634 


TUBERCULOSIS  635 

type  obtained  from  the  common  tuberculous  lesions  in  cattle  and  the  human 
type.  Others  later  recognized  avian,  reptilian,  and  even  piscine  types, 
which  are  probably  still  more  remote  from  the  human  type.  The  bovine 
bacillus  is  shorter  and  stouter  than  the  human  form  and  grows  less  easily 
upon  artificial  media.  In  acid  glycerin  bouillon  it  tends  to  produce  an 
alkaline  reaction,  while  the  human  type  only  accentuates  the  acid  reaction. 
But  most  definite  of  all  is  the  far  greater  virulence  of  the  bovine  type,  since 
it  infects  rabbits  easily,  is  rather  often  found  producing  fatal  tuberculosis 
in  man,  and  readily  infects  cattle.  The  human  type,  on  the  contrary, 
while  readily  causing  tuberculous  lesions  in  guinea-pigs  and  man,  will 
hardly  infect  rabbits  and  may  be  injected  with  impunity  into  cattle. 
Indeed,  it  is  used  as  a  harmless  organism  still  possessed  of  the  family 
characteristics  to  immunize  cattle  against  the  bovine  form.  The  tuber- 
culin produced  from  these  two  forms  is  probably  identical.  There  has 
been  some  question  as  to  whether  the  human  type  is  not  merely  an  at- 
tenuated bovine  type  through  long  passage  in  human  beings,  but  all  ob- 
servations and  experiments,  such  as  passage  through  monkeys,  show  that 
this  is  unlikely,  and  that  the  types  maintain  their  identity. 

In  1901  Koch  went  so  far  in  an  address  in  London  as  to  say  that  there 
was  so  little  in  common  between  the  tubercle  bacilli  of  cattle  and  that  of 
man  that  precautions  against  infection  from  milk  might  safely  be  omitted. 
The  weight  of  his  authority  was  so  great  as  to  insure  the  acceptance  of 
any  statement  he  might  make,  and  for  a  second  time  the  whole  world  was 
stirred.  But  since  even  then  fatal  cases  of  human  tuberculosis  due  to 
the  bovine  type  of  bacillus  were  known,  practically  all  other  experienced 
workers,  including  von  Behring  and  Theobald  Smith,  immediately  at- 
tacked and  disproved  Koch's  assertion,  to  avert  the  danger  which  would 
follow  neglect  of  the  measures  then  in  use  to  prevent  the  consumption  of 
infected  milk. 

Distribution  and  Transportation  of  Tubercle  Bacilli. — Nothing  is  known 
as  to  any  life  or  development  of  the  bacilli  apart  from  the  animal  body, 
so  that  as  sources  of  infection  we  must  look  to  infected  animals.  It  is 
true  that  the  tubercle  bacilli  can  remain  alive  for  a  long  time  even  when 
dried  up  in  sputum  or  in  dust,  and  probably  even  longer  when  kept  moist. 
But  exposure  to  bright  sunlight  quickly  kills  them,  whether  moist  or  dried, 
so  that  it  seems  probable  that  street  dust  is  of  little  importance  in  trans- 
mitting the  disease. 

Bacilli  in  this  disease  are  discharged  in  quantities  from  the  bodies  of 
infected  animals  because  they  are  abundant  in  the  softened  material 
set  free  from  ulcerations  in  the  lungs,  intestines,  or  urinary  bladder. 
When  there  are  tuberculous  sinuses  draining  from  some  internal  focus 
the  discharges  from  these  canals  carry  abundant  bacilli.  But  they  are 
also  set  free  with  milk  from  cows  which  have  tuberculosis  of  the  udder. 
Therefore,  not  only  milk  but  butter  and  even  cheese  may  contain  them. 
They  are  expectorated  by  consumptives  in  the  sputum,  but  according  to 


636  TEXT-BOOK    OF    PATHOLOGY 

Fliigge  and  his  students,  they  are  also  sent  forth  suspended  in  a  spray  of 
fine  droplets  with  the  breath  of  such  a  person,  especially  when  he  coughs 
or  sneezes  or  talks  loudly. 

Since  the  organism  is  so  tenacious  of  life  and  so  abundantly  evacuated 
from  the  bodies  of  those  infected,  there  is  small  wonder  that  tuberculosis 
is  so  wide-spread.  It  was  not,  however,  until  recent  years  that  we  had  any 
idea  of  the  extraordinary  prevalence  of  this  infection,  although  the  extent 
to  which  actual  illness  resulted  was  well  enough  known.  This  is  primarily 
because  in  most  people  the  infection  is  quickly  overcome  and  never  pro- 
gresses beyond  the  formation  of  a  tiny  focus  of  destruction  of  tissue  which 
ends  in  a  scar  or  in  a  calcified  nodule  in  a  lymph-gland. 

Two  methods  have  been  employed,  however,  to  discover  how  wide-spread 
infection  has  been:  one,  the  search  for  the  traces  of  tuberculous  lesions  in 
all  bodies  at  autopsy,  the  other,  the  application  of  the  tuberculin  test  to 
large  numbers  of  persons  in  a  community.  The  results  are  astounding, 
for  while  they  agree  almost  precisely,  they  show  that  the  percentage  of 
all  persons  examined  and  found  to  show  evidence  of  having  been  infected 
with  the  bacilli,  increases  from  about  15  in  the  first  decade,  through 
30  to  60  in  the  second,  to  99  in  the  sixth  and  seventh.  Such  are  the  sta- 
tistics of  Nageli,  in  Zurich,  and  Burckhardt,  in  Dresden,  from  autopsy 
material,  while  Nothmann,  in  Dusseldorf,  and  Hamburger  and  Monti,  in 
Vienna,  found  by  the  tuberculin  test  in  children  a  steady  rise  from  the 
second  year  to  90  to  100  per  cent,  in  the  fourteenth  year.  These  figures 
are  from  large  cities  in  the  central  European  countries  where  tuberculosis 
is  notoriously  common,  and  are  taken  from  the  proletariat  of  these  cities, 
in  whom  no  doubt  infection  occurs  more  readily  than  in  the  classes  which 
live  in  a  more  cleanly  way.  Hillenberg  has  shown  that  practically  the 
same  condition  exists  in  the  country  in  Germany,  but  still  it  seems  pos- 
sible that  in  other  less  densely  populated  lands  where  people  are  not  so 
crowded  infection  may  be  less  inevitable. 

Two  things  are  argued  from  this:  first,  that  in  spite  of  almost  universal 
infection,  relatively  few  develop  progressive  tuberculosis,  and  second, 
that  those  who  do  develop  tuberculosis  in  later  life  must  in  many  cases 
have  been  infected  before  as  children. 

Modes  of  Infection.— The  determination  of  the  mode  of  entrance  of 
the  tubercle  bacilli  into  the  body  is  of  prime  importance  and,  of  course, 
every  possibility  has  been  minutely  canvassed.  It  would  seem  that  the 
tubercle  bacillus  which  produces  such  characteristic  lesions  should  leave 
a  plain  trace  behind  it,  and  usually  it  does  so.  Nevertheless  there  is  little 
that  is  certain  in  the  explanation  offered  for  the  commoner  forms  of  in- 
vasion. The  rarer  forms  are  clear  enough — for  example,  when  in  a  ritual 
circumcision,  a  tuberculous  individual  officiating,  applies  his  mouth  to  the 
bleeding  prepuce  of  the  infant,  it  is  easy  to  understand  the  subsequent 
appearance  of  tuberculous  lesions  there  and  in  the  inguinal  glands. 

But  infection  through  the  skin  or  genitalia  is  relatively  unimportant. 


TUBERCULOSIS  637 

It  is  true  that  tubercles  may  form  upon  the  hands  of  pathologists,  butchers, 
and  others  who  expose  their  skin  directly  to  infectious  material,  but  such 
infections  are  usually  self-limited  and  seldom  give  rise  to  pulmonary  or 
other  wide-spread  tuberculosis. 

The  great  portals  of  entry  are  clearly  the  respiratory  and  intestinal 
tracts,  and  a  little  consideration  of  the  distribution  of  the  bacilli  will  con- 
vince one  that  the  common  sources  of  infection  are  to  be  found  in  intimate 
contact  with  consumptives  and  in  the  swallowing  of  infected  milk  and  milk 
products.  All  sources  of  bacilli  other  than  the  exhalations  and  sputum 
of  consumptives  and  the  milk  from  tuberculous  cows  seem  remote  and 
rarely  to  be  regarded  as  important. 

Congenital  transmission  of  the  infection,  it  is  true,  has  been  prominent 
in  the  minds  of  those  who  are  accustomed  to  see  several  cases  of  tuber- 
culosis in  a  family  and  who  look  upon  it  as  an  hereditary  disease,  but  there 
is  little  actual  evidence  to  show  that  it  can  occur.  Congenital  infection 
may  conceivably  be  of  two  sorts — that  in  which  either  the  ovum  or  the 
spermatozoon  is  infected,  or  that  in  which,  in  a  tuberculous  mother,  tuber- 
culous disease  of  the  placenta  forms  the  path  of  transmission  of  the 
bacilli  into  the  body  of  the  foetus.  In  the  first  of  these  it  is  possible  that 
the  bacilli  may  be  merely  carried  along  with  the  sperm.  In  animal 
experiments  with  normal  mothers  and  males  with  infected  seminal  ves- 
icles, vasa  deferentia,  or  testicles,  there  may  be  produced  foetuses  in  which 
bacilli  are  found  without  any  evidence  of  reaction,  or  offspring  with  no 
bacilli  or  ether  sign  of  tuberculosis.  Schmorl  has  found  that  placental 
tuberculosis  is  not  uncommon,  but  that  its  results  are  of  no  great  practical 
importance  in  explaining  the  origin  of  tuberculosis  in  later  life,  since  if 
tuberculosis  does  appear  in  the  suckling  it  is  rapidly  fatal. 

Most  cases  of  tuberculous  infection  are,  therefore,  to  be  regarded  as 
either  due  to  aspiration  or  to  deglutition  of  the  bacilli.  Since  the  demon- 
stration by  Fltigge  of  the  ease  with  which  tubercle  bacilli  are  floated  out 
upon  the  air  in  a  spray  of  droplets  for  at  least  a  metre  from  the  face  of  a 
consumptive,  there  seems  no  difficulty  in  the  way  of  their  inhalation. 
The  same  may  be  said  in  the  case  of  infected  dust  from  dried  sputum 
stirred  up  in  the  house  of  a  consumptive,  or  in  an  institution  where  there 
are  many  tuberculous  inmates,  by  shuffling  feet  or  by  brooms.  Kissing 
of  children  by  consumptives  and  the  transfer  of  moist  sputum  to  the 
mouths  of  infants  who  crawl  on  the  floor  or  sidewalk  must  also  offer  chances 
of  infection.  Having  reached  the  mouth,  nose,  and  pharynx,  the  great 
question  arises  as  to  how  they  are  introduced  into  the  lungs.  The  finding 
of  lesions  in  the  lungs,  which  appear  to  be  the  oldest  and  best  established 
of  all  the  lesions  in  the  body,  leads  at  once  to  the  suggestion  that  the 
bacilli  are  directly  inhaled  or  aspirated  into  the  bronchioles,  where  they 
produce  destructive  changes,  with  a  later  distribution  to  the  lymph- 
glands  at  the  hilum  and  to  other  parts  of  the  lung.  It  would  appear  that 
the  distribution  of  coal  pigment  in  the  lung  must  offer  a  model  upon  which 


638  TEXT-BOOK    OF    PATHOLOGY 

we  could  reconstruct  the  destribution  of  the  bacilli.  This  pigment  un- 
questionably reaches  the  most  distant  parts  of  the  organ,  and  while  part 
of  it  is  wafted  back  by  the  bronchial  epithelium,  much  of  the  rest  is 
lodged  in  phagocytic  cells  as  it  is  carried  back  in  the  lymphatics  through 
the  connective  tissue  toward  the  bronchial  nodes.  It  is  difficult  to  help 
believing  that  it  often  happens  that  tubercle  bacilli  are  carried  in  this  way 
directly  into  the  cavities  of  the  lung,  ebbing  back  in  the  substance  of  the 
tissue  by  way  of  the  lymphatics,  but  lodging  in  various  places  and  producing 
lesions.  Indeed,  Heymann  and  others  have  settled  this  question  conclu- 
sively by  exposing  guinea-pigs  to  inhalation  of  dust  or  spray  laden  with 
tubercle  bacilli,  after  which  the  animals  were  killed  at  short  intervals 
and  the  lungs  examined  in  stained  sections.  Tubercle  bacilli  were  found 
in  the  most  distant  bronchioles  and  alveoli.  This  seems  a  more  accurate 
proof  than  that  afforded  by  the  inoculation  of  portions  of  such  lungs 
into  other  guinea-pigs,  which,  however,  gave  the  same  results. 

It  is  clear,  however,  that  there  are  other  possibilities.  The  study  of 
streptococcal  infections  of  the  lungs  following  measles  showed  me  how 
easily  bacteria  may  be  transmitted  by  the  peribronchial  and  perivascular 
lymphatics  in  any  direction,  so  that  pleura!  infection  as  well  as  infection 
of  the  bronchial  nodes  is  readily  produced.  Injections  of  these  lymph- 
atics show  the  extraordinary  richness  of  the  networks  running  in  the  walls 
of  bronchi  and  vessels  and  in  the  interlobular  septa,  and  a  preparation 
shown  me  recentty  by  Winternitz  demonstrated  particularly  their  net- 
like  arrangement  in  the  trachea  with  broad  anastomoses  with  those  of 
the  bronchi.  It  seems  possible,  therefore,  as  a  second  method  of  infection 
of  the  lung  that  the  bacilli  might  gain  entrance  into  this  network  any- 
where along  the  upper  part  of  the  respiratory  tract  and  extend,  with  the 
aid  of  multiple  thrombosis,  into  the  network  of  the  lung.  A  priori  this 
seems  less  plausible  than  the  first  method,  but  it  is  thought  an  important 
factor  in  pneumonia,  and  its  true  significance  is  yet  to  be  learned. 

The  third  possibility  is  that  the  bacilli  absorbed  into  the  lymphatics 
may  pass  by  way  of  the  subclavian  vein  to  the  heart,  and  thus  with  the 
blood  of  the  pulmonary  artery  to  the  lungs.  While  this  is  easily  con- 
ceivable, it  would  leave  us  with  the  necessity  of  explaining  the  strictly 
local,  beginning  of  most  pulmonary  tuberculosis.  The  rather  frequent 
finding  of  isolated  lesions  of  the  bronchial  walls  affecting  especially  the 
bronchus  which  leads  to  the  apex  of  the  lung,  would  be  hard  to  explain 
upon  this  theory,  and  equally  hard  to  understand  if  we  accept  the  idea  of 
a  distribution  by  way  of  the  very  capable  lymphatic  network. 

In  connection  with  all  these  three  possibilities  search  for  lesions  in  the 
upper  respiratory  tract  indicating  the  path  of  the  bacilli  has,  of  course, 
been  recognized  as  important.  Sinus  infections,  tuberculous  infection  of 
carious  teeth,  tonsillar  tuberculosis,  tuberculosis  of  the  larynx  and  of  the 
trachea,  and  perhaps  especially  the  less  completely  explained  secondary 
steps  shown  in  tuberculosis  of  the  cervical  lymph-glands—all  these  have 


TUBERCULOSIS  639 

been  studied,  but  without  demonstrating,  as  it  seems  to  me,  a  frequency 
of  occurrence  quite  adequate  to  explain  all  the  cases  of  pulmonary  tuber- 
culosis. 

While  keeping  a  perfectly  receptive  attitude  toward  the  proof  for  the 
origin  of  pulmonary  tuberculosis  through  transport  of  the  bacilli  to  the 
lungs  by  way  of  the  lymphatics  or  the  blood-vessels,  I  think  we  must  still 
accept  as  valid  in  most  cases  the  old  explanation  of  the  direct  aspiration 
of  the  bacilli  into  the  bronchioles. 

As  far  as  concerns  the  other  great  portal  of  entry,  the  alimentary  tract, 
there  need  be  little  difficulty  in  accepting  the  possibility  of  the  safe  pas- 
sage through  the  gastric  juice  with  its  disinfecting  hydrochloric  acid,  of 
such  resistant  and  wax-bound  organisms  as  the  tubercle  bacilli.  At 
least  it  appears  that  they  do  reach  the  intestine  in  persons  with  advanced 
pulmonary  tuberculosis  who  must  swallow  much  of  their  sputum.  In 
these  cases,  however,  it  may  well  be  that  temporary  disturbances  of  gas- 
tric secretion  make  the  passage  of  the  bacilli  easy. 

Von  Behring  points  out  the  fact  that  in  the  very  young  infant  the  fer- 
ment-secreting glands  of  the  digestive  tract  are  little  developed  and  the 
epithelial  lining  not  yet  a  serious  obstacle  to  the  passage,  unchanged,  of 
any  foreign  protein.  Antitoxin  can  be  administered  effectively  by  mouth. 
In  these  infants,  therefore,  he  finds  no  great  obstruction  offered  to  the 
rapid  absorption  of  tubercle  bacilli,  which  leave  no  trace  behind. 

Rossle,  Calmette,  Ravenel,  Orth,  and  others  find  a  rapid  general  spread 
of  such  bacteria  throughout  the  body,  lodging  in  lymphoid  tissues  every- 
where, and  sometimes  (Bartel)  producing  no  visible  lesions  whatever. 
All  argue  that  tubercle  bacilli  brought  into  contact  with  any  mucosa  are 
readily  absorbed  without  leaving  a  destructive  lesion  to  mark  the  place 
of  entrance. 

Hence,  the  uncertainty  about  the  mode  of  entrance  of  those  bacilli 
which  ultimately  cause  pulmonary  phthisis.  They  may  be  directly  as- 
pirated into  the  lungs,  so  that,  as  Ghon  maintains,  the  primary  lesion  is 
in  the  lung.  Absorbed  through  the  intestine  in  infancy,  as  Vcn  Behring 
claims,  they  may  give  rise  years  later  to  pulmonary  disease  as  an  autoin- 
fection,  much  as  the  tertiary  lesions  of  syphilis  appear  months  or  years 
after  the  primary  and  secondary  stages.  Or  the  pulmonary  tuberculosis 
may  be  caused  by  a  second  infection,  with  organisms  from  outside  the  body 
acting  upon  tissues  whose  resistance  has  been  changed  by  the  previous 
infection.  It  is  not  possible  to  exclude  any  of  these  conceptions,  and  per- 
haps all  are  true  in  their  turn. 

They  can,  however,  scarcely  be  discussed  until  the  fundamentally  im- 
portant work  of  Romer  is  considered. 

Immunity  and  Hypersensitization. — Koch,  as  stated  above,  had  ob- 
served that  the  progress  of  tuberculous  infection  in  animals  which  had 
suffered  a  previous  infection  was  different  from  that  in  fresh  uninfected 
animals,  but  he  pursued  the  subject  no  further.  Romer  repeated  the 


640  TEXT-BOOK    OF    PATHOLOGY 

experiment,  being  careful  to  measure  the  dosage  of  tubercle  bacilli  pre- 
cisely, and  found  that  the  first  infection  of  a  normal  animal  produces 
tubercles  which,  if  the  dose  is  small  and  the  organism  feebly  virulent,  may 
be  completely  healed,  but  otherwise  may  progress  so  as  to  produce  a  wide- 
spread and  fatal  tuberculosis. 

If  now,  after  the  preliminary  inoculation  has  been  survived  a  long  time, 
fresh,  uninfected  guinea-pigs  and  these  tuberculous  guinea-pigs  be  in- 
oculated, side  by  side,  with  a  constant,  small,  measured  dose  of  virulent 
bovine  tubercle  bacilli  by  injecting  the  bacilli  into  the  skin  itself,  it  is 
found  that  the  normal  guinea-pigs  proceed  to  die  with  extensive  tuberculosis 
of  the  organs  and  with  a  tuberculous  ulcer  at  the  point  of  inoculation, 
while  the  lesions  in  the  organs  of  those  already  tuberculous  are  not  much 
increased,  and  the  point  of  inoculation,  although  for  a  time  intensely 
inflamed  and  necrotic,  heals  up  completely.  It  is  evident  that  the  previous 
infection  affords  a  fairly  satisfactory  protection  against  a  reinfection, 
provided  the  dosage  in  the  second  inoculation  is  not  too  great.  Krause, 
in  repeating  this  work,  has  shown  me  the  contrasting  effects  at  the  points 
of  inoculation  with  the  virulent  bacilli.  In  the  normal  animal  the  reac- 
tion is  slow  and  steadily  progressive  until  an  extensive  ulcer  with  tubercles 
is  formed.  In  the  previously  infected  animal  there  is  a  rapid  appearance 
of  an  area  of  redness  and  swelling,  the  skin  becomes  necrotic  and  drops 
out,  and  the  gap  thus  produced  quickly  heals,  leaving  only  a  thin  scar. 
This  rapid  inflammatory  reaction  with  destruction  of  tissue  indicates  an 
anaphylactic  condition.  It  is  like  the  well-known  tuberculin  reaction, 
and  it  is  immediately  destructive.  A  larger  dose  of  the  virulent  organism 
might  produce  so  intense  a  reaction  as  to  kill  the  animal  after  an  acute 
illness,  although  in  the  normal  animal  it  would  merely  produce  a  more 
extensive,  slowly  progressing  tuberculosis.  This  is,  then,  the  character  of 
hypersensitization  in  the  immunity  produced  by  a  previous  infection. 
It  is  an  altered  attitude  of  the  body  toward  the  new  infection,  the  allergy 
of  Von  Pirquet,  which  brings  with  it  an  altered  reaction  of  the  internal 
organs  to  a  later  dose.  This  phenomenon  has  been  studied  in  various 
internal  organs,  and  although  the  results  are  complex  and  difficult  to  inter- 
pret, they  appear  to  be  fairly  constant. 

Nichols  found  that  normal  animals  upon  subcutaneous  injection  of 
tubercle  bacilli  developed  numerous  tubercles  in  the  lungs,  while  the 
previously  immunized  animals,  after  going  through  an  acute  hsemorrhagic, 
inflammatory  process,  with  tubercle  formation,  survived  for  a  long  time 
with  encapsulated  and  fibroid  caseous  areas  in  the  lungs.  Paterson 
found  that  injection  of  bacilli  into  the  pleura  produced  no  obvious  change 
in  normal  rabbits,  although  the  bacilli  were  quickly  absorbed  and  set  up 
tubercles  in  the  lungs  and  other  organs.  In  immunized  rabbits,  in  con- 
trast with  this,  there  was  an  immediate  outpouring  of  bloody  exudate 
which  filled  the  pleura,  but  healing  processes  followed,  and  these  animals 
survived  the  others  by  a  long  time.  Soper  found  the  same  contrast  in 


TUBERCULOSIS  641 

the  liver.  Injection  of  bacilli  into  the  portal  vein  produces  the  pro- 
gressive tubercles  in  normal  animals;  in  the  sensitized  immune  animal 
the  tubercles  are  formed  more  rapidly,  and  the  lesion  is  apparently  more 
serious,  but  after  two  or  three  weeks  it  begins  to  heal  and  disappear,  so 
that  these  animals  long  survive  the  others. 

Besangon  and  de  Serbonnes  injected  virulent  bacilli  into  the  bronchi 
in  normal  animals  and  in  those  previously  infected,  and  found  that  in  the 
fresh  animals  there  arose  a  caseous  pneumonia  rich  in  bacilli,  while  in  those 
which  had  been  previously  infected  there  was  first  an  extraordinary 
dilatation  of  the  capillaries  with  desquamation  of  the  alveolar  epithelium. 
Later,  there  being  a  few  bacilli  there,  no  caseation  occurred,  but  the  lung 
tissue  became  sclerotic. 

It  is  rather  difficult  to  interpret  this  in  terms  of  what  occurs  in  natural 
infections  and  reinfections.  There  is,  undoubtedly,  a  distinct  immunity 
conferred  which,  even  when  the  bacteria  of  the  first  inoculation  are  still 
producing  lesions  in  the  internal  organs,  prevents  a  progressive  new  in- 
fection in  the  skin.  In  this  respect  it  resembles  the  condition  in  syphilis 
in  which,  so  long  as  the  spirochsetes  are  present,  reinfection  is  difficult. 

In  most  cases  the  early  infection  of  childhood  successfully  protects 
against  the  later  infection,  but  if  the  first  infection  is  too  severe,  it  leads 
to  progressive  tuberculosis  and  death.  Similarly,  if  the  second  infection 
is  too  severe,  the  protection  is  broken  through,  with  the  same  result.  Can 
we  then,  on  this  basis,  decide  whether  the  pulmonary  phthisis  which 
develops  in  adult  life  is  a  late  manifestation  of  the  original  childhood 
infection,  the  effect  of  too  large  a  second  infection  from  outside,  which  is 
accentuated  by  the  phenomena  due  to  the  anaphylactic  hypersensitiza- 
tion,  or,  finally,  the  result  of  a  second  infection  modified  by  the  existing 
immunity,  but  gradually  overcoming  it?  It  is  difficult  to  tell,  but  I,  for 
my  part,  lean  to  the  last  possibility. 

More  work  is  required  in  the  exact  analysis  of  the  lesions  in  pulmonary 
tuberculosis  and  the  determination  of  their  relations  to  these  phases  of 
infection.  It  is  quite  true  that  throughout  the  whole  course  of  chronic 
tuberculosis  of  the  lungs  there  are  evidences  of  great  powers  of  resistance. 
Usually  the  tracheal  and  laryngeal  mucosa,  which  are  constantly  covered 
with  tubercle  bacilli,  show  no  lesions,  although  in  a  normal  person  such 
exposure  would,  it  seems,  surely  infect  them. 

Should  we  then  attempt  to  prevent  the  early  infection  which  is  so  com- 
mon in  childhood  and  thus  sacrifice  its  protective  effect  throughout  life, 
should  we  merely  try  to  limit  it  to  a  small  dose,  or  should  we  deliberately 
inoculate  the  children  with  non-virulent  bacilli?  The  problem  is  an  open 

one. 

Susceptibility. — Much  has  been  said  as  to  individual  predisposition  to 
tuberculosis,  and  there  is  an  impression  in  the  minds  of  most  people  that 
even  though  actual  cases  of  the  inheritance  of  tuberculosis  cannot  be  dis- 
covered, there  is  inherited  a  weakened  constitution  which  makes  the  off- 
42 


642  TEXT-BOOK    OF    PATHOLOGY 

spring  of  tuberculous  parents  especially  susceptible  to  the  disease.  While 
this  idea  is  rather  vague,  it  can  be  shown  that  certain  deformities  of  the 
thorax  which  lead  to  narrowing  of  its  upper  portion  favor  the  development 
of  apical  tuberculous  disease.  Ill  development  of  the  circulatory  organs 
and  of  the  respiratory  musculature  may  also  play  a  part.  Indeed,  there  is 
a  recognizable  phthisical  habitus  which  may  finally  be  seen  in  actual 
consumptives,  but  whether  this  is  a  forerunner  of  future  tuberculosis  or 
the  effect  of  its  unobserved  existence  it  is  difficult  to  say. 

Practically  very  important  is  the  predisposition  to  tuberculous  infec- 
tion produced  by  traumatism,  as  seen  especially  in  the  case  of  the  bones 
and  joints,  but  also  in  some  other  situations  in  the  body.  This  may  be 
regarded  as  due  to  the  establishment  of  a  point  of  lowered  resistance,  where 
the  bacilli  easily  gain  a  foothold.  Something  similar  is  doubtless  true  of 
the  predisposing  effects  of  an  attack  of  measles  or  other  infectious  disease. 
Indeed,  measles  is  reckoned  as  a  very  serious  affection,  largely  on  account 
of  the  frequency  with  which  it  is  followed  by  tuberculosis.  Pregnancy, 
diabetes  mellitus,  and  other  conditions  affecting  the  whole  body  predis- 
pose in  some  more  general  way,  and  it  is  known  that  tuberculosis  arising 
in  the  course  of  diabetes  is  usually  very  intense  and  rapidly  destructive. 

LITERATURE 

Romer  and  Joseph:  Brauer's  Beitr.  zur  Klinik  der  Tuberkulose,  1910,  xvii;  281-427. 
Koch:  Mitth.  a.  d.  kais.  Gesundheitsamte,  1884,  ii.  i.    Berkl.  klin.  Woch.,  1882,  xix,  221. 
Smith,  Th.:  Jour.  Exp.  Med.,  1898,  iii,  451.     Jour.  Med.  Research,   1905,   xiii,  253; 

1907,  xvi,  435.     Trans.  Massachusetts  Med.  Soc..  1907.     Harvey  Soc.,  1906. 
von  Behring:  Deutsch.  Med.  Woch.,  1903,  xxix,  689. 
Bezangon  et  Serbonnes:  Annales  de  Medicine,  1914,  149. 
Nichols:  Med.  News,  1905,  Ixxxvii,  638. 
Paterson:  Amer.  Rev.  of  Tuberculosis,  1917,  i,  353. 
Soper:  Ibid.,  385. 
Krause:  Ibid.,  1919,  iii,  1. 
Ghon  and  Roman:    Sitzb.  d.  k.  Akad.  d.  Wiss.  in  Wien,  Math,  naturw.  Kl.,  1913, 

cxxii,  1. 

Orth:  Sitzb.  d.  k.  Preuss.  Adad.  d.  Wiss.,  1913,  iii,  51. 
Trudeau:  New  York  Med.  Jour.,  1903,  Ixxviii,  105. 
Fliigge:  XIV  Hygien.  Kongr.,  1907,  ii,  42. 
Baldwin:  Harvey  Lectures,  1914-15,  Series  X,  154. 
Heymann:  Ztschr.  f.  Hygiene  u.  Infectionskr.,  1908,  lx,  490. 

Effects  of  the  Tubercle  Bacillus  on  the  Tissues. — The  lesions  produced 
by  the  tubercle  bacillus  are,  in  their  ultimate  analysis,  essentially  like 
those  found  in  any  acute  and  chronic  inflammation,  but  the  proliferative 
changes  are  so  marked  and  come  so  quickly  as  to  give  a  quite  foreign  air 
to  them.  Then,  too,  they  have  in  common  the  peculiarity  that  wherever 
the  bacteria  are  present  in  sufficient  number  with  their  poisons,  the  whole 
area  dies  and  becomes  coagulated. 

Tubercles. — Most  commonly  on  reaching  the  tissue  the  bacilli  produce 


TUBERCULOSIS 


643 


minute,  translucent,  grayish  nodules,  which,  from  being  supposed  to  be 
of  about  the  size  of  millet-seeds,  were  called  miliary  tubercles  (Fig.  307). 
We  now  know,  however,  that  those  were  really  little  groups  of  tubercles, 
and  that  a  single  tubercle  is  a  great  deal  smaller  and  scarcely  visible  to 


Fig.  307. — Acute  miliary  tuberculosis.     Small  tubercles  scattered  through  the  lung. 
There  is  an  old  caseous  mass  near  the  apex. 

the  naked  eye.  The  tendency  to  grouping  and  coalescence  is  very  strong, 
and  such  a  mass,  instead  of  being  round,  is  really  lobulated  or  mulberry 
shaped.  While  the  tubercles  are  very  fresh  and  young  they  remain  trans- 
lucent, but  very  soon  they  show  a  spot  of  yellowish  opacity  in  the  centre. 


644 


TEXT-BOOK   OF   PATHOLOGY 


Microscopically,  a  fresh  tubercle  is  a  roughly  concentric  mass  of  cells, 
pretty  sharply  marked  off  from  the  surrounding  tissue  (Fig.  308).  These 
cells,  clustered  around  a  central  area,  are  sometimes  arranged  in  laminae, 
but  are  usually  attached  to  one  another  in  less  orderly  fashion  to  form 
a  pale  staining  tissue.  They  have  elongated  vesicular  nuclei,  with  little 
chromatin  and  a  faintly  outlined  cell-body,  which  is  irregular  in  form  and 
branches  to  connect  itself  with  its  neighbors.  These  are  the  cells  com- 
monly known  as  epithelioid  cells,  which  form  the  most  constant  feature 


Fig.  308. — A  single  tubercle,  rather  sharply  outlined  with  a  giant-cell  sending  proto- 
plasmic processes  among  the  epithelioid  cells. 

of  the  tubercle.  Often,  but  not  always,  the  central  part  of  the  mass  is 
occupied  by  a  giant-cell,  a  large  mass  of  protoplasm  containing  a  great 
number  of  nuclei  which  are  usually  arranged  around  its  periphery  or  at 
the  opposite  poles  (Figs.  308  and  309). 

This  protoplasmic  mass  also  gives  off  processes  which  ramify  among 
those  of  the  epithelioid  cells.  In  the  marginal  portion  of  the  tubercle  one 
usually  finds  numbers  of  mononuclear  wandering  cells  of  the  lymphoid 
type.  The  whole  is  supported  by  a  newly  formed  framework  or  reticulum, 


TUBERCULOSIS 


645 


which  can  be  demonstrated  by  digesting  away  the  cells.     Usually,  too, 
there  can  be  shown  to  exist  a  delicate  network  of  fibrin. 

Tubercle  bacilli  may  be  found  in  the  body  of  the  giant-cell  or  lying  in 
crevices  between  the  epithelioid  cells.  But  there  is  absolutely  no  pro- 
vision for  a  blood-supply  in  such  nodules,  and  those  capillaries  which  were 
present  at  that  point  before  are  found  to  be  obliterated,  so  that  if  an  organ 


Fig.  309. — A  single  tubercle  showing  rather  irregularly  arranged  epithelioid  cells, 
a  large  giant-cell,  and  the  peripheral  lymphoid  cells.  The  drawing  shows  also  the  re- 
ticulum  of  the  tubercle. 

studded  with  tubercles  be  injected  through  the  artery  with  blue  gelatin, 
each  tubercle  will  stand  out  as  a  white  nodule  against  the  blue  background; 
This  circumstance  may  aid  in  bringing  about  the  necrosis  of  the  nodules, 
although  they  are  so  small  that  they  might  absorb  enough  nourishment 
from  the  surrounding  fluids.  More  important  is  the  action  of  the  poison 
produced  by  the  bacilli  which  first  causes  degeneration,  and  finally  death 
of  the  cells.  The  epithelioid  cells  become  distorted,  their  nuclei  elongated 
and  twisted,  so  that  they  lie  radially  and  for  a  time  take  a  deep  stain  (Fig. 


646 


TEXT-BOOK   OF    PATHOLOGY 


311).  Then,  beginning  sometimes  in  the  giant-cell  and  involving  the  whole 
centre  of  the  nodule,  there  occurs  a  complete  disintegration  of  the  cells, 
which  melt  together  into  a  formless  hyaline  mass. 

There  has  been  much  dispute  over  the  origin  of  the  cells  which  consti- 
tute the  tubercle.  Baumgarten  has  always  maintained  that  the  epi- 
thelioid  cells  are  derived  from  the  fixed  tissue,  possibly  the  endothelial 
cells,  while  certain  French  authors  have  regarded  them  as  wandering  cells. 
It  was  shown  by  Wechsberg  and  others  that  the  first  effect  of  the  lodgment 
of  the  bacilli  is  the  destruction  of  a  few  adjacent  cells,  responded  to  by 
an  inwandering  of  polymorphonuclear  leucocytes,  but  that  this  process  is 


Fig.  310.-  Conglomerated  tubercles  composed  chiefly  of  epithelioid  cells. 

soon  masked  by  the  development  of  the  epithelioid  cells.  The  matter  is 
still  under  discussion,  and  Wallgren,  in  his  detailed  studies  of  the  early 
development  of  tubercles  in  the  liver,  lays  stress  on  the  participation  of 
lymphoid  cells  and  polyblasts,  finding  that  the  fibroblasts  play  a  secondary 
and  protective  role.  He  recognizes  an  occasional  proliferation  of  the  endo- 
thelium  of  the  capillaries.  Similarly,  v.  Fieandt,  in  studying  meningeal 
and  cerebral  tubercles,  finds  a  primary  invasion  of  leucocytes  and  later 
a  secondary  invasion  when  they  are  attracted  by  the  dead  tissue.  The 


TUBERCULOSIS 


647 


part  played  by  the  polyblasts  or  large  mononuclear  wandering  cells  is 
specially  important,  the  plasma  and  lymphoid  cells  occupying  a  second 
place.  It  is  much  later — one  to  two  weeks  after  the  infection — that 
the  fibroblasts  proliferate,  but  then  they  play  the  same  part  as  the  poly- 
blasts,  forming  epithelioid  and  giant-cells.  More  recently  Evans,  Bow- 
man, and  Winternitz  have  studied  the  formation  of  tubercles  in  the 
liver,  after  the  injection  of  the  bacilli  into  the  portal  vein,  in  animals  in 
which  the  so-called  Kupffer's  cells  of  the  capillary  endothelium  are  stained 


Fig.  311. — Rather  older  tubercles  with  beginning  central  degeneration  and  radial  ar- 
rangement of  the  epithelioid  cells. 

blue  by  the  administration  of  a  vital  stain.  They  find  that  the  part  played 
by  the  leucocytes  is  transitory,  and  that  the  giant-cells  are  clearly  de- 
rived from  the  Kupffer's  cells,  which  take  up  the  bacilli,  and  become 
greatly  enlarged,  the  nucleus  dividing  by  mitosis,  although  the  cyto- 
plasm remains  unaltered.  The  epithelioid  cells  arise  also,  they  think, 
from  endothelial  cells. 

Even  yet,  however,  it  cannot  be  regarded  as  entirely  settled,  since  this 
rather  convincing  demonstration  of  the  part  played  by  the  Kupffer's 
cells  is  hardly  applicable  to  all  the  other  tissues  where  there  are  no  cells 


648  TEXT-BOOK    OF    PATHOLOGY 

of  this  sort,  but  only  the  ordinary  endothelial  cells.  In  the  fully  formed 
tubercle  the  character  of  the  mass,  as  a  coherent  tissue  with  the  produc- 
tion of  a  reticulum,  strongly  suggests  the  participation  of  fibroblasts. 
But  in  other  cases  the  tubercle  may  be  a  more  atypical  mass  of  rounded 
and  evidently  independent  cells,  which  are  probably  wandering  cells. 

The  formation  of  the  giant-cell  has  always  offered  difficulties,  and  two 
main  ideas  have  been  put  forward  to  explain  it.  The  nucleus  of  the  cell 
may  divide  without  the  division  of  the  cell  body,  or  the  multinucleated 
cell  may  arise  from  the  fusion  of  several  smaller  cells.  Mitoses  have  rarely 
been  seen,  and  an  amitotic  division  of  the  nucleus  has  been  suggested. 
Coalescence  of  several  cells  is  thought  possible  even  by  those  who  have 
found  mitoses  in  the  Kupffer  cells,  and  was  definitely  shown  to  occur  in  the 
formation  of  foreign  body  giant-cells  in  vitro  by  Lambert.  All  are  agreed 
that  the  lymphoid  cells  are  wandering  cells  which  have  been  attracted  to 
the  tubercle. 

As  has  been  said,  there  is  a  great  tendency  toward  coalescence  in  these 


Fig.  312. — Large  tubercles  in  the  spleen. 

tubercles,  and  caseation  or  the  production  of  a  cheese-like,  necrotic  sub- 
stance usually  takes  place  in  the  whole  central  part  of  such  a  mulberry-like 
mass.  It  follows  that  the  opaque  white  material  is  left,  surrounded  by  a 
scalloped  margin  composed  of  the  remnants  of  the  outermost  tubercles. 
Tumor-like  masses  of  cheesy  material  as  large  as  a  walnut  are  sometimes 
formed  in  this  way,  especially  in  the  spleen  or  in  the  brain  (solitary  tuber- 
cles) (Fig.  312). 

The  coagulative  necrosis  produces  at  first  a  fairly  firm  material,  in  which 
all  cell  outlines  and  nuclear  staining  are  lost.  This  may  be  softened  later, 
often  because  of  a  secondary  infection,  or  in  other  instances  it  may  be  con- 
verted into  a  mortar-like  material  or  even  a  stony  block  by  the  deppsit  of 
calcium  salts.  Healing  may  occur  in  every  sort  of  tubercle — in  the  large 
caseous  ones  by  inspissation  of  the  necrotic  material  and  the  formation  of  a 
dense  surrounding  capsule,  while  the  fresh,  translucent  miliary  tubercles  at 
times  are  changed  into  hyaline  fibrous  nodules.  It  is  cheering  evidence  of 
the  great  powers  of  resistance  possessed  by  most  individuals  when  it  is 


TUBERCULOSIS 


649 


found,  as  Naegeli  and  others  have  shown,  that  nearly  all  adults  harbor 
somewhere  a  healed  tuberculous  lesion. 

LITERATURE 

Baumgarten:  Ueber  Tuberkel  und  Tuberkulose,  Berlin,  1885. 
Wechsberg:  Ziegler's  Beitr.,  1901,  xxix,  203. 
Wallgren:  Arb.  a.  d.  path.  Inst.,  Helsingfors,  1911,  iii,  139. 
Evans,  Bowman,  and  Winternitz:  Jour.  Exp.  Med.,  1914,  xix,  283. 
Miller:  Jour.  Pathology  and  Bacteriology,  1904,  x,  1. 

Tuberculous  Granulation  Tissue. — Tuberculous  lesions  are  by  no  means 
exclusively  tubercles.  There  may  be  formed,  especially  on  a  free  surface, 
abundant  highly  vascular 
granulation  tissue,  which 
is  in  most  places  quite  like 
ordinary  granulation  tis- 
sue, -except  in  that  it  is 
perhaps  more  thickly  in- 
filtrated with  large  and 
small  mononuclear  wan- 
dering cells  and  contains 
fewer  polymorphonuclear 
leucocytes.  It  is  produced 
as  a  reaction  to  the  pres- 
ence of  numerous  tubercle 
bacilli,  and  is  especially 
distinguished  by  its  con- 
tent of  scattered  epithe- 
lioid  cells  and  giant-cells, 
or  even  well-formed  tu- 
bercles (Fig.  313).  Further, 
however,  it  is  character- 
ized by  its  strong  tendency 
to  undergo,  despite  its  rich 
vascular  supply,  coagu- 
lative  necrosis  or  casea- 

tion.  When,  as  is  so  common,  it  replaces  the  ulcerated  mucosa  in  lining 
a  canal,  the  caseous  material  produced  by  the  necrosis  of  its  superficial 
layers  is  often  sufficient  to  choke  the  canal. 

The  tuberculous  granulation  tissue  may,  however,  escape  this  fate  in 
part,  in  persons  whose  resistance  is  high,  and  then  contracts  to  form  a 
dense  fibrous  layer  upon  which  new  granulations  form.  Sometimes  the 
healing  is  complete  and  nothing  remains  but  a  scar  or  dense  fibrous  ad- 
hesions. An  example  of  this  is  great  thickening  of  the  capsule  of  the  liver 
and  spleen,  regarded  by  many  as  the  remains  of  an  old  tuberculous  process. 

The  formation  of  tuberculous  granulation  tissue  is  most  commonly  the 


Fig.  313. — Tuberculous  granulation  tissue. 


650  TEXT-BOOK    OF    PATHOLOGY 

sequel  to  an  outpouring  of  inflammatory  exudate  due  to  the  tubercle  bacilli, 
and  in  this  respect  it  once  more  resembles  closely  the  analogous  tissue 
found  after  other  inflammatory  processes. 

Acute  Tuberculous  Inflammation. — The  occurrence  of  an  acute  inflam- 
matory reaction  caused  by  the  tubercle  bacillus,  and  resembling  rather 
closely  that  which  follows  the  invasion  of  other  organisms,  has  always 
roused  the  interest  of  pathologists.  It  is  a  process  so  different  from  that 
found  in  the  formation  of  tubercles  that  there  is  little  that  is  surprising 
in  the  confusion  which  prevailed  as  to  its  nature  before  the  discovery  of 
the  bacillus.  However,  the  dispute  as  to  the  duality  of  tuberculosis 
was  concerned  rather  with  the  contrast  between  all  extensive  caseous 
lesions  and  the  small  gray  tubercles. 

Even  now  it  is  not  clearly  known  why  there  should  be  in  some  cases  an 
acute  inflammatory  reaction,  in  others  the  ,  formation  of  tubercles.  It 
seems  simple  enough  to  say  that  when  few  and  scattered  bacilli  reach  the 
tissues  and  find  them  resistant  they  produce  at  most  tubercles,  while 
when  great  numbers  of  virulent  bacilli  are  introduced  into  less  resistant 
individuals  they  produce  an  acute  inflammation.  But  this  is  not  all 
true,  for  it  is  claimed  that  even  large  quantities  of  virulent  bacilli  when 
introduced  subcutaneously  or  intravenously  or  intraperitoneally  into 
fresh  normal  animals  produce  only  tubercles,  while  if  they  are  in- 
jected into  previously  infected  animals  which  have  resisted  the  former 
infection  and  acquired  immunity  and  hypersensitization  as  well,  they 
rapidly  produce  a  violent  hsemorrhagic  inflammation,  but  are  ultimately 
resisted  and  overcome.  When  introduced  into  the  lungs,  however,  by  way 
of  the  trachea  it  is  the  normal  animal  which  acquires  a  caseating  pneumo- 
nia, while  the  immunized  one  goes  through  a  stage  of  great  hyperaemia,  but 
finally  overcomes  the  bacteria  and  recovers  with  some  scarring  of  the  lung. 

It  may  be  said  that  practically  all  of  the  acute  tuberculous  inflam- 
mations occuring  spontaneously  are  in  individuals  who  have  for  some  time 
had  an  old'  focus  of  disease,  and  may  therefore  be  thought  of  as  hyper- 
sensitive and  immunized.  Reinfection  in  such  cases  should,  according  to 
the  animal  experiments,  produce  only  a  temporary  reaction  with  favorable 
outcome  and  prompt  limitation  of  the  multiplication  of  the  bacilli,  but 
the  reverse  is  the  case  when  large  quantities  of  bacilli  escape  from  an  old 
lesion  to  be  distributed  into  other  parts  of  the  lung.  The  bacilli  multiply 
rapidly  and  the  tissue  is  not  only  inflamed,  but  becomes  necrotic.  Re- 
covery is  exceptional  and  the  outcome  most  unfavorable.  It  appears 
that  the  size  of  the  dose  of  bacilli  is  most  important  in  determining  the 
nature  of  the  reaction,  and  that  when  an  acute  inflammatory  exudate  ap- 
pears in  response  to  their  introduction  it  is  because  they  are  so  numerous 
and  so  virulent  that  whatever  protective  immunity  has  been  developed 
is  completely  overwhelmed  and  tends  only  to  add  its  anaphylactic  reac- 
tion at  the  beginning.  The  whole  question  demands  much  further  quanti- 
tative study. 


TUBERCULOSIS  651 

The  acute  tuberculous  inflammation  proceeds  as  follows: 
An  exudate  of  fluid  and  wandering  cells  with  subsequent  coagulation 
of  fibrin  comes  from  the  widened  blood-vessels,  and  in  the  fresher  stages 
it  may  be  difficult  to  distinguish  such  an  exudate  as  clearly  tuberculous. 
There  are  several  peculiarities  about  it,  however,  which  make  the  diagnosis 
fairly  easy  after  the  condition  is  well  established.  Polymorphonuclear 
leucocytes  seem  to  be  very  little  attracted  to  a  tuberculous  infection,  and 


**%* 


Fig.  314. — Edge  of  a  fresh  area  of  caseous  and  gelatinous  pneumonia.     Note  the  numer- 
ous large  cells  in  the  less  affected  alveoli. 

their  place  is  taken  by  lymphoid  cells  and  larger  mononuclear  wandering 
cells.  Haemorrhage  is  sometimes  a  striking  feature,  together  with  the  des- 
quamation  of  the  lining  cells  of  the  cavity  in  which  the  process  occurs.  Of 
course,  the  appearance  of  characteristic  tuberculous  granulation  tissue  and 
tubercles  in  the  attempt  to  organize  such  an  exudate  makes  its  nature  clear 
at  once.  In  all  cases  the  extreme  liability  of  exudate  and  included  tissue  to 
become  caseous,  and  finally  liquefied,  marks  out  such  acute  tuberculous  in- 


652  TEXT-BOOK   OF   PATHOLOGY 

flammations  from  the  other  forms  (Fig.  314).  The  most  brilliant  examples 
are  seen  in  the  lungs,  the  serous  cavities  of  the  body,  and  in  the  meninges, 
probably  because  in  those  situations  a  great  number  of  bacilli  can  be  read- 
ily brought  into  contact  with  the  tissues. 

While  these  are  the  typical  effects  of  the  tubercle  bacillus,  they  must  not 
be  regarded  as  totally  distinct  reactions,  but  only  as  the  appropriate  reac- 
tions to  the  different  degrees  of  intensity  with  which  the  bacilli  affect  the 
tissues.  If  the  person  lives  and  acquires  a  little  more  resistance,  the  acute 
inflammatory  lesion  is  soon  surrounded  by  tubercles  and  tuberculous  granu- 
lation tissue  which  appear  in  its  marginal  portions  and  represent  an  ineffec- 
tual attempt  at  healing.  In  every  case  the  tubercles  and  tuberculous  gran- 
ulation tissue  develop  as  the  effect  of  an  initial  injury  and  acute  reactive 
inflammation  which  may  be  inconspicuous. 

Distribution  of  Bacilli  in  the  Body. — Having  once  entered  the  body, 
the  bacilli  may  be  transported  by  at  least  four  methods — (1)  mechanically 
along  with  air,  food,  secretions,  etc.;  (2)  by  growth  through  the  tissues 
with  the  production  of  lesions;  (3)  by  way  of  the  lymphatic  channels; 
(4)  by  way  of  the  blood-stream. 

The  first  of  these  is  most  important  in  the  respiratory  organs,  where 
bacilli  breathed  in  may  lodge  in  the  tissues  or  be  wafted  back  again  by  the 
ciliated  epithelium.  Later,  when  lesions  are  established  in  the  lungs, 
bacillus-holding  fluid  from  a  diseased  area  may  be  poured  out  into  the 
bronchus  and  aspirated  back  into  another,  or  it  may  pass  out  over  the 
laryngeal  mucosa.  In  either  case  new  lesions  can  be  produced  in  this  way. 
So,  also,  in  the  digestive  tract,  the  large  serous  cavities,  the  urinary  organs, 
etc.,  the  organisms  are  moved  about  by  the  contents  of  these  cavities 
under  the  influence  of  gravity,  secretory  streams,  and  muscular  activity. 
In  the  second  case  the  movement  of  the  bacilli  is  largely  commensurate 
with  the  formation  of  lesions,  with  the  gradual  involvement  of  new  tissue, 
and  the  caseation  of  that  previously  affected.  The  third  method  is  often 
dependent  upon  this,  since  the  lymphatic  channels  may  be  invaded  by  the 
spreading,  caseating  new  tissue,  but,  quite  aside  from  this,  the  bacilli  may 
be  carried  into  terminal  lymphatics  and  swept  along  with  the  stream  until 
they  lodge  somewhere — usually  in  the  next  lymph-node.  Extension  of 
a  caseous  tuberculous  focus  so  as  to  erode  through  the  wall  of  a  blood- 
vessel is  the  usual  basis  of  the  fourth  mode  of  transport  (Fig.  315).  It  is 
true  that  actual  tuberculous  lesions  are  sometimes  formed  inside  the 
vessels,  but  this  is  rare,  while  the  extension  of  a  caseating  process  through 
the  wall  of  a  vein  or  artery,  so  that  the  bacilli  are  shed  into  the  passing 
stream,  is  extremely  common.  Great  numbers  of  the  organisms  can  in 
this  way  be  suddenly  thrown  into  the  circulating  blood  before  the  exposed 
caseous  material  becomes  covered  with  a  protecting  thrombus.  It  must  be 
remembered  that  infusion  of  bacilli — (1)  into  the  systemic  veins,  brings 
them  by  way  of  the  right  heart  to  the  lungs;  (2)  into  the  pulmonary  veins, 
distributes  them  into  the  whole  systemic  arterial  circulation,  while  (3)  the 


TUBERCULOSIS  653 

invasion  of  an  artery  causes  a  distribution  only  in  the  field  to  which  it  sup- 
plies blood.  Less  local  in  its  effects  is  the  entrance  of  bacilli  into  the 
thoracic  duct,  for  that  empties  into  the  subclavian  vein,  and  the  result  is 
the  same  as  in  the  case  of  any  systemic  vein.  The  bacilli  are  very  minute, 
however,  and  in  any  case  they  should  theoretically  be  able  to  pass  the 
capillaries  and  quickly  infect  any  tissue  supplied  with  blood-vessels. 
It  happens,  however,  that  these  bacilli  are  quickly  caught  in  such  a  passage 
through  capillaries,  so  that  an  organ  through  which  the  blood  passes  acts 
as  a  very  good  sieve. 


?X«SF. 


Fig.  315. — Caseous  tubercle  developed  in  the  wall  of  the  pulmonary  vein,  and  separated 
from  the  blood  by  a  partly  organized  thrombus. 

In  spite  of  the  existence  of  so  many  ways  by  which  the  bacilli  may  be 
carried  from  one  part  of  the  body  to  another,  tuberculous  infection  is  gen- 
erally a  rather  localized  process,  if  we  count  all  cases  in  which  the  organism 
gains  a  foothold  in  the  tissues.  This  is  due  to  the  great  power  of  anni- 
hilating these  bacteria  possessed  by  most  persons,  so  that  in  the  end  even 
when  they  have  produced  distinct  lesions  they  are  killed  and  nothing  but 
a  scar  remains  to  show  where  they  have  been.  Still  it  is  clear  that  when 


1 654  TEXT-BOOK   OF    PATHOLOGY 

there  is  an  active  focus  of  disease  they  get  into  the  blood  in  small  numbers 
and  are  either  killed  or  produce  minute  local  lesions  in  other  organs.  The 
different  size  and  different  degree  of  progression  of  these  tubercles  toward 
caseation  or  healing  show  that  the  bacilli  have  entered  the  circulation  a  few 
at  a  time,  sometimes  at  long  intervals.  Disturbances  of  organic  function 
can  scarcely  be  expected  from  such  scattered  nodules.  Other  organisms 
behave  in  the  same  way,  and  we  are  just  becoming  familiar  with  the 
effects  of  occasional  intermittent  escape  of  such  bacteria  as  the  streptococci 
and  staphylococci  into  the  blood-stream.  With  them  we  have  been  more 
accustomed  to  observe  the  sudden  pouring  into  the  circulation  of  great 
numbers  of  cocci,  which  in  the  form  of  an  acute  septicaemia  cause  the  most 
profound  intoxication  and  set  up  destructive  processes  everywhere.  This 
happens  with  the  tubercle  bacillus  also,  and  not  only  is  the  mechanism  by 
which  it  reaches  the  blood-stream  far  more  distinct  than  is  usual  in  the  case 
of  the  pyogenic  cocci,  but  practically  all  the  bacilli  can  be  traced  by  the 
conspicuous  nature  of  the  reaction  they  stir  up  wherever  they  lodge.  This, 
which  is  really  an  acute  tuberculous  septicaemia,  is  called,  from  its  ana- 
tomical results,  acute  miliary  tuberculosis. 

Acute  Miliary  Tuberculosis. — The  sudden  introduction  of  thousands  of  bacilli  into 
the  circulating  blood  produces  thousands  of  minute  tubercle  nodules,  all  of  the  same  age. 
There  is  no  reason  why  several  such  crops  should  not  be  produced,  and  occasionally  one 
may  distinguish  such  differences  in  size  and  age  among  the  tubercles  as  to  be  able  to 
conclude  that  several  distinct  immigrations  of  the  bacilli  have  occurred.  Usually, 
however,  the  occurrence  of  one  extensive  outbreak  is  enough  to  kill  the  person. 

With  sufficient  diligence  hi  the  use  of  scissors  in  following  the  blood-vessels  it  is  nearly 
always  possible  to  find  the  hole  through  which  the  bacilli  were  discharged  into  the 
blood,  and  Weigert,  Sigg,  Schmorl,  and  others  have  gradually  approached  100  per 
cent.  The  relative  number  and  size  of  tubercles  in  the  lungs  and  systemic  circula- 
tion may  give  some  clue  to  aid  in  this  search.  It  is  perhaps  most  usual  to  find  the 
portal  of  entry  in  a  branch  of  the  pulmonary  vein,  but  if  this  fail,  the  systemic  veins 
and  the  thoracic  duct  must  be  surveyed.  It  is,  of  course,  more  likely  that  those 
veins  which  run  through  or  near  an  extensive  caseous  area  should  be  involved,  and 
it  proves  especially  common  to  find  that  a  caseous  lymph-gland  attached  by  adhesions 
to  the  vein- wall  is  the  source  of  the  material.  When  the  vein  is  laid  open  in  the 
right  place,  it  is  found  to  be  partly  obstructed  by  a  granular,  cheesy  mass,  projecting 
into  its  lumen  in  such  a  way  that  the  soft,  bacillus-laden  material  is  washed  by  the 
passing  stream  into  the  general  current,  or  else  there  is  a  hole  in  the  wall  opening  into  a 
cavity  in  an  adherent  caseous  tissue  from  which  bacilli  are  swept  by  an  eddy  of  the 
stream  out  into  the  vessel.  The  discharge  of  bacilli  in  either  case  is  soon  limited  by 
the  deposit  of  a  protective  covering  of  thrombus  material  on  the  exposed  surface. 

Of  course,  it  must  not  be  forgotten  that,  as  Benda*  and  others  point  out,  the  dis- 
tributing tuberculous  lesion  may  be  formed  on  the  endothelial  lining  of  the  vessel  (or 
even  through  the  entrance  of  bacilli  into  the  vasa  vasorum),  and  set  free  new  and 
abundant  bacilli  only  when  it  has  become  caseous.  This  is  specially  true  of  the  thoracic 
duct,  which  receives  bacilli  through  its  branches  and  comes  in  time  to  be  lined  with 
caseous,  ulcerating  areas  from  which  newly  grown  bacilli  are  poured  off  into  the  blood. 
Rarely  one  may  find  tuberculous  caseous  lesions  in  the  heart  discharging  bacilli  into  the 

*  Benda:  Ergebn.  d.  allg.  Path.,  1900,  v,  447.     Cornet,  Nothnagel:  Spec.  Path.  u. 
Therap.,  1900,  xiv. 


TUBERCULOSIS 


655 


blood.  Intimal  tubercles  and  erosions  in  the  aorta  and  smaller  arteries  are  uncommon, 
and  distribute  their  bacilli  into  a  limited  area  only. 

The  tubercles  which  are  formed  by  this  wholesale  distribution  may  appear  practically 
anywhere.  They  are  sprinkled  over  the  serous  surfaces,  where  they  are  conspicuous 
and  are  scattered  profusely  in  such  organs  as  the  spleen,  liver,  and  lungs,  where  they 
are  often  easier  to  feel  than  to  see.  They  are  beautifully  seen  with  the  ophthalmo- 
scope in  .the  choroid  of  the  living  patient.  Some  tissues,  such  as  those  of  the  pancreas, 
thyroid,  muscle,  skin,  etc.,  seem  very  little  prone  to  develop  tubercles,  but  even  here 
they  are  found  at  times. 

The  profound  intoxication,  like  that  of  typhoid  fever,  is  doubtless  due  to  the  sudden 
exposure  of  so  many  bacilli  through  the  body,  so  that  they  multiply  and  produce  and 
disseminate  their  poisons.     No  doubt  in  advanced  phthisis  there  may  be  in  the  lung 
just  as  many  bacilli  and  even  more  caseous 
tissue,  but  there  the  process  is  localized  and 
the  caseous  substance  is  characteristically 
withdrawn  from  relations  with  the  blood- 
vessels, so  that,  in  a  sense,  the  poison  is 
imprisoned. 

The  fact  that,  apart  from  the  acute 
miliary  form,  tuberculosis  is  com- 
monly a  localized  affection,  makes  it 
possible  to  refer  to  the  lesions  pro- 
duced according  to  their  situation.  It 
will  be  seen,  however,  that,  regard- 
less of  the  organ  involved,  the  same 
general  characters  are  maintained. 

Tuberculosis  of  the  Upper  Respiratory 
Tract. — The  mucosa  of  the  nose  and  phar- 
ynx may  become  infected  by  the  breathing- 
in  of  bacilli,  but  probably  more  often  by 
the  direct  introduction  of  the  organisms 
from  handkerchiefs,  etc.  Ulcers  are  formed 
and  may  extend  to  the  underlying  bone  and 
to  the  communicating  sinuses.  Tubercu- 
lous ulceration  of  the  larynx  is  common, 
and  although  thought  to  be  sometimes  pri- 
mary, is  without  doubt  most  often  caused 
by  the  passage  of  tuberculous  sputum. 

Tubercles  are  formed  just  under  the  epi- 
thelium and  become  confluent  and  necrotic. 

Ulceration  of  the  mucosa,  which  results,  affects  chiefly  the  vocal  cords,  false  cords, 
aryepiglottic  folds,  and  epiglottis.  The  latter  is  sometimes  completely  eroded  away,  so 
that  swallowing  becomes  very  difficult.  The  ulceration  of  the  vocal  cords  changes  the 
voice  to  a  husky,  toneless  whisper.  If  it  extends  so  as  to  denude  the  cartilages  of  the 
larynx,  they  may  become  necrotic  and  prone  to  serious  secondary  infections.  In  the 
trachea  the  infection  of  the  mucosa  from  the  sputum  leads  to  the  formation  of  numerous 
shallow  lenticular  ulcerations  (Fig.  316). 

Tuberculosis  of  the  Lungs. — In  the  lung  the  first  lesion  is  commonly, 
though  by  no  means  always,  in  the  wall  of  a  bronchus,  a  centimetre  or  more 


Fig.  316. — Tuberculous  lenticular  ulcers 
of  the  trachea. 


656 


TEXT-BOOK   OF    PATHOLOGY 


below  the  apex.  Why  this  should  be  so  is  not  clear,  although  many  expla- 
nations have  been  offered,  based  upon  supposed  differences  in  the  blood 
supply,  diminished  aeration,  immobility,  more  direct  access  to  the  bronchus 
of  that  part,  etc.  Freund  specially  emphasizes  the  immobility,  which  may 
be  caused  by  a  rigid  first  rib,  and  Bacmeister  has  found  that  if,  in  rabbits, 
the  apical  portion  of  the  chest  be  held  rigidly  immobile  in  a  wire  basket, 
intravenous  inoculation  of  bacilli  produces  an  apical  tuberculous  lesion. 


Fig.  317. — Caseous  tuberculous  bronchitis  and  peribronchitis.     The  mucosa  on  one  side 

is  still  well  preserved. 


The  apical  or  subapical  lesion  was  shown  by  Birch-Hirschfeld  to  be  the 
formation  of  a  tuberculous  granulation  tissue  in  the  wall  of  the  bronchus. 
This  quickly  becomes  caseous  and  softened  (Fig.  317),  and  is  discharged 
through  the  bronchus,  not,  however,  before  the  bacilli  have  extended  their 
growth  into  the  adjacent  alveoli,  where  they  form  numerous  tubercles. 
In  such  a  case  a  cavity  is  the  central  feature  in  a  mass  of  airless  lung  sub- 


TUBERCULOSIS  657 

stance  in  which  the  air-cells  are  occupied  or  obliterated  by  conglomerated 
and  partly  caseous  tubercles,  embedded  in  a  radiating  fibrous  tissue.  If 
the  development  of  the  focus  has  been  rapid  enough,  it  may  be  possible 
to  see  that  some  of  this  occlusion  of  the  air-cells  has  been  produced  by  a 
cellular  inflammatory  exudate,  which  becomes  caseous  and  surrounded 
by  epithelioid  cells,  so  that  it  comes  to  look  like  caseous  conglomerate 
tubercles. 

In  many  other  cases  the  whole  lesion  heals  and  there  is  found  accidentally 
at  autopsy  an  irregular  or  pyramidal  mass  of  deeply  pigmented  scar  tissue, 
sometimes  containing  desiccated  and  encapsulated  cheesy  nodules,  but 
devoid  of  any  resemblance  to  normal  lung  tissue.  It  may  be  hardened 
by  a  deposit  of  lime  salts,  or  still  later  bone  may  develop  there,  with  a  dis- 
tinct cancellous  arrangement  and  marrow  cavities  with  marrow.  Most 
often,  however,  the  patch  is  contracted  and  reduced  to  mere  fibrous  tissue 
in  which  no  clear  evidence  of  a  tuberculous  origin  can  be  found.  It  appears, 
then,  -as  a  flat,  scale-like  scar  occupying  the  surface  of  the  apex  of  the  lung. 
It  is  somewhat  difficult  to  prove,  however,  that;  such  subpleural  scars  are 
really  the  remains  of  tuberculous  lesions,  or,  at  least,  of  such  lesions  as  are 
seen  in  their  active  form  in  the  subapical  tissue.  Grober  tries  to  explain 
them,  and,  indeed,  the  apical  tuberculosis  in  general,  as  being  due  to  the 
passage  of  bacilli  from  the  tonsils  by  way  of  the  cervical  lymph-channels 
to  the  dome  of  the  pleura,  and  thence  to  the  apex  of  the  lung,  but  this 
view  has  not  been  generally  accepted,  and  requires  confirmation. 

While  the  establishment  of  a  tuberculous  focus  with  subsequent  cavity 
formation  near  the  apex  is  extremely  common,  it  is  not  the  only  way  in 
which  the  disease  can  begin  in  the  lung.  The  same  process  may  take  place 
in  one  of  the  lower  lobes,  or  simultaneously  in  several  places.  In  the 
opposite  lung,  by  infection  from  that  first  involved,  hundreds  of  lesions  may 
be  simultaneously  produced.  Or  in  the  entire  absence  of  any  primary 
lesion  there,  miliary  tubercles  may  be  showered  over  both  lungs,  from  a 
focus  somewhere  else  in  the  body.  Especially  in  children  is  it  common 
to  find  caseous  softening  of  the  bronchial  lymph-glands,  which,  by  eroding 
through  the  bronchial  wall,  pour  bacilli  into  its  lumen  and  set  up  at  once 
wholesale  tuberculous  disease  of  the  lung. 

But  in  spite  of  these  occasional  cases,  the  every-day  type  of  tuberculosis 
of  the  lungs  in  adults  is  that  in  which  there  is  found  a  cavity  in  the  upper 
lobe,  with  all  the  sequelae  which  we  must  now  describe. 

Since  the  cavity  is  formed  by  the  caseation  and  hollowing  out  of  the 
bronchial  wall  and  the  surrounding  tissue,  it  is  always  widely  open  into  the 
bronchus  (Fig.  318) .  Secondary  connections  with  other  bronchi  are  formed 
wherever  these  are  cut  across  as  the  cavity  enlarges,  and  through  all  these 
openings  the  fluid  contents  pass  out  into  the  trachea  and  are  coughed  up. 
It  is  clearly  unavoidable  that  in  such  violent  coughing  some  of  this  turbid 
fluid  loaded  with  bacilli  should  be  drawn  into  other  bronchi,  and  thus  into 
parts  of  the  lung  not  yet  diseased.  The  result  is  to  produce,  all  through  the 
43 


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lower  parts  of  that  organ  and  in  the  opposite  lung,  patches  of  tuberculous 
bronchopneumonia,  exactly  as  the  inhalation  of  material  infected  with 


Fig.  318. — Chronic  pulmonary  tuberculosis  with  cavity  formation  and  aspiration  of 
tubercle  bacilli  by  way  of  the  bronchus,  which  opens  into  a  cavity.  Conglomerate 
patches  of  caseous  pneumonia  in  lower  lobe.  Pleurisy  with  many  small  tubercles. 

other  virulent  organisms  produces  little  clusters  of  solid,  airless  alveoli 
about  the  ends  of  the  bronchioles.     In  the  beginning  these  parts  of  the  lung 


TUBERCULOSIS  659 

may  be  pale  or  congested,  and  rough,  dry,  grayish-red  areas  stand  out 
a  little  above  the  cut  surface.  At  that  stage  the  alveoli  are  found  full  of 
fibrinous  exudate,  with  many  leucocytes  and  some  red  corpuscles.  Mono- 
nuclear  cells  prevail  over  the  polynuclear,  and  there  quickly  appear  great 
numbers  of  large  pale  cells  with  vesicular  nuclei  which  are  generally  stated 
to  be  epithelial  cells  shed  from  the  alveolar  walls,  although  Orth  maintains 
that  they  are  large  mononuclear  wandering  cells.  The  process  is  a  true 
pneumonia,  even  though  the  type  of  wandering  cells  is  somewhat  different 
from  that  seen  with  pneumococcus  infection.  In  the  neighborhood  (see 


. 

IF 


t  -        f 

V 

"       < 


Fig.  319. — Large  cells  found  in  the  alveoli  in  the  neighborhood  of  areas  of  caseous  pneu- 
monia.    They  are  seen  to  contain  fat-globules. 

Fig.  314)  the  alveoli  are  filled  with  a  thick,  glutinous  fluid,  in  which  float 
many  more  of  the  desquamated  epithelial  cells,  which  often  become 
conspicuously  yellow  from  their  content  of  neutral  and  anisotropic  fat  (Fig. 
319).  At  a  slightly  later  stage  nearly  the  whole  consolidated  area  turns 
white  and  becomes  soft  and  cheesy,  and,  although  the  outlines  of  the 
alveolar  walls,  undisturbed  in  their  position,  can  long  be  discerned  in  virtue 
of  their  highly  resistant  elastic  tissue,  every  cell  dies,  loses  its  nuclear  stain- 
ing, and  is  disintegrated.  The  bronchial  walls  become  caseous  also,  and 
among  such  areas  of  caseous  and  gelatinous  lobular  pneumonia  they  may  be 


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seen  coursing  through  the  tissue  as  conspicuous  tubes  with  thick,  opaque, 
yellowish-white  walls  (caseous  bronchitis)  (Fig.  320). 

Occasionally,  when  very  great  numbers  of  tubercle  bacilli  are  introduced 


Fig.  320. — Caseous  lobular  pneumonia  with  caseous  bronchitis. 

into  the  bronchioles  at  one  time,  a  lobar  caseous  pneumonia  follows  (Fig. 
321).  In  such  a  case  a  whole  lobe  or  even  a  whole  lung  may  be  uniformly 
consolidated,  so  that  if  it  were  seen  in  an  early  stage,  it  might  be  confused 


^ 

^P  "«(••'. JB^M 
fv-*A  •-,••--.'>• 


Fig.  321. — Caseous  lobar  and  lobular  pneumonia. 

with  an  ordinary  lobar  pneumonia.     The  character  of  the  exudate,  with  its 
predominant  mononuclear  cells  and  the  gelatinous,  translucent  appearance 


TUBERCULOSIS 


661 


of  the  adjacent  lung  tissue,  which  is  not  so  intensely  affected,  serve  even 
then  to  distinguish  it,  and  the  subsequent  caseation  en  masse  makes  the 


Fig.  322. — Caseous  and  gelatinous  pneumonia.     The  consolidation  and  caseation  are 
practically  lobar  in  their  distribution. 

differentiation  clear  (Fig.  322) .     In  a  lung  studied  recently  only  the  tissue 
immediately  about  the  great  vessels  and  bronchi  remained  alive.     Prac- 


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tically  all  the  rest  had  assumed  the  consistence  of  cream-cheese  and  was 
perfectly  opaque  and  yellowish  white  (Fig.  323).  Naturally,  the  softening 
and  discharge  of  such  necrotic  material  will  leave  huge  cavities  in  the  lung, 
and  the  rapidity  with  which  the  organ  is  destroyed  in  this  way  has  given 
rise  to  the  name  phthisis  florida,  or  galloping  consumption.  Frankel  and 
Troje  first  clearly  described  this  form  of  the  disease,  and  drew  attention  to 
its  clinical  features,  which  resemble  those  of  a  frank  lobar  pneumonia  until, 
with  the  protracted  course,  there  appear  signs  of  breaking  down  of  the  lung 
and  the  discharge  of  a  green  sputum  full  of  shreds  of  elastic  tissue. 

Even  small  lobular  areas  of  consolidation  become  caseous  and  spill  their 
contents,  when  they  have  become  fluid  enough,  into  the  bronchi.     This 
liquefaction  seems  to  be  partly  the  work  of  the  enzymes  of  the  surround- 
ing cells,  but  partly  the  conse- 
quence of  a  secondary  infec- 
tion— at  least  there  are  always 
found  numbers  of  other  organ- 
isms in  a  cavity  of  any  size.* 

~^?&5  i  «  Were    it    to    proceed    un- 

/  9ft      checked,  such  destructive  tu- 

^  berculosis  would  eat  away  the 
whole  lung  very  shortly,  but 
from  the  beginning  there  are 
efforts  at  building  up  a  cellu- 
lar barrier  against  the  exten- 
sion of  the  caseation,  and  these 
efforts,  pushed  to  their  ut- 
most and  lasting  over  months 
and  years,  bring  about  the 
scarring  and  fibrous  indura- 
tion of  the  lung  so  character- 
istic of  the  more  chronic  sorts 
of  phthisis. 

In  the  pneumonic  patches,  before  the  central  parts  where  the  bacilli  are 
most  numerous  have  become  necrotic,  a  loose  wall  is  formed  all  around  in 
the  outskirts  of  the  exudate  by  its  organization.  This  process,  so  rare  in 
lobar  pneumonia,  commoner  in  bronchopneumonia,  is  practically  the  rule 
here.  New  formation  of  epithelioid  cells  and  of  fibroblasts  springs  up  in 
the  walls  of  these  alveoli,  and  shortly  a  definite  tuberculous  granulation 
tissue,  including  abortive  and  well-formed  tubercles,  surrounds  the  rapidly 
caseating  area.  This  wall  becomes  firmer  and  more  resistant,  although 
itself  prone  to  caseation  and  disintegration,  and  even  in  advance  of  the 

*  In  this  connection  it  should  be  stated  that  streptococci,  pneumpcocci,  etc.,  are 
sometimes  the  chief  agents  in  bringing  about  the  lobular  pneumonia  which  results  from 
the  aspiration  of  the  contents  of  a  cavern.  In  such  a  case  both  symptoms  and  anatom- 
ical changes  are  modified. 


Fig.   323. — Caseous    pneumonia    (lens    enlarge- 
ment) . 


TUBERCULOSIS 


663 


caseating  process  it  is  backed  up  constantly  by  new  tissue  formed  in  the 
same  way  outside  (Fig.  324) .  At  this  stage  one  could  scarcely  say  whether 
this  is  a  conglomerate  tubercle,  caseous  in  its  centre,  or  a  pneumonic  area, 
caseous  but  surrounded  by  a  wall  of  tuberculous  tissue.  Outside  such  a 
place,  and  even  at  quite  a  distance,  the  walls  of  the  air-cells  become  thick- 
ened and  firm.  Such  indurative  pneumonia  is  most  pronounced  when  the 


Fig.  324. — Caseous  and  gelatinous  pneumonia;   beginning  encapsulation  of  the  caseous 

areas. 

spread  of  the  tuberculosis  has  been  most  successfully  combated  over  a 
long  time. 

The  appearance  of  a  tuberculous  cavity  or  vomica  in  the  lung  might  be 
constructed  from  what  has  been  said.  The  bronchus  may  have  shallow 
ulcers  in  its  mucous  lining,  but  it  is  not  widened.*  It  suddenly  comes  to  an 

*  There  is  a  common  statement  that  bronchiectasis  is  most  frequent  in  tuberculosis. 
This  is  not  true  of  the  rapidly  advancing  forms  of  phthisis,  although  it  is  found  in  the 
old  scarred  and  indurated  lungs,  where  healing  is  going  on  with  retraction  of  the  scars. 


664  TEXT-BOOK    OF   PATHOLOGY 

eroded  rough  end,  where  it  opens  into  the  cavity.  The  cavity  may  reach 
an  enormous  size,  occupying  a  whole  lobe  or  even  nearly  the  whole  lung, 
in  which  case  the  organ  comes  to  be  a  mere  sac  whose  wall  is  formed  by  the 
thickened  pleura.  If  this  in  its  turn  is  perforated,  the  contents  of  the  cav- 
ity, including  air,  escape  into  the  pleura  unless  it  has  been  obliterated  by 
adhesions.  The  cavity  usually  contains  a  thick,  opaque,  greenish-yellow, 
somewhat  glutinous  fluid,  which  is  full  of  bacteria,  leucocytes,  cellular  debris, 
fragments  of  elastic  tissue,  etc.  If  it  be  cleaned  out,  the  wall  is  still  covered 
by  an  opaque,  yellowish-white,  caseous  necrotic  layer,  beneath  which  is  a 
tuberculous  granulation  tissue  (see  Fig.  318).  All  bronchi  and  most  of 
the  blood-vessels  which  lay  in  the  area  of  cavity  formation,  are  inter- 
rupted, but  some  of  the  blood-vessels  are  still  found  stretching  across  from 
wall  to  wall,  or  standing  up  as  high  ridges  against  one  side.  If  they  be  cut 
across,  many  of  them  prove  to  be  solid  cords,  but  others  still  have  a  cen- 
tral lumen,  from  which  one  can  squeeze  a  drop  of  blood.  This  persistence 
is  due  to  an  obliterating  endarteritis  which  thickens  the  wall,  and  especially 
the  intimal  layer,  on  the  approach  of  the  tuberculous  inflammation. 
Sometimes  loose  cords  of  these  vessels  hanging  in  the  cavity  show  that  they 
have  finally  been  corroded  all  the  way  through,  but  no  haemorrhage  has 
occurred.  In  other  cases,  when  the  patient  has  died  from  a  sudden  tre- 
mendous coughing  up  of  blood,  the  cavity  is  found  full  of  blood-clot,  and 
study  of  its  walls  usually  shows  an  artery  approached  too  suddenly  to 
allow  time  for  obliteration.  Then,  as  its  wall  is  weakened  by  the  advancing 
caseation,  it  bulges  out  into  a  little  sac  or  aneurysm  which  bursts  with  some 
effort  of  coughing. 

In  all  such  cases  the  pleura  is  thickened  and  covered  with  a  fibrinous 
exudate.  Tubercles  are  to  be  found  in  the  granulation  tissue  which  lies 
beneath  this  exudate,  and  frequently  there  are  quite  dense  adhesions, 
especially  over  the  region  where  the  cavity  approaches  the  surface.  The 
lymph-glands  in  the  lung,  and  especially  those  at  the  hilum,  contain 
tubercles  or  larger  caseous  areas.  All  this  makes  up,  as  we  have  said,  one 
of  the  commonest  combinations  found  in  the  lungs  of  consumptives  at 
autopsy,  namely,  a  cavity  at  the  apex  opening  widely  into  the  bronchus 
and  surrounded  by  consolidated  fibrous  lung  tissue  studded  with  caseous 
foci,  and,  below  this,  numerous  patches  of  pneumonic  consolidation,  vary- 
ing in  age  from  the  freshest  to  the  completely  caseous  area,  walled  round 
by  organized  exudate  and  tuberculous  granulation  tissue. 

Aside  from  the  pneumonic  patches  following  bronchial  transportation, 
there  is  a  great  variety  of  anatomical  lesions  in  the  lung  which  are  due 
to  the  passage  of  bacilli  along  the  lymphatics  or  blood-vessels,  or  to  the 
direct  extension  of  the  infection  through  the  lung  tissue.  In  all  these 
cases  the  lesion  consists  in  the  formation  of  tubercles  and  tuberculous 
granulation  tissue,  without  much  outpouring  of  cellular  inflammatory 
exudate.  Tubercles  produced  in  the  lung  by  bacilli  brought  with  the 
blood-stream  develop  in  the  alveolar  wall,  but  soon  project  into  the 


TUBERCULOSIS 


665 


alveolus  so  as  to  fill  it  or  become  conglomerated  with  adjacent  nodules. 
Sometimes  they  are  so  small  that  their  point  of  origin  can  be  clearly 
determined.  Such  tubercles  may  be  scattered  in  any  indefinite  order 
through  the  lung.  When  carried  by  the  lymphatic  channels,  the  bacilli 
produce  similar  tubercles  in  strings  or  clusters  along  the  interlobular 
septa  (Fig.  325),  in  the  bronchial  walls,  or  in  the  walls  of  the  blood-vessels. 
Sometimes  this  can  be  plainly  seen,  but  when,  in  advanced  stages,  they 
cluster  around  bronchi  and  are  caseous,  it  is  hard  to  say  whether  they 
were  not  small  bronchopneumonic  patches.  There  is  one  common  type 
of  tuberculous  lesion  secondary  usually  to  an  apical  cavity  formation,  in 


Fig.  325. — Distribution  of  tubercle  bacilli  by  lymphatics,  with  development  of  tubercles 

in  the  interlobar  septa. 

which  large  and  small  firm  masses  are  felt  in  the  otherwise  air-containing 
lung  (Fig.  326).  On  section  these  are  found  to  be  quite  sharply  outlined 
and  edged  by  a  border  of  gray,  caseating  tubercles.  The  whole  mass, 
measuring  sometimes  5  cm.  in  diameter,  is  radially  arranged,  and  its  inner 
part,  back  of  the  progressing  margin  of  fresh  tubercles,  is  a  solid,  pigmented 
fibrous  tissue  with  still  some  tubercles  and  caseous  points,  but  giving 
the  impression  of  having  been  formed  by  the  healing  or  obsolescence  of 
tuberculous  tissue,  which  is  still  advancing  rapidly  at  the  margin  into 
the  healthy  lung  substance.  Some  such  process  as  this  seems  to  occur 
in  many  cases  about  the  early  apical  lesions,  and  it  is  a  process  which  is 


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undoubtedly  of  great  importance  in  the  ordinary  spread  of  any  focus  of 
the  disease  in  the  lung. 


Fig.  326.  —  Pulmonary  phthisis  with  cavity  formation.  There  are  extensive  masses 
of  pigmented  scarred  tuberculous  tissue  the  advancing  margin  of  which  is  made  up  of 
fresh  tubercles. 


The  rate  of  progression,  while  perhaps  about  the  same  in  the  majority 
of  cases,  is  capable  of  great  variation,  so  that,  on  the  one  hand,  we  find  a 


TUBERCULOSIS 


667 


man  dying  a  few  weeks  after  the  first  symptoms  appear,  on  the  other,  a 
man  who  has  had  pulmonary  tuberculosis  for  many  years  and  finally  dies 
from  something  else,  revealing  extensive  scarred  and  almost  healed  lesions 
in  his  lungs. 

This  scarring  may  consist  in  the  permanent  encapsulation  of  each  caseous 
area,  leaving  air-containing  and  functional  lung  substance  between,  but 


Fig.  326A. — Chronic  pulmonary  phthisis  with  cavity  formation  and  scattered  scarred 

tuberculous  areas. 


more  often  it  extends  far  and  wide,  and  a  whole  lobe,  or  even  the  whole  lung, 
bound  as  it  usually  is  in  thick  pleural  adhesions,  is  distorted  and  indurated 
and  greatly  contracted.  On  section  such  a  lung  reveals  cavities  at  the  ends 
of  short  wide  stumps  of  bronchi,  separated  by  a  gray  pigmented  tissue  with 
only  islands  of  recognizable  alveoli  here  and  there.  Microscopically  the 
alveolar  walls  in  these  islands  are  greatly  thickened  by  connective  tissue, 


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and  on  account  of  their  rigidity  the  epithelial  cells  have  become  cubical  or 
even  columnar.  In  other  places,  and  especially  near  the  edges  of  the  lung, 
the  alveoli  which  remain  are  enormously  dilated  and  thin  walled  (collateral 
or  compensating  emphysema).  Even  quite  large  cavities  may  be  cleaned 
out  and  relined  by  a  smooth  layer  of  epithelium,  a  step  toward  healing  which 
must  indicate  the  most  tenacious  resistance  on  the  part  of  the  host  (Figs. 
326A,  326B,  326C,  326D). 
It  is  important  to  indicate  the  functional  disturbances  produced  by  the 


Fig.  326B. — Chronic  pulmonary  phthisis  with  cavity  formation  and  bronchiectasis. 


disease.  The  formation  of  even  very  many  minute  tubercles  in  the  lungs 
as  part  of  a  generalized  miliary  tuberculosis  need  not  cause  any  great  dis- 
turbance of  respiration,  but  with  wide-spread  pneumonic  consolidation  the 
case  is  different.  So,  too,  with  extensive  cavity  formation  and  such 
scarring  of  the  lung  as  has  been  described  there  is  quite  naturally  a  great 
diminution  of  the  respiratory  surface.  The  bed  of  the  blood-stream  through 
the  lungs  is  largely  obliterated,  and  the  remaining  lung  substance  is  over- 
distended,  so  that  one  might  expect  to  find  hypertrophy  of  the  right  side  of 


TUBERCULOSIS 


669 


the  heart  caused  by  the  effort  to  force  the  blood  through.  Curiously 
enough,  this  is  seldom  the  case  except  in  those  individuals  in  whom  the 
disease  has  been  held  in  check  for  years  and  the  lungs  are  extensively 
scarred. 

Disturbances  of  temperature  regulation  (fever  in  the  afternoon,  etc.) 
are  common  in  pulmonary  phthisis,  but  it  seems  that  the  most  intense 
symptoms  of  this  kind  are  due  to  secondary  invaders  of  all  sorts  (pyogenic 


Fig.   326C. — Chronic  pulmonary  phthisis  with  cavity  formation  in   the  upper  lobe. 
There  are  also  several  cavities  in  the  lower  lobe  opening  widely  into  a  bronchus. 


cocci  and  bacteria  of  every  other  type,  yeasts,  moulds,  and  even  insect 
larvae),  which  may  get  into  the  cavities  and  grow  there. 

Changes  in  the  general  metabolism  are  of  regular  occurrence — the  con- 
sumptive wastes  away  and  becomes  anaemic;  the  metabolism  of  fat  is  dis- 
turbed, so  that  it  accumulates  especially  in  the  liver,  and  there  are  general, 
though  somewhat  intangible,  evidences  of  poisoning,  doubtless  from  the 
absorption  of  toxic  substances  which  the  bacilli  produce. 


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Persons  with  pulmonary  phthisis  almost  invariably  infect  themselves 
further.  The  lymph-glands  at  the  hilum  of  the  lung  inevitably  contain 
tubercles,  and  other  more  distant  nodes  may  also  be  infected.  The  out- 
pouring of  tuberculous  sputum  very  often  sets  up  ulcer  formation  in  the 
trachea  and  larynx,  while,  especially  in  children  who  do  not  expectorate 
and  in  adults  who  swallow  their  sputum,  the  intestines  and  sometimes  even 


Fig  326D. — Chronic  pulmonary  phthisis  with  extreme  induration  and  clean  cavities. 


the  stomach  develop  ulcers.  These  are  the  obvious  ways  for  the  bacilli 
to  spread,  but  in  every  such  autopsy  one  finds  a  few  scattered  tubercles  in 
nearly  all  the  organs,  which  must  indicate  the  entrance  of  bacilli  into  the 
blood-stream.  Although  it  cannot  always  be  traced,  the  point  of  en- 
trance is  usually  quite  clear  when  the  invasion  is  extensive  enough  to 
produce  an  unmistakable  acute  miliary  tuberculosis.  Localized  disease 


TUBERCULOSIS  671 

in  some  distant  organ,  as  in  a  bone  or  in  the  kidney  or  epididymis,  may 
be  started  in  this  way,  and,  on  the  contrary,  primary  disease  of  the  lymph- 
glands  or  of  a  bone  may  in  the  end  give  rise  to  pulmonary  tuberculosis. 


LITERATURE 

Birch-Hirschfeld:  Deutsch.  Arch.  f.  klin.  Med.,  1909,  Ixiv,  58. 

Frankel  and  Troje:  Zeitsch.  f.  klin.  Med.,  1894,  xxiv,  30. 

Durck:  Erg.  d.  allg.  Path.,  1897,  ii,  196;  1901,  vi,  84. 

Pertik:  Ibid.,  1904,  viiii,  1. 

Orth:  Nachr.  d.  k.  Gesellsch.  f .  Wiss.,  Gottingen,  1901,  Heft  2. 

Bartel:  Wien.  klin.  Woch.,  1905,  1906,  1907,  1908,  1913. 

Ribbert:  Deutsch.  Med.  Woch.,  1906,  No.  40;  1907,  No.  42;  1918,  xliv,  144. 

Ophuls:  Trans.  Nat.  Assoc.  Study  and  Prevention  Tuberculosis,  7th  Ann.  Meeting, 

Amer.  Jour.  Med.  Sci.,  July  1900.    Trans.  Brit.  Congr.  Tuberc.,  1901,  iii. 
Shennan:  Lancet,  Feb.  28  and  Mar.  7,  1914. 
Harbitz:  Jour,  of  Infect.  Dis.,  1905,  ii,  143. 


Tuberculosis  of  the  Digestive  Organs. — From  what  was  said  above,  it 
is  evident  that  while  tubercle  bacilli  may  be  taken  into  the  digestive  tract 
with  the  food,  it  is  still  questionable  whether  their  entrance  into  the  body 
by  that  path  is  of  great  importance  in  the  production  of  pulmonary  and 
general  tuberculosis.  Isolated  primary  tuberculosis  of  the  intestine  can 
rarely  be  demonstrated  in  adults,  although  commoner  in  children.  Indeed, 
as  a  consequence  of  the  study  of  the  results  of  a  great  many  investigators 
Beitzke  concludes  that  in  tuberculous  children  about  25  per  cent,  of  the 
cases  show  a  primary  intestinal  infection.  The  result  is  infection  of  the 
mesenteric  lymph-glands,  or  even  of  the  ductus  thoracicus,  or,  on  the 
other  hand,  the  transportation  of  the  bacilli  by  the  portal  blood  to  the 
liver,  where  tubercles  may  be  formed.  Miliary  tuberculosis  is  apparently 
rarely  or  never  the  direct  outcome  of  primary  intestinal  tuberculosis,  but 
if  a  partial  immunity  be  set  up  or  if  the  bacteria  be  relatively  non-virulent, 
pulmonary  tuberculosis  may  follow.  Thus  while  it  is  recognized  that 
pulmonary  tuberculosis  may  follow  an  intestinal  absorption  or  intestinal 
tuberculosis,  the  readiness  with  which  it  is  produced  by  aspiration  leaves 
this  method  of  infection  in  a  place  of  secondary  importance,  which  in  adults, 
at  least,  is  probably  very  slight. 

Tuberculous  lesions  of  the  mouth,  pharynx,  oesophagus,  and  stomach 
occur,  but  are  quite  rare.  They  arise  by  direct  infection  of  the  mucosa, 
or  sometimes,  as  in  the  case  of  the  oesophagus,  from  invasion  by  caseous 
glands  or  other  tissues  from  without.  In  the  stomach  the  lesions  are 
miliary  and  conglomerate  tubercles  in  the  mucosa,  or  ragged  and  precipitous 
ulcers. 

The  liver  regularly  presents  very  minute  miliary  tubercles  when  there  is 


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a  general  distribution  of  the  bacilli  by  the  blood-stream.  In  some  cases 
these  become  conglomerate,  and  even  quite  large  and  centrally  caseous. 
A  type  of  cirrhosis  of  the  liver  results  from  the  presence  of  these  nodules, 
or  at  least  occurs  commonly  in  association  with  them.  The  most  inter- 
esting form  is  that  in  which  caseous  nodules  appear  near  the  bile-ducts, 
and  after  the  discharge  of  their  contents  into  -the  ducts  become  deeply 
bile  stained.  Tuberculosis  of  the  pancreas  is  not  often  observed,  and 
usually  consists  in  the  presence  of  miliary  tubercles. 

It  is  in  the  intestine,  however,  that  the  bacilli  cause  their  greatest  rav- 
ages, and  the  lesions  there  are  of  interest  not  only  in  themselves,  but 
because  they  may  lead  to  other  extensions  of  the  disease.  Aside  from  the 
rare  instance  of  isolated  primary  tuberculosis  in  adults  and  those  in  children, 

m  whicn  the  bacilli  are 
probably  swallowed  in 
quantities  in  the  milk,  the 
intestinal  lesions  are  usu- 
ally caused  by  the  swallow- 
ing of  sputum  from  tuber- 

€Z^?i.rW  culous  cavities  in  the  lungs. 

The  mucus  of  the  sputum 
protects  the  bacilli  in  their 
passage  through  the  acid 
gastric  juice,  so  that  they 
reach  the  intestine  alive. 


% 


Fig.  327. — Tuberculous  ulcer  of  the  ileum. 


Intestinal  Tuberculosis.  —  The 
lesions  in  the  intestine  are  pre- 
dominantly ulcerative,  and  are 
found  in  their  greatest  intensity 
in  the  small  intestine  above  the 
ileocsecal  valve.  Often  enough, 
however,  they  both  extend  far  up 
in  the  small  intestine,  and  are 

found  in  numbers  in  the  colon.  They  have,  therefore,  broadly,  the  same  general  distri- 
bution as  the  ulcers  in  typhoid  fever,  but  they  are  not  nearly  so  sharply  limited  to  the 
Peyer's  patches  and  solitary  nodules.  Even  though  the  bacilli  may  lodge  there,  they  soon 
produce  an  ulceration  which  extends  wide  of  those  structures  and  involves  indifferently 
the  surrounding  mucosa.  Indeed,  the  ulcers  have  a  rather  strong  tendency  to  encircle 
the  whole  gut,  whence  they  are  often  called  girdle  ulcers.  Their  beginnings  can  be  seen 
as  swollen,  conglomerate  nodules  with  central  caseation,  but  the  softening  and  discharge 
of  this  yellow,  opaque  central  substance  into  the  intestine  leaves  an  ulcer  which,  when  it 
has  reached  a  larger  size,  is  characteristic  enough  and  very  unlike  the  typhoid  ulcer  in 
its  details.  The  margin  is  ragged,  nodular  and  irregular,  thickened,  and  undermined 
(Fig.  327).  The  base  is  generally  covered  with  yellow  necrotic  material,  but  this  is 
sometimes  cleaned  off  so  as  to  reveal  the  tuberculous  granulation  tissue  which  really 
lines  the  ulcer,  and  which  is  generally  studded  with  palpable  nodules.  The  submucosa 
or  musculature  may  be  exposed,  or  the  ulcer  may  perforate  the  whole  wall. 

Such  ulcers  can  generally  be  located  from  the  outside  by  the  congestion  of  the  vessels 
in  that  spot,  and  especially  by  the  crop  of  minute  gray  tubercles  which  spring  up  in  the 


TUBERCULOSIS 


673 


subserous  tissue  and  cluster  along  the  lymphatic  channels.  Evidently  from  the  mucosa 
the  bacilli  are  carried  into  these  lymph-channels,  and  the  tubercles  are  actually  formed 
inside  them  in  such  a  way  as  to  block  the  lumen.  It  is  for  that  reason  that  these  lymph- 
atics become  so  conspicuous  as  they  run  over  the  surface  of  the  intestine  to  the  mesentery 
(Fig.  328).  Sometimes  they  are  greatly  distended  with  clear  fluid,  or  even  with  opaque 
white  chyle,  and  are  beaded  or  like  a  string  of  sausages,  because  they  are  obstructed  at 
intervals.  In  such  a  case  they  can  often  be  traced  through  the  mesentery  to  the  lymph- 
gland,  into  which  they  empty  and  which  usually  shows  tuberculous  lesions  too. 

Microscopically  (Fig.  330),  the  tuberculous  granulation  tissue  is  found  not  only  lining 
the  base  of  the  ulcer,  but  formed  in  the  submucosa  wide  of  the  actually  undermined 
part,  and  through  the  crevices 
of  the  muscle  layer  even  into 
the  subserous  tissue.     It  often 
shows    patches    of    caseation 
and  abortive  tubercles,  but  the 
tubercles    are   usually    rather 
indefinite  in  their  structure. 

There  is  one  form  of  intesti- 
nal tuberculosis  which  is  rather 
sharply  localized  about  the 
ileocsecal  valve  and  there  pro- 
duces a  great  mass  of  hard, 
tuberculous  scar  tissue,  which 
may  constrict  the  intestinal 
lumen  until  only  a  large  probe 
will  pass.  In  one  such  case  seen 
recently  that  whole  stretch  of 
the  intestine  was  removed  by 
the  surgeon  and  the  young 
man  has  been  quite  well  ever 
since.  More  common  is  the 
localized  ulcerative  tuberculo- 
sis of  the  rectum,  which,  ex- 
tending in  the  form  of  a  sinus 
to  the  skin  at  the  anus,  gives 
rise  to  the  so-called  anal 

fistula.  In  nearly  all  these  cases  the  granular  lining  of  the  sinus  is  found  to  be 
tuberculous. 


I 


j 


Fig.  328. — The  same  ulcer  of  the  ileum  from  the 
outside,  showing  the  chains  of  tubercles  along  the 
lymphatic  channels. 


It  follows,  from  the  anatomical  relations,  that  if  tuberculous  ulcers  extend 
in  the  intestinal  wall  so  as  to  present  bacillus-holding  tissue  on  the  peri- 
toneal surface,  or  if  tuberculous  disease  of  the  lungs  reaches  the  pleura,  or 
if  tuberculous  and  caseous  lymph-glands  approach  or  break  into  either  of 
these  cavities  or  the  pericardium,  it  will  not  be  difficult  for  the  bacilli  to 
gain  access  there  and  to  be  spread  over  an  extensive  surface  by  the  active 
movements  of  the  contained  organs.  It  is  usually  in  this  way  that  tuber- 
culous pleurisy,  pericarditis,  and  peritonitis  arise,  although  those  surfaces 
may,  like  other  tissues,  be  involved  in  a  general  miliary  tuberculosis. 

Tuberculous  Peritonitis. — The  principles  followed  in  the  pleura  and  pericardium  are 
so  well  exemplified  by  the  conditions  found  in  tuberculous  peritonitis  that  a  description 
of  the  latter  will  suffice.     The  varied  types  of  tuberculous  disease  of  the  peritoneum 
44 


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seem  to  depend  upon  the  number  and  virulence  of  the  organisms  introduced  and  the 
resistance  of  the  host,  for  in  some  cases  there  is  an  extensive  destruction  of  tissue, 
while  in  others  there  is  rather  the  formation  of  adhesions  and  scars  which  may  hi  time 
lose  much  of  their  distinctive  tuberculous  character. 

The  organisms  may  enter  the  peritoneum  with  the  blood-stream,  as  in  the  produc- 
tion of  acute  miliary  tuberculosis,  when  they  will  be  deposited  in  the  omentum  and  sub- 
serous  tissues.  Or  they  may  be  directly  poured  into  the  cavity  from  exposed  caseous 
masses,  when,  for  example,  a  tuberculous  focus  in  a  lymph-gland  or  in  the  kidney  or  a 
neighboring  bone  forms  a  communication  with  the  peritoneum.  Caseous  disease  of  the 


Fig.  329. — Tuberculous  erosions  of  the  lower  ileum.     Both  sides  of  the  intestine  are 

shown  at  the  same  level. 

Fallopian  tubes  is  a  prominent  source  of  infection  in  women,  and  in  some  instances  a 
generalized  peritoneal  tuberculosis  may  arise  in  the  same  way  from  tuberculous  ulceration 
of  the  intestine.  The  latter,  however,  more  commonly  causes  rather  a  localized  peritonitis 
with  adhesions.  The  bacilli  are  distributed  by  the  prevalent  streams  in  the  abdominal 
cavity,  and  reach  the  vault  of  the  diaphragm  and  the  floor  of  the  pelvis  in  great  numbers. 
Sometimes  their  effects  in  the  form  of  tubercles  are  seen  in  hernial  sacs.  In  the  earliest 
stages  minute  gray,  translucent  tubercles  may  be  scattered  everywhere  over  the  surface 
of  the  peritoneum  and  of  the  omentum,  without  disturbing  the  normal  gloss. 

In  other  cases  the  tubercles  are  quickly  covered  by  an  exudate  of  fibrin,  sometimes 
nearly  dry,  sometimes  with  the  effusion  of  a  very  great  amount  of  clear  or  slightly  turbid 
fluid,  sufficient  to  float  up  the  intestinal  coils  and  prevent  them  from  being  glued  together. 
A  soft,  friable,  vascular  granulation  tissue  springs  up  and  replaces  the  fibrin,  so  as  to 
form  organized  adhesions  in  the  cases  where  there  is  no  fluid,  and  in  these  adhesions  the 


TUBERCULOSIS 


675 


tubercles  become  larger  and  centrally  caseous.  The  omentum  is  retracted  and  folded 
so  as  to  form  a  solid,  prismatic  mass,  which  can  readily  be  felt  stretching  across  the 
abdomen.  In  its  substance  tubercles  and  caseous  areas  are  embedded  with  the  fat  lob- 
ules in  a  tuberculous  granulation  tissue.  With  the  lapse  of  time  the  adhesions  become 


Fig.  330. — A  tuberculous  ulcer  of  the  ileum,  with  undermined  edges.  The  ulcer 
has  penetrated  the  muscularis,  and  there  are  tubercles  in  the  submucosa  and  hi  the 
thickened  subserous  tissue. 


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dense  and  tough,  so  as  to  bind  the  abdominal  contents  inextricably  together  into  a 
matted  mass.  Over  the  liver  and  spleen,  and  especially  between  the  liver  and  the  dia- 
phragm, quite  large  caseous  areas  may  form  in  these  adhesions,  and  even  the  tearing 
apart  of  the  intestines  may  open  cavities  and  canals  filled  with  soft  caseous  material. 
Withal  the  intestinal  mucosa  may  be  quite  intact. 

In  those  cases,  however,  in  which  the  peritoneal  infection  is  due  to  the  exposure  of 
caseous  tubercles  outside  intestinal  ulcers,  the  affected  areas  are  usually  bound  together, 
so  that  finally  perforation  of  the  ulcer  produces  only  localized  faecal  abscesses  in  the 
adhesions,  or  fistulous  communications  between  adjacent  coils.  Where  the  resistance 
is  high,  the  intestines  may  be  found  matted  together  by  adhesions  which  are  loose 
and  fibrous  and  which  show  only  here  and  there  scattered  encapsulated  tubercles. 


'''.'•  4:'-  .•&< 


Fig.  331. — Scattered  tubercles  in  a  lymph-gland. 

In  other  cases  large  encapsulated  and  sometimes  pedunculated  tubercles  may  occur  in 
association  with  old  adhesions,  or  even  without  much  other  change  in  the  peritoneum. 
All  these  things  indicate  the  possibility  of  healing,  and,  indeed,  the  idea  has  been  widely 
entertained  that  those  thick  fibrous  plates  which  are  often  found  partly  covering  the 
liver  and  spleen  (the  so-called  iced  liver)  may  perhaps  be  due  to  a  healed  tuberculosis, 
even  though  they  show  no  distinct  anatomical  evidences  of  their  origin.  In  the  acute 
forms,  where  there  is  much  fluid  exudate,  definite  advances  toward  healing  may  some- 
times be  attained  by  opening  the  peritoneum  and  removing  the  exudate.  This  has  been 
explained  by  Wright  on  the  ground  that  the  accumulated  fluid  has  exhausted  its  bac- 
tericidal power,  and  that  the  advent  of  fresh  fluid  and  cellular  exudate  brings  with  it 
new  powers  of  destroying  the  organisms. 


TUBERCULOSIS 


677 


The  distribution  of  the  tubercle  bacilli  is  particularly  well  followed  in  the 
study  of  the  lesions  of  the  lymph-nodes,  for  these  organs  act  as  sieves  in  the 
course  of  the  lymph-channels  along  which  the  bacilli  are  so  commonly 
carried.  For  this  reason  changes  produced  and  registered  in  these  nodes 
are  of  assistance  as  a  clue  to  the  portal  of  entry  of  the  organisms. 

Tuberculosis  of  Lymph-glands. — The  lesions  are  quite  the  same  in  character  as  else- 
where. The  bacilli  lodge  in  the  sinuses  of  the  gland  or  are  carried  into  the  lymph- 
cords,  and  produce  tubercles  often  with 
associated  tuberculous  granulation  tis- 
sue and  an  inwandering  of  many  large 
mononuclear  phagocytic  cells  (Fig. 
331).  The  tubercles  are  sometimes 
discrete  and  remain  so,  but  more  often 
they  become  conglomerated  and  suffer 
extensive  caseation,  so  that  almost  the 
whole  gland  may  be  reduced  to  a  soft, 
cheesy  mass.  Healing  occurs  through 
hyaline  changes  and  scarring,  generally 
with  the  deposit  of  calcium  in  coarse 
grains,  or  in  such  a  way  as  to  convert 
the  whole  gland  into  something  like  an 
irregular  pebble  tightly  bound  up  in  a 
fibrous  capsule. 

All  these  lesions  are  most  common 
in  the  bronchial  glands,  but  are  very 
frequent  in  the  mesenteric  nodes  also, 
where,  especially  in  children,  very  great 
enlargement  may  take  place  and  is 
sometimes  known  as  tabes  mesenterica. 

From  tuberculous  foci  in  the  tonsils 
and  upper  air-passages  the  cervical 
chain  of  glands  may  be  infected  and 
caseous.  In  such  a  case  they  become 
matted  together  by  fibrous  growth  and 
present  a  great  swelling  along  the  side 

of  the  neck  (Fig.  332).  The  caseous  material  may  sometimes  burrow  out  to  the  skin, 
so  that  a  discharging  sinus  is  established.  More  rarely  a  similar  condition  is  met  with 
in  the  axilla  or  groin,  sometimes  as  the  result  of  peripheral  tuberculous  infections.  The 
thoracic  duct,  receiving  bacilli  from  tuberculous  abdominal  glands,  may  develop  caseat- 
ing  tubercles  along  its  lining  and  thus  contribute  to  the  formation  of  an  acute  miliary 
tuberculosis. 

In  the  spleen  there  occur  miliary  and  conglomerate  tubercles,  often 
rather  loose  and  cellular  in  their  structure,  and  without  the  coherent 
tissue  formation  seen  elsewhere.  In  this  organ,  too,  there  arise  very  large 
caseous  solitary  tubercles  with  dense  fibrous  capsule  (see  Fig.  312). 

Tuberculosis  of  the  Genito-urinary  Tract. — The  development  of  the 
tuberculous  lesions  and  their  anatomical  form,  as  well  as  their  ultimate 
fate,  are  quite  the  same  in  these  organs  as  elsewhere,  but  the  mode  of  en- 
trance of  the  bacilli  and  their  further  distribution  have  long  been  debatable. 

As  has  been  stated,  direct  introduction  of  bacilli  by  coitus  is  rarely  shown 
to  be  productive  of  genital  tuberculosis.  Infection  of  the  genito-urinary 


Fig.  332. — Pocket  of  caseous  cervical  lymph- 
glands. 


678  TEXT-BOOK    OF    PATHOLOGY 

tract  is  practically  limited  to  the  deposition  there  of  bacilli  brought  into 
the  blood-stream,  but  even  then  there  are  favorable  and  unfavorable  local- 
izations. In  general  miliary  tuberculosis  tubercles  can  develop  nearly 
everywhere.  When  fewer  bacilli  are  in  circulation,  however,  and  the 
development  of  a  tuberculous  focus  depends  in  some  degree  upon  favorable 
conditions  in  an  organ,  we  find  that  the  kidney,  the  epididymis,  and  some- 
times the  Fallopian  tubes  are  the  most  susceptible  to  the  infection.  It  is 
in  them  that  the  oldest  lesions  are  found,  and  it  is  from  these  primary  foci 
of  disease  that  bacilli  spread  to  infect  the  rest  of  the  genito-urinary  tract. 
Walker  and  Sawamura  find  that  the  initial  lesion  is  practically  never  in  the 
bladder  or  ureters,  in  the  prostate,  seminal  vesicles,  vasa  deferentia,  or 
testis,  but  that  all  these  structures  are  readily  enough  infected  secondarily, 
when  great  quantities  of  bacilli  are  poured  into  them  from  a  caseous  kid- 
ney or  epididymis.  So,  also,  in  the  female  the  ovary  and  uterus  are  rarely 
affected  primarily,  while  the  tissue  of  the  Fallopian  tube  seems  specially 
susceptible  and  later  distributes  bacilli  in  quantity  elsewhere. 

With  these  results  in  mind  there  are  relatively  few  difficulties  in  explain- 
ing the  distribution  of  the  disease.  With  regard  to  the  genital  glands  in 
the  male,  it  is  not  impossible  that  tuberculosis  of  prostate  and  seminal 
vesicles  should  arise  by  infection  from  the  bladder,  and  that  the  disease 
should  extend  along  the  vas  deferens  to  the  epididymis,  but  the  reverse 
direction  is  more  common.  More  dispute  has  arisen  as  to  the  possibility 
of  an  ascending  tuberculous  infection  of  the  kidney  from  tuberculous  dis- 
ease of  the  bladder,  in  a  way  analogous  to  that  admittedly  followed  in  the 
ascending  suppurative  pyelonephritis  following  cystitis.  A  priori  this  would 
seem  the  most  plausible  explanation  when  one  finds,  at  autopsy,  an  old 
caseous  focus  in  the  epididymis,  tuberculosis  of  the  prostate  and  bladder 
and  of  the  ureter,  pelvis,  and  kidney  on  one  or  both  sides.  This  is  especially 
striking  when,  as  is  so  frequently  the  case,  the  tuberculosis  of  the  kidney 
is  limited  to  the  development  of  small  patches  of  caseous  tuberculous 
granulation  tissue  at  the  tips  of  the  papillae  and  along  the  walls  of  the 
calyces,  without  any  sign  of  involvement  of  the  cortex.  This,  in  connec- 
tion with  the  continuous  affection  of  the  ureteral  mucosa  from  the  ulcerated 
bladder,  makes  it  hard  to  resist  the  idea  that  the  bacilli  have  been  floated 
up  from  the  bladder  in  the  lumen  of  the  ureter.  Still  the  mucosa  of  the 
ureter  is  not,  as  a  rule,  continuously  tuberculous  in  these  cases,  and  may 
show  little  change;  on  the  other  hand,  when  the  renal  tuberculosis  is  some- 
what more  advanced  the  whole  wall  of  the  ureter  is  usually  thickened 
and  rigid,  suggesting  the  involvement  of  the  lymphatics  as  well,  and  there 
are  many  who  would  explain  the  advance  of  the  infection  from  the  bladder 
to  the  kidney  by  this  route.  In  spite  of  much  investigation  of  this  pos- 
sibility, which  has  generally  led  to  negative  results,  it  is  not  finally  settled 
and  should  be  studied  further. 

Experiments,  especially  those  of  Walker,  show  that  while  fluids  may  pass 
out  of  the  bladder  into  the  ureter  when,  through  ulceration,  the  valve-like 


TUBERCULOSIS 


679 


ureteral  orifice  is  destroyed,  or,  when  through  obstruction,  the  bladder 
contracts  against  a  quantity  of  urine  which  cannot  readily  escape,  deliberate 
infection  of  the  bladder  rarely  results  in  the  production  of  an  ascending 
infection.  Although  Walker  had  a  few  positive  cases,  he  leans  to  the  view 
that  infection  is  hsematogenous  and  primarily  brought  by  the  blood  to 
the  kidney  and  only  secondarily  to  the  pelvis  and  ureter. 

The  conditions  found  at  autopsy  leave  me  still  with  the  belief,  however, 
that  tuberculosis  of  the  kidney  is  often  an  ascending  affection,  and  that 
the  conditions  of  the  experiments  and  the  different  anatomical  arrange- 
ments of  the  animals  explain  the  experimental  results. 

*L. 


Fig.  333. — Renal  phthisis.     The  tuberculous  process  has  excavated  the  calyces  of  the 
'    kidney  far  into  the  cortex.     There  is  great  thickening  of  the  ureter. 


Tuberculosis  of  the  Kidney. — In  generalized  miliary  tuberculosis  minute  tubercles 
are  found  in  the  cortex  of  the  kidney,  beginning,  as  Benda  states,  in  the  glomerular 
capillaries,  where  masses  of  bacilli  are  lodged  as  emboli.  Doubtless  they  may  be 
formed  also  about  the  other  capillaries,  and  in  their  growth  and  conglomeration  they  soon 
extend  in  a  direction  parallel  with  that  of  the  conducting  tubules,  to  form  gray  streaks, 
often  with  an  opaque  yellow  centre,  reaching  from  the  cortex  into  the  pyramid. 

Probably  tubercles  are  also  formed  by  bacilli  which  lodge  in  the  tubules  in  the  course 
of  excretion  (Aschoff),  and  these  may  take  part  in  the  production  of  the  more  extensive 


680 


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caseous  areas  which  arise  in  the  margin  between  cortex  and  pyramid  (Israel).  Such 
caseous  areas  grow  until  they  destroy  much  of  the  kidney  substance  and  discharge  their 
contents  into  the  pelvis.  In  other  cases  the  caseating  area  begins  in  the  papillary  part 
of  the  pyramid,  usually  up  in  an  angle  of  the  calyx,  and  from  there  the  process  of  erosion 
extends  deeply  into  the  kidney.  These  are  the  cases  which  specially  suggest  an  origin 
from  an  ascending  infection.  In  any  event  the  late  result  is  the  great  destruction  of 
the  kidney  substance.  What  remains  of  the  pelvis  is  ulcerated;  the  papillae  have  dis- 
appeared, and  the  calyces  are  represented  by  irregular  cavities  lined  by  caseous  granula- 
tion tissue  and  excavated  deep  into  the  kidney  (Fig.  333).  The  organ  may  be  enormously 

enlarged  and  finally  appear  as  a 
lobulated,  sacculated  mass,  in  the 
walls  of  which  hardly  any  kidney 
substance  remains.  If  the  capsule 
is  perforated,  a  perirenal  tubercu- 
lous infection  occurs,  and  the  ex- 
tension of  the  caseating  process, 
preceded,  as  always,  by  the  forma- 
tion of  tuberculous  granulation  tis- 
tue,  can  go  on  until  a  fistulous  tract 
is  opened  into  the  peritoneum  or 
out  through  the  skin.  Healing 
must  be  very  rare,  but  one  finds 
occasionally  shrunken  kidneys  with 
encapsulated,  mortar-like,  or  stcny 
masses  of  probable  tuberculous  ori- 
gin. In  persons  whose  resistance  is 
great  the  caseation  is  often  limited 
by  the  enormous  production  of  scar 
tissue,  so  that  the  kidney,  while 
being  greatly  enlarged,  contains 
relatively  small  pyramidal  cavities 
surrounded  by  thick  walls  of  fibrous 
tissue. 


It  is  perhaps  unnecessary  to 
describe  in  any  detail  the  tu- 
berculous lesions  in  the  rest  of 
the  genito-urinary  tract,  since 
in  each  case  they  are  due  to  the 
Fig.  334. — Tuberculosis  of  epididymis  (bilateral),  development  of  tubercles  in  or 

under  the  mucosa,  soon  be- 
coming associated  with  abundant  granulation  tissue  which  undergoes  casea- 
tion, but  causes  great  thickening  of  the  walls  of  these  organs. 


The  ureter  becomes  a  wide  but  rigid  tube,  with  ragged  ulcerated  lining,  and  is  easily 
felt  through  the  abdominal  wall.  In  the  bladder  miliary  and  conglomerate  tubercles 
occur  in  the  mucosa.  especially  of  the  trigonum,  followed  later  by  shallow,  ragged 
ulcerations  with  nodular  base.  The  seminal  vesicles  show  tubercles  in  the  mucosa,  or 
the  wall  is  thickened  and  the  lumen  choked  with  the  product  of  its  caseation.  Distinct 
tubercles  are  not  usually  seen  in  the  prostate,  but  the  gland  becomes  enlarged  and 


TUBERCULOSIS  681 

riddled  with  caseous  patches.  The  vasa  deferentia  are  enlarged  and  filled  with  caseous 
material,  so  as  to  be  impervious,  and  in  quite  the  same  way  the  tuberculous  epididymis 
(Fig.  334)  forms  a  great  caseous  mass  which  may  discharge  by  fistulse  through  the  skin 
of  the  scrotum.  Invasion  into  the  testicle  may  take  the  same  form,  or  there  are  scattered 
tubercles. 

In  the  ovary  tubercles  may  be  found  in  preformed  cysts  or  in  the  tissue  itself,  the  case- 
ation  and  softening  of  which  produce  a  cavity.  The  Fallopian  tubes  behave  much  like 
the  seminal  vesicles — their  walls  are  sometimes  thickened  and  studded  with  small 
tubercles,  which,  when  on  the  outside,  appear  really  as  a  form  of  localized  tuberculous 
peritonitis.  The  tube  may  later  become  distended  and  obstructed  with  caseous  sub- 
stance. In  the  uterus  caseation  of  the  endometrium  of  the  fundus  is  not  very  rare. 


LITERATURE 

Benda:  Orth's  Festschrift,  Berlin,  1903,  520. 
Sawamura:  Deutsch.  Arch.  f.  Chir.,  1910,  ciii,  203. 
Walker:  Johns  Hopkins  Hosp.  Reports,  1911,  xvi,  1. 


Tuberculosis  of  the  Nervous  System. — The  central  nervous  system  does 
not  escape  tuberculous  infection,  which  is  usually  carried  to  it  by  the  blood- 
stream, although  occasionally  it  may  be  due  to  direct  extension  from  a 
caseous  focus  in  neighboring  bony  structures.  In  the  substance  of  the 
brain  or  cord  caseating  tubercles  of  every  size  appear.  These  may  be 
multiple,  and  are  found  scattered  everywhere  as  yellow,  opaque,  caseous 
nodules  surrounded  by  a  hsemorrhagic  zone.  It  is  in  the  brain  that 
there  occur  sometimes  tumor-like  caseous  masses  of  great  size,  which  are 
merely  enormously  overgrown  caseous  tubercles.  These  "solitary  tuber- 
cles" cause  great  disturbances  both  through  the  destruction  of  tissue  and 
the  pressure  which  they  produce.  In  the  spinal  cord  they  are  especially 
sure  to  interrupt  important  conducting  tracts. 

When  the  bacilli  are  not  thus  localized  in  certain  areas  in  the  brain,  they 
may  be  carried  into  the  meninges  and  there  produce  miliary  tubercles, 
or  more  commonly  a  combination  of  tubercles,  with  an  effusion  of  cellular 
and  fluid  exudate  which  constitutes  tuberculous  meningitis.  This  is  often 
spoken  of  as  basilar  meningitis,  since  the  exudate  is  likely  to  be  found 
especially  over  the  pons,  the  floor  of  the  third  ventricle,  and  the  optic 
chiasm.  Nevertheless,  it  extends  into  the  fissures  over  the  surface  of 
the  brain,  and  on  pulling  open  the  Sylvian  fissure,  one  can  nearly  al- 
ways find  tubercles  along  the  blood-vessels  with  the  yellowish  exudate 
about  them. 

The  ependymal  lining  of  the  ventricles  usually  presents  similar  minute 
tubercles  on  its  surface,  and  the  ventricles  are  often  distended  with  a  turbid 
flaky  fluid  constituting  an  inflammatory  hydrocephalus.  The  accumula- 
tion of  fluid  is  increased,  however,  by  the  obstruction  to  its  outflow  caused 
by  the  obliteration  of  the  foramina  of  Majendie  and  Luschka  or  of  the 
meshes  and  cisternse  of  the  arachnoid,  by  the  dense  exudate.  In  the 
meninges  the  tuberculous  lesions  develop  in  the  walls  of  the  vessels,  where 


682 


TEXT-BOOK   OF   PATHOLOGY 


they  may  be  seen  in  sections  (Fig.  335)  as  eccentric  thickenings  affecting 
especially  the  adventitial  coat,  but  causing  also  an  obliterative  growth 
of  the  intima.  The  media  is  generally  passively  invaded  and  destroyed 
by  the  growth  of  the  mass.  Such  tubercles  are  usually  not  sharply  de- 
nned, like  those  miliary  tubercles  seen  in  the  liver  or  a  lymph-gland,  but 
appear  as  irregular  collections  of  epithelioid  cells  by  no  means  concentric- 
ally arranged.  Ordinarily  the  person  dies  before  any  extensive  caseation 


?*\ 


'        •          .»  •. 


^     ''"••*£  "*"^-****  ^''•« 


: 


Fig.  335. — ^A  portion  of  the  meninges  from  a  case  of  tuberculous  meningitis,  showing  the 
formation  of  a  thick  wall  of  tuberculous  tissue  in  the  adventitia  of  each  vessel. 


occurs,  and  generally  the  tubercles  are  found  translucent.  They  are  in 
the  most  acute  cases  surrounded  on  all  sides  by  an  exudate  which  distends 
the  meshes  of  the  pia,  and  even  overflows  on  its  surface.  This  exudate 
is  rich  in  fibrin  and  full  of  mononuclear  wandering  cells,  many  of  which 
are  of  the  lymphoid  form,  while  the  large,  pale  phagocytic  forms  with 
abundant  protoplasm  are  very  numerous  and  give  a  special  character 
to  the  exudate.  Polymorphonuclear  leucocytes  are  in  the  minority, 
if  they  are  present  at  all. 


TUBERCULOSIS  683. 

Tuberculosis  of  the  Ductless  Glands. — Among  the  organs  of  internal 
secretion  the  only  instance  in  which  we  know  that  tuberculous  disease  is  of 
practical  importance  is  that  of  the  adrenal  glands.  Miliary  and  conglomer- 
ate tubercles  occur  there,  but  more  commonly  extensive  caseous  areas 
develop  which  can  involve  the  whole  gland  on  both  sides  and  destroy  it 
completely.  In  such  cases  Addison's  disease,  of  which  we  shall  speak  in 
another  place,  generally  follows. 

Tuberculosis  of  the  Skin. — In  the  skin  there  are  certain  definitely  tuber- 
culous conditions,  among  which  lupus  vulgaris  is  the  most  common,  in 
which  the  bacilli  may  be  found  producing  tubercles  and  tuberculous  granu- 
lation tissue.  Recently  in  a  case  of  generalized  miliary  tuberculosis  I  have 
seen  numerous  papules  and  vesicles  scattered  all  over  the  body  and  contain- 
ing tubercle  bacilli.  There  are  other  lesions  of  the  skin,  however,  such  as 
lichen  scrophulosorum,  which  are  known  as  tuberculides,  and  which,  though 
always  associated  with  tuberculosis,  have  yet  been  studied  without  avail 
in  the  search  for  bacilli  or  tuberculous  tissue.  They  have  been  thought  to 
be  due  to  diffused  toxins,  or  even  to  be  the  expression  of  an  anaphylactic 
reaction. 

Tuberculosis  of  Bones  and  Joints. — This  subject  is  so  far  reaching  in 
its  details  that  no  attempt  can  be  made  here  to  give  more  than  the  barest 
outline.  For  the  rest,  surgical  works  must  be  consulted. 

The  bacilli  are  brought  to  the  bones  and  joints  by  the  blood-stream  or  by 
extension  from  a  neighboring  lesion.  It  is  especially  in  the  bones  that 
traumatism  aids  in  the  development  of  the  infection  by  forming  a  point  of 
lowered  resistance  where  the  bacteria  can  gain  a  foothold.  Accordingly,  it 
is  not  uncommon  to  find  lesions  formed  in  the  bones  in  the  apparent  absence 
of  tuberculosis  elsewhere. 

Tuberculous  lesions  usually  begin,  as  Guillemain  has  maintained  in 
opposition  to  Konig,  in  the  bone  rather  than  in  the  synovial  cavities 
of  the  joints,  and  it  is  the  cancellous  bone  which  is  usually  first  involved — 
practically  never  the  shafts  of  long  bones.  Miliary  tubercles  may,  of 
course,  occur,  but  far  more  important  is  the  tuberculous  osteomyelitis, 
which  is  not  part  of  a  general  miliary  tuberculosis.  This  begins  in  one  of 
the  short  bones,  such  as  a  vertebra  or  tarsal  bone,  or  in  the  epiphyseal 
ends  of  the  long  bones,  and  is  doubtless  the  result  of  the  lodgment  of  the 
bacilli  in  a  small  vessel.  Miliary  and  conglomerate  tubercles  with  tuber- 
culous granulation  tissue  form  in  the  cancellous  bone,  and  caseation  occurs 
more  or  less  rapidly.  Some  authors  distinguish  as  "fungous"  forms  those 
in  which  the  granulation  tissue  persists  a  long  time  without  caseation. 
In  any  case  the  bone  lamellae  are  destroyed  or  remain  as  splinters.  Hardly 
any  new  bone  formation  occurs  around  the  focus — indeed,  it  is  not  un- 
common to  find  a  great  rarefaction  with  replacement  of  the  marrow  by  fat. 
Such  a  caseous  area  often  extends  in  pyramidal  or  rounded  form  to  the 
joint  surface,  whereupon  the  joint  becomes  infected  also;  the  cartilage 
becomes  necrotic,  uplifted,  and  softened.  At  first,  miliary  tubercles 


684 


TEXT-BOOK   OF   PATHOLOGY 


may  appear  on  the  synovial  membranes,  with  effusion  of  fluid.  Later  the 
joint  is  lined  by  a  tuberculous  granulation  tissue,  and  the  condition  may 
last  for  a  long  time,  with  persistence  of  the  fluid,  induration  of  the  tissues 
around  the  joint,  formation  of  polypoid  clusters  of  fat  tissue  and  of  small 
hyaline  bodies,  like  rice  grains,  in  its  cavity.  Irregular  erosions  of  the 


Fig.  336. — An  old  healed  tuberculous  lesion  of  the  hip  which  has  left  the  acetabulum 
greatly  distorted  and  with  numerous  exostoses. 


surfaces  occur,  and  indeed  there  follow  the  most  extensive  excavations  into 
the  bone,  with  collapse  and  wide  destruction  of  the  mechanism  of  the  joint. 
Fistulse  are  burrowed  out  through  the  surrounding  muscles  and  fascise  to 
the  skin,  through  which  caseous  debris  and  spicules  of  bone  are  discharged. 
Such  destructive  processes  are  very  common  in  the  hip-joint  and  especially 


TUBERCULOSIS 


685 


in  children.  The  whole  head  of  the  femur  may  be  destroyed  and  the  bone 
dislocated.  To  relieve  the  tenderness  and  pain  the  leg  is  drawn  up  and 
rotated  inward,  and  through  disuse  it  atrophies.  When  the  joint  disease 
heals,  there  remains  the  condition  so  often  seen  in  people  in  the  street  who 
walk  with  the  affected  leg  held  stiffly  bent  and  with  the  aid  of  a  crutch. 

Tuberculosis  of  a  vertebra  pro- 
ceeds in  practically  the  same  way 
(Fig.  337).  When  caseation  has  ad- 
vanced far  enough  to  soften  the 
bone,  the  affected  centrum  is  crushed 
together  by  the  weight  of  the  body, 
and  an  angular  deformity  of  the 
spine  ensues.  The  burrowing  of  the 
material  produced  in  this  process 
under  the  sheath  of  the  psoas  mus- 
cle, to 'appear  below  Poupart's  liga- 
ment, gives  rise  to  the  so-called 
psoas  abscess.  A  similar  thing  can 
happen  in  the  case  of  other  bones, 
and  we  have  seen  recently  an  ex- 
tensive burrowing  from  the  region 
of  a  tuberculous  knee-joint. 

Tuberculosis  of  the  bones  of  the 
face  and  of  the  ribs  is  generally  in 
the  beginning  a  periosteal  affection 
which  erodes  the  bone  and  pro- 
duces accumulations  of  caseous 
material — the  so-called  "cold  ab- 
scess." In  the  fingers  there  may 
be  central  caseation  in  the  diaphy- 
sis  of  the  phalanges,  with  secondary 
new-growth  of  bone  outside.  The 

enlargement  of  the  internal  cavity  and  the  repetition  of  the  reparatory 
process  result  finally  in  a  spindle-shaped  enlargement  of  the  bony  shell 
(spina  ventosa). 

LITERATURE 

Hartel:  "Tuberc.  Peritonitis,"  Ergeb.  d.  Chir.,  1913,  vi,  370. 

Fedor  Krause:  "Tuberculosis  of  Bones,"  Deut.  Chirurgie,  1899,  Lief  28a. 

F.  Konig:  Tuberculose  d.  Knochen  u.  Gelenke,  Berlin,  1884. 


Fig.  337. — Tuberculosis  of  the  verte- 
brae, with  caseation  and  collapse  of  the 
centra  which  cause  compression  of  the 
spinal  cord. 


CHAPTER  XXXIV 
TYPES  OF  INJURY.— INFECTIONS  OF  UNCERTAIN  NATURE 

Typhus:  Epidemic  distribution.  Anatomical  lesions.  Experimental  studies,  transmis- 
sion by  lice.  A  bacillus  recently  discovered. 

Acute  poliomyelitis:  Infectious  nature.  The  organism.  Febrile  illness,  subsequent  paraly- 
sis. Lesions  of  nervous  system. 

TYPHUS  INFECTION 

THE  disease  has  long  been  recognized  as  occurring  in  great  epidemics  with 
high  mortality.  In  1819  and  1846  it  raged  with  especial  violence  in  Eng- 
land and  Ireland,  although  extensive  epidemics  had  been  more  common  in 
Russia  and  the  Balkan  countries.  It  is  a  disease  which  associates  itself 
with  the  crowding  and  unsanitary  conditions  of  war  and  famine.  It  was 
common  in  prisons.  We  are  even  now  hearing  daily  of  its  ravages  in  the 
Balkan  States,  where  all  the  favoring  conditions  exist. 

In  spite  of  the  unfortunate  choice  of  name  (Typhus  exanthematicus), 
it  has  nothing  whatever  to  do  with  typhoid  fever  (typhus  abdominalis). 
The  distinction  between  the  two  diseases  was  clearly  made  by  W.  W.  Ger- 
hard in  a  vivid  description  which  is  to  be  found  in  the  American  Journal 
of  the  Medical  Sciences,  1836,  after  Louis  had  described  the  lesions  of 
typhoid. 

Typhus  is  an  acute  infectious  disease  marked  by  high  fever,  intense  illness 
and  weakness,  an  outbreak  of  a  macular  or  papular  eruption  which  is  often 
hsemorrhagic,  laryngitis,  with  cough  or  the  more  serious  symptoms  of 
lobular  pneumonia.  Death  occurs  with  evidence  of  general  intoxication 
and  circulatory  collapse. 

Lesions. — At  autopsy  there  has  been  found  until  recently  only  the 
general  condition  found  in  nearly  all  acute  infectious  diseases,  namely, 
an  acute  splenic  tumor  and  some  cloudiness  of  the  organs.  But  many 
investigators  have  taken  advantage  of  the  opportunities  for  the  study 
of  the  disease  which  occurred  during  the  war  when  typhus  was  so  prev- 
alent, and  new  pathological  changes  have  been  found.  They  are  well 
described  by  Nicol,  although  neither  he  nor  any  of  the  other  students  of 
this  disease  demonstrate  any  relationship  between  these  lesions  and 
any  of  the  setiological  agents  which  have  been  described.  They  consist 
in  vascular  changes  in  the  brain,  affecting  especially  the  minuter  vessels 
of  the  medulla,  but  also  those  of  other  parts  of  the  brain,  of  the  skin, 
and  of  the  heart  muscle.  The  lesion  is  an  arteriolitis  and  periarteriolitis 
nodosa,  with  circumscribed  proliferation  and  accumulation  of  wandering 
cells  and  leucocytes  about  the  arteriole,  but  beginning  with  proliferation 

686 


TYPHUS   INFECTION  687 

and  necrosis  of  the  endothelium.  The  illustrations  show  a  perivascular 
infiltration  much  like  that  seen  in  the  brain  of  cases  of  encephalitis 
lethargica,  for  which  the  causative  factor  is  also  unknown.  It  is  pointed 
out  that  the  localization  of  these  lesions,  which  bring  with  them  some  ob- 
struction of  the  small  vessels,  may  well  explain  those  symptoms  which 
depend  upon  disturbances  in  the  function  of  the  important  organs  which 
are  represented  in  the  nuclei  in  the  floor  of  the  fourth  ventricle. 

Brill  has  recognized  the  existence  of  a  disease  in  New  York  which  has 
all  the  characteristics  of  mild  typhus  infection,  and  there  is  in  Mexico 
another  affection,  called  tabardillo,  which  is  quite  similar. 

Experimental  work  in  recent  years  has  done  a  good  deal  to  clear  up  the 
nature  and  relation  of  these  infections,  although  it  is  by  no  means  finished. 
Nicolle,  Goldberger  and  Anderson,  Ricketts,  and  Wilder  have  studied 
especially  the  transmission,  using  monkeys  as  test  animals.  Nicolle  and 
his  associates  found  that  they  could  transmit  the  typhus  found  in  Tunis 
to  monkeys  by  inoculating  the  blood  of  patients.  Further,  that  while  it 
became  evident  that  infection  is  not  transferred  directly,  nor  through 
bedding,  clothes,  etc.,  nor  by  fleas  or  bed-bugs,  it  could  be  shown  that  the 
body-louse  (Pediculus  vestimentorum),  becomes  infected  by  biting  those 
who  have  the  disease  and  transmits  it  in  full  virulence  by  biting  others. 
Goldberger  and  Anderson,  and  Ricketts,  were  able  to  confirm  this  in  Mexico 
by  allowing  such  infected  lice  to  bite  monkeys  or  by  grinding  them  and 
injecting  a  suspension  of  their  bodies  subcutaneously.  The  monkeys  de- 
velop a  fever  and  sometimes  die,  but  do  not  show  the  roseola  which  is  so 
characteristic  of  human  infection.  Nevertheless  they  become  immune  and 
after  recovery  are  insusceptible  even  to  injections  of  blood  from  a  typhus 
patient.  All  this  is  also  true  of  Brill's  disease,  and  Goldberger  and  Ander- 
son think  it  therefore  identical  with  Mexican  and  European  typhus.  They 
found  in  Mexico  that  the  causative  agent  is  too  large  to  pass  through  a 
Berkefeld  filter,  but  could  not  associate  it  with  any  particular  element  of 
the  blood.  They  found,  however,  a  bacillus  in  the  blood  which  they  could 
not  cultivate.  The  question  remains  undecided,  therefore,  whether  the 
virus  which  causes  the  disease  is  merely  transferred  by  the  louse,  or  under- 
goes some  stage  of  development  in  its  body.  Even  the  fact  that  the  lice 
appear  not  to  be  able  to  transfer  the  infection  until  a  period  of  four  or 
five  days  has  elapsed  may  mean  that  only  after  that  period  has  the  or- 
ganism multiplied  to  a  sufficient  quantity  for  infection,  and  not  that  it 
has  undergone  part  of  a  definite  life  cycle  within  the  louse. 

The  general  impression  of  typhus  fever  at  this  stage  was  that  it  resembled 
closely  such  other  diseases  as  are  transmitted  by  insects  and  would  probably 
turn  out  to  be  caused  by  a  parasite  of  protozoan  character.  We  have, 
however,  in  the  plague,  a  good  example  of  a  bacterial  disease  transmitted 
by  fleas. 

Quite  recently,  Plotz,  of  Mount  Sinai  Hospital,  New  York  City,  has 
stated  that  he  finds  in  all  cases  of  Brill's  disease  and  of  imported  typhus 


688  TEXT-BOOK   OF   PATHOLOGY 

fever  an  anaerobic,  Gram-staining  bacillus  in  the  circulating  blood  which 
produces  the  disease  on  being  inoculated  in  pure  culture  into  animals, 
and  which  is  agglutinated  by  the  blood-serum  of  the  patients.  Prac- 
tically every  postulate  for  the  recognition  of  the  cause  of  a  disease  has 
been  fulfilled  by  Plotz  in  connection  with  this  bacillus,  and  it  is  to  be  hoped 
that  the  problem  is  solved.  It  is  too  soon,  however,  to  judge,  and  there 
are  many  who  find  the  results  inconclusive. 

Despite  many  publications  during  the  last  three  years  on  the  aetiology 
of  this  disease,  it  cannot  be  said  that  any  one  of  the  numerous  bacteria, 
protozoa,  and  spirochaetes  appears  to  have  a  clear  title  to  that  distinction. 
The  Weil-Felix  agglutination  reaction  with  a  form  of  Bacillus  proteus 
has  attracted  much  attention. 

LITERATURE 

Ceelen:  Med.  Klin.,  1916,  xii,  402. 
Jaffe:  Ibid.,  1918,  xiv,  210. 

von  Prowazek:  Beitr.  z.  Klin.  d.  Infektionskr.,  1914-16,  iv,  5. 
Nicol:  Ziegler's  Beitr.,  1919,  Ixv,  120. 

Curschmann:  Das  Fleckfieber,  Nothnagel's  Spec.  Path.  u.  Ther.,  1900,  iii,  Th.  2. 
Virchow:  Virch.  Arch.,  1849,  Bd.  ii,  143;  iii,  154. 

Nicolle,  Comte,  and  Conseil:  Comptes  Rendus  Acad.  de  Sci.,  1909,  cxlix,  157,  486. 
Goldberger  and  Anderson:    Hygienic  Laboratory  Bull.,  1912,  No.  86.     Public  Health 

Reports,  1910,  xxv,  177;  ibid.,  1912,  xxvii,  71. 
Ricketts  and  Wilder:  Jour.  Amer.  Med.  Assoc.,  1910,  liv,  463. 
Brill,  N.  E.:  Amer.  Jour.  Med.  Sci.,  1910,  cxxxix,  484;  1911,  cxlii,  196. 
Friedmann:  Arch,  of  Int.  Med.,  1911,  viii,  427. 
Plotz,  Olitsky,  Baehr:  N.  Y.  Path.  Soc.,  1915,  xv,  41;  Jour.  Infect.  Dis.,  1915,  xvii,  1. 

ACUTE  POLIOMYELITIS  (HEINE-MEDIN'S  DISEASE;  INFANTILE  PARALYSIS) 

Recent  studies  have  shown  that  this  disease  of  children,  which  was  formerly 
regarded  as  a  type  of  paralysis  with  sudden  and  unheralded  onset,  is  really 
an  acute  infectious  disease  which  is  transmitted  from  person  to  person, 
occurs  in  epidemics,  and  can  be  reproduced  by  inoculation  in  monkeys 
(Popper  and  Landsteiner,  Flexner).  Indeed,  it  has  been  shown  that  the 
causative  agent  is  small  enough  to  pass  through  a  porcelain  filter  (Flexner, 
Landsteiner),  that  it  can  be  grown  in  pure  culture,  and  that  it  will  produce 
the  disease  in  animals  (Flexner,  Noguchi).  The  precise  nature  of  the 
organism  and  its  relations  to  other  living  beings  are  not  made  clear,  but 
it  is  said  to  be  an  extremely  minute  globoid  body,  coccus-like  in  form, 
sometimes  appearing  in  chains  and  causing  a  clouding  of  the  fluid  medium. 
It  can  be  isolated  from  the  infected  brain  and  cord  and  can  be  shown  to 
be  present  in  the  nasal  mucosa  of  inoculated  monkeys  and  persons  ill  of  the 
disease.  It  seems  that  all  the  postulates  for  the  proof  of  the  relation  of  an 
organism  to  a  disease  have  been  fulfilled  in  this  case.  Several  other  in- 
vestigators have  attempted  to  show  that  a  streptococcus  is  constantly 
present  in  these  cases  and  may  well  be  regarded  as  the  setiological  factor, 
but  these  claims  have  been  satisfactorily  refuted  by  Flexner,  Bull,  and 
others. 


ACUTE    POLIOMYELITIS  689 

The  disease  begins,  usually  in  children,  with  vomiting,  fever,  leucocytosis, 
and  general  malaise.  Pain  in  the  back,  neck,  and  extremities  is  nearly 
always  present  and  is  sometimes  extreme,  so  that  the  child  winces  and  cries 
out  on  being  moved.  After  several  days'  illness,  paralyses  suddenly  appear 
and  extend  to  involve  one  or  both  legs  or  a  leg  and  arm  or  even  all  the  ex- 
tremities, together  with  the  trunk  muscles.  Paralyses  of  the  muscles  sup- 
plied by  the  cranial  nerves  are  not  frequent.  When  the  respiratory  muscles 
are  thus  involved,  death  ensues. 

The  paralysis  is  most  commonly  of  the  flaccid  type  but  in  some  cases  it  is 
spastic.  The  mortality  is  fairly  high  but  many  cases  recover  with  perma- 
nent paralysis.  Atrophy  of  the  muscles  with  subsequent  contractures 
lead  to  the  most  crippling  deformities.  On  the  other  hand,  there  are  many 
so-called  abortive  cases  in  which,  after  the  initial  febrile  symptoms  are 
over,  recovery  takes  place  without  any  paralysis.  Survival  of  the  disease 
leaves  an  immunity,  and  the  serum  of  such  immune  individuals  has  a  pro- 
tective effect  in  animals  inoculated  with  the  disease-producing  agent.  It 
is  through  the  discovery  of  the  existence  of  such  an  immunity  that  one  may 
recognize  those  persons  who  have  passed  through  an  abortive  attack. 

Transmission. — Doubtless  they,  as  well  as  those  more  seriously  affected, 
can  act  as  carriers  and  transmitters  of  the  disease,  and  it  was  partly  through 
the  recognition  of  this  fact  that  the  chain  of  events  could  be  made  complete 
in  the  explanation  of  the  epidemic  occurrence  of  this  affection.  An  at- 
tempt was  made  to  show  that  the  transfer  of  infection  was  effected  by  the 
bites  of  stable  flies,  but  further  study  has  proved  that  this  is  not  true. 
Flexner  has  shown  that  it  is  difficult  to  inoculate  monkeys  successfully,  but 
that  repeated  apparently  ineffectual  inoculations  may  finally  produce  the 
disease.  The  subdural  inoculation  of  material  from  the  brain  or  cord  of  a 
case  of  poliomyelitis  is  the  most  effective  means  of  transmission,  but  mon- 
keys can  also  be  infected  through  the  nasal  mucosa.  When  the  virus  is 
injected  into  the  blood,  it  requires  a  much  longer  time  to  develop.  It 
seems,  therefore,  that  the  organisms  must  gain  access  to  the  cerebrospinal 
fluid,  either  by  direct  transmission  from  the  nasal  passages  or  possibly  along 
the  lymphatics  of  the  nerve-sheaths.  Perhaps  the  tonsils  and  digestive 
tract  may  play  some  part  as  portals  of  entry. 

Lesions. — The  chief  lesions  are  found  in  the  central  nervous  system, 
and  commonly  the  predominant  changes  are  found  in  the  anterior  part  of 
the  spinal  cord.  There  are  such  variations,  however,  that  Mtiller  has 
proposed  a  division  into  cerebral,  bulbar  and  spinal  forms.  Peabody, 
Draper  and  Dochez  suggest  what  seems  a  better  division,  into  affections  of 
the  upper  and  of  the  lower  neurone,  but  this  too  is  open  to  objections.  It 
is  useful  in  separating  the  spastic  cases  which  are  affections  of  the  upper 
motor  neurone  from  those  with  flaccid  paralysis  in  which  the  anterior  horn 
ganglion-cells  are  especially  attacked.  The  changes  begin,  as  can  be 
studied  in- experimental  animals  and  in  the  cases  which  end  fatally  in  the 
early  stages,  with  hypersemia  of  the  pia  and  of  the  blood-vessels  which  pass 


690 


TEXT-BOOK    OF    PATHOLOGY 


into  the  cord  through  the  anterior  fissure  and  with  the  accumulation  of 
lymphocytes  and  polymorphonuclear  leucocytes  about  them  (Fig.  338). 
This  process  quickly  extends  into  the  substance  of  the  cord,  and  not  only 
in  the  gray  matter  of  the  anterior  horns,  as  was  formerly  thought,  but 
everywhere,  the  small  arterioles  and  venules  are  found  surrounded  with  a 


J;v  '^?^ 

•••  -;  :-     •"  ::"' 


*36SS9Sai 


Fig.  338.— Acute  poliomyelitis.  Spinal  cord,  showing  a  portion  of  the  gray  matter 
infiltrated  with  leucocytes  accumulated  about  the  vessels.  Ganglion-cells  of  the  anterior 
horn  have  become  indistinct  or  lost. 

mantle  of  such  cells.  Isolated  groups  of  leucocytes  are  scattered  through 
the  tissue.  Destructive  changes  become  apparent  in  the  ganglion-cells, 
perhaps  especially  in  those  of  the  anterior  horn,  and  they  are  soon  found  to 
be  in  the  process  of  disintegration  or  shrinkage.  There  is  disintegration  and 
fusion  of  the  tigroid  bodies  and  later  the  nucleus  in  each  cell  shrinks  and 
becomes  deeply  stained  or  fades  away  and  disappears.  Direct  invasion  of 


ACUTE    POLIOMYELITIS  691 

phagocytic  cells  into  the  bodies  of  such  ganglion-cells  is  often  observed 
and  the  remains  are  surrounded  by  a  cluster  of  them.  Many  writers  try 
to  show  that  the  mechanical  effect  of  the  inflammation  causes  the  injury 
to  the  ganglion-cells,  but  it  seems  more  probable  that  it  is  the  direct  result 
of  the  presence  of  the  infective  agent. 

With  recovery,  the  injured  ganglion-cells  disappear  completely,  and  after 
the  fading  of  the  inflammatory  reaction  the  place  is  occupied  by  a  dense 
neuroglia  scar.  Quite  analogous  lesions  are  found  in  the  medulla  oblongata, 
where  the  nuclei  of  cranial  nerves  become  affected,  and  in  the  higher  parts 
of  the  brain  as  well.  This  is  referred  to  as  polioencephalitis  (Strumpell). 

In  the  other  organs  less  characteristic  changes  are  found,  but  reference 
may  be  made  to  minute  focal  necroses  of  liver-cells  with  lymphocyte  ac- 
cumulation, and  to  similar  changes  in  the  lymph-glands  which  have  been 
described  by  Peabody,  Draper,  and  Dochez.  In  such  lymph-glands  the 
sinuses  are  filled  with  large  phagocytic  cells,  as  in  typhoid  fever.  Cloudy 
swelling  of  liver  and  kidneys  is  usual. 

LITERATURE 

Amoss:  Jour.  Exp.  Med.,  1917,  xxv,  545. 

Bull:  Ibid.,  557. 

Wickman:    Heine-Medinsche  Krankheit,  Berlin,   1907.     Akute  Poliomyelitis,  Berlin, 

1911.     Transl.    New  York,  1913. 
Harbitz  and  Scheel:   Ak.  Poliomyelitis  u.  verwandte  Krankheiten,  Christiania,  1907. 

Jour.  Amer.  Med.  Assn.,  1907,  xlix,  1420;  lix,  782.     Dtsch.  med.  Woch.,  1907, 

xxiii,  1992. 

I.  Strauss:  Rep.  Collective  Investig.  Comm.  N.  Y.  Epidemic,  1907. 
Peabody,  Draper,  and  Dochez:  Ac.  Poliomyelitis,  Rockefeller  Inst.  Monographs,  1912, 

No.  4. 
Flexner,  with  Lewis,  Noguchi,  and  Amoss:    Many  papers  in  Jour.  Exp.  Med.,  1913, 

xviii,  461;    1914,  xix,  411;   xx,  249;    1915,  xxi,  91,  etc.     Jour.  Amer.  Med.  Assn., 

1913,  Ix,  362,  etc. 


CHAPTER  XXXV 
TYPES  OF  INJURY.— SPIROCILETAL  INFECTION 

Syphilis:  ^Etiology  and  distribution.  Course  of  the  disease.  Nature  of  different 
Immunity  and  transmission.  Primary  stage,  secondary  lesions,  tertiary  stage.  Lymph- 
glands,  blood,  digestive  tract,  liver,  respiratory  tract,  bones  and  joints,  heart  and  blood- 
vessels, nervous  system.  Syphilitic  lesions  of  genital  organs.  Orchitis. 

SYPHILIS 

Etiology  and  Distribution. — Syphilis  is  an  infectious  disease  caused  by  in- 
vasion of  the  Spirochseta  pallida,  an  organism  discovered  by  Schaudinn 
and  Hoffman  in  1905.  The  disease  itself  had  been  studied  in  great  detail 
throughout  centuries,  and  numerous  other  supposed  causes  had  been  de- 
scribed, but  the  discovery  of  the  true  setiological  factor  has  caused  a  great 
flood  of  light  to  be  shed  upon  it  during  the  few  years  which  have  followed. 

The  infection  is  not  one  which  remains  local — instead,  it  gives  rise  in 
each  case  to  a  generalized  distribution  of  the  organisms  with  numerous 
local  manifestations,  often  due  to  concentration  of  the  spirochsetse  in  those 
places. 

First  introduced  through  an  abrasion  of  the  skin  or  through  a  mucous 
surface,  it  produces  within  a  short  time  a  general  septicaemia,  which  in  turn 
gives  rise  to  the  local  lesions,  almost  countless  in  their  variety. 

The  organism  is  not  limited  to  man  as  its  host,  although  until  the  recent 
experimental  work,  it  seems  to  have  been  practically  so  limited.  It  is  now 
known  that  anthropoid  apes,  and  indeed  most  of  the  monkey  tribe,  even  to 
the  lower  forms,  are  susceptible,  and  that  with  proper  precautions  rabbits, 
sheep,  goats,  and  other  animals  may  be  successfully  inoculated.  Not  in 
all  these  animals  do  the  lesions  present  themselves  in  form  and  order  like 
those  found  in  the  human  being,  but  all  the  postulates  necessary  to  prove 
the  relation  of  the  organism  to  the  disease,  whether  produced  experi- 
mentally or  not,  have  been  complied  with,  including  the  isolation  and  pure 
culture  of  the  spirochaetse  in  an  artificial  medium. 

Ordinarily  the  disease  is  transmitted  by  coitus,  but  it  is  also  quite  fre- 
quently traceable  to  extragenital  infection,  as  through  kissing,  the  use  of 
infected  utensils,  towels,  etc.,  or  through  shaving  with  an  infected  razor. 
The  danger  to  surgeons  and  dentists  of  infecting  their  fingers  through  cuts 
or  abrasions  during  an  operation  upon  a  syphilitic  is  considerable. 

Course  of  the  Disease. — Syphilis  is  usually  a  very  slowly  progressing 
disease,  and  except  in  the  so-called  "  syphilis  maligna,"  it  advances  pretty 
regularly  through  a  series  of  stages  first  clearly  recognized  by  Ricord. 
Thus,  after  an  incubation  period  of  varying  duration  (8  to  40  days),  there 

692 


SYPHILIS  693 

appears  a  characteristic  local  lesion  which  often  ulcerates  at  the  point  of 
inoculation.  Regional  lymph-glands  become  infected  and  swollen. 

After  a  second  incubation  period  of  varying  length,  often  eight  to  ten 
weeks  after  the  first  infection,  there  appear  in  the  skin  and  mucous  surfaces 
new  manifestations  caused  by  a  distribution  of  the  spirochaBtse  by  the  blood 
and  their  multiplication  in  certain  places.  These  are  the  lesions  of  the 
secondary  stage,  and  here  the  greatest  variety  of  form  is  shown.  Lymph- 
glands  in  general  are  enlarged,  and  some  other  tissues,  such  as  the  iris, 
cerebral  vessels,  testes,  etc.,  may  be  involved.  The  secondary  lesions 
usually  heal  without  leaving  any  great  destruction  behind  them. 

After  another  period,  which  may  stretch  out  over  very  many  years  during 
which  the  patient  has  supposed  himself  cured,  the  destructive  lesions  of  the 
tertiary  stage  appear.  These  arise  in  any  situation  in  the  internal  organs 
or  the  skin — no  tissue  seems  exempt.  Characteristic  is  the  formation  of 
tubercle-like  nodules,  often  of  large  size  and  firm  consistence  (gummata), 
becoming  caseous  internally  and  ending,  after  wide  destruction  of  tissue, 
in  healing  which  leaves  behind  a  most  extensive  scar.  Or  a  less  char- 
acteristic, wide-spread,  cellular  granulation  tissue  may  in  the  same  way  lead 
to  destruction  of  the  tissue  and  distortion  from  scar  formation.  Warthin 
especially  emphasizes  this  in  what  he  calls  the  new  pathology  of  syphilis, 
and  describes  in  detail  focal  accumulations  of  plasma  and  lymphoid 
cells  about  the  small  vessels  and  in  the  interstices  of  almost  all  the  organs 
in  cases  of  late  and  often  unsuspected  or  latent  syphilis.  In  many  of 
these,  especially  in  the  heart,  blood-vessels,  and  central  nervous  system, 
but  also  in  the  pancreas,  adrenals,  and  testes,  he  has  sometimes  demon- 
strated the  spirochsetse,  while  others  are  recognized  as  syphilitic  by  their 
histological  identity  with  those  of  assured  origin.  These  lesions  are  so 
much  more  frequent  and  therefore  of  so  much  greater  significance  than 
definite  gummata  that  Warthin  objects  to  the  usual  statement  that  the 
gumma  is  the  characteristic  lesion  of  tertiary  syphilis.  In  autopsies  upon  un- 
treated Chinese  coolies  at  the  Tan  Tock  Seng  Hospital  in  Singapore  I  found 
gummata  so  regularly  and  in  a  form  so  suitable  for  the  illustration  of  a 
text-book  that  I  am  inclined  to  the  surmise  that,  were  it  not  for  a  certain 
inherited  immunity  in  our  race  and  the  effects  of  treatment,  the  gumma 
would  still  easily  hold  its  place  as  the  most  characteristic  feature  of  ter- 
tiary syphilis.  Nevertheless,  as  the  disease  exists,  Warthin  is  doubtless 
right  in  stating  that  the  less  conspicuous  but  wide-spread  and  destructive 
focal  lesions  are  much  more  important,  since  they  disable  the  vital 
organs. 

Following  the  tertiary  stage  there  may  appear  still  other  lesions  involving 
especially  injury  and  scarring  in  the  central  nervous  system  (tabes  and 
progressive  paralysis),  which  have  long  been  suspected  of  being  syphilitic 
and  spoken  of  as  parasyphilitic  affections.  Recently  the  spirocha3ta3 
have  been  demonstrated  in  these  tissues  (Noguchi)  and  the  matter  set 
upon  a  firm  basis.  Even  successful  treatment  by  specific  medication  has 


694  TEXT-BOOK    OF    PATHOLOGY 

been  carried  out.  Such  lesions  are  often  said  to  constitute  a  quaternary 
stage  of  the  disease. 

Thus,  syphilis  is  seen  to  be  a  generalized  infection  of  extraordinary 
chronicity  and  tenacity  in  which,  at  some  periods,  the  whole  blood  and 
tissues  of  the  host  are  infected  with  the  spirochsetse,  while  during  years  they 
seem  to  disappear  or  remain  hidden  somewhere  only  to  multiply  again  at 
some  point  and  produce  new  changes.  There  is  a  certain  regularity  in  the 
progression  of  the  different  stages,  although  the  length  of  time  required  for 
the  appearance  of  each  varies  extremely. 

It  was  at  one  time  thought  (Ricord)  that  a  person  who  had  once  had 
syphilis  was  quite  immune  from  further  infection,  and  also  that  while 
materials  from  the  primary  lesion  or  initial  sclerosis  as  well  as  those  from 
secondary  lesions  were  highly  infective,  the  tertiary  lesion  were  non- 
infective.  All  of  this  has  proven  untrue.  Finger  and  Landsteiner  showed 
that  a  gumma  contains  living  spirocha3tse  which  can  produce  an  initial 
lesion  followed  by  secondary  rashes  when  inoculated,  and  they  and  others 
have  also  shown  that  while  a  certain  increased  resistance  may  appear  after 
the  first  infection  a  new  inoculation  may  be  successful  in  any  stage  of  the 
disease  (superinfection).  There  are  many  instances  in  which  a  whole 
series  of  chancres  or  primary  lesions  has  appeared  as  the  result  of  successive 
exposures  to  infection. 

It  must  be  said,  however,  at  this  point,  that  inoculation  of  the  person's 
own  spirochsetse,  or  of  spirochsetse  of  foreign  origin,  when  it  causes  new 
lesions  to  develop  in  a  person  already  syphilitic,  produces  not  always  chancres 
but  lesions  which  belong  to  the  stage  of  the  disease  in  which  he  is.  Thus 
fresh  inoculation  of  a  man  harboring  tertiary  lesions  will  produce  a  gum- 
matous  or  tertiary  lesion  of  the  skin  and  not  a  chancre,  which  is  a  lesion  of 
the  primary  stage.  It  appears,  therefore,  that  the  stages  of  the  disease 
represent  different  reactions  to  the  same  poison  and  the  idea  has  been  sug- 
gested, though  perhaps  not  proven,  that  the  various  rashes  and  other  skin 
outbreaks  are  largely  allergic  phenomena. 

Congenital  Infection. — Syphilis  may  be  transmitted  from  infected 
parents  to  their  offspring  during  the  course  of  gestation,  so  that  they  are 
born  with  the  disease.  This  is  clearly  not  a  matter  of  inheritance,  but 
strictly  an  intra-uterine  infection.  As  to  the  mode  of  transmission  there  has 
been  much  dispute,  but  it  is  clear  that  the  infection  may  come  from  either 
the  father  or  the  mother.  It  is  shown  that  while  the  spirochseta  does  not 
actually  invade  the  sperm  cell,  as  has  been  surmised,  it  may  nevertheless 
accompany  it  mixed  in  the  spermatic  fluid  or  the  secretions  of  prostate 
or  seminal  vesicles.  When  the  mother  is  definitely  syphilitic  there  is 
little  doubt  that  the  transmission  occurs  through  the  placenta  by  passage 
of  the  spirochsetse  into  the  foetal  blood.  Sometimes  this  seems  to  occur 
only  in  the  late  stage,  during  partial  separation  of  the  placenta  and  direct 
admixture  of  maternal  and  fcetal  blood.  Then,  there  may  be  an  incuba- 
tion period  of  apparent  health  after  birth  before  the  symptoms  develop  in 


SYPHILIS  695 

the  child.  But  the  great  problem  is  whether  all  infection  of  the  offspring 
is  placental  or  whether  infection  of  the  foetus  alone  can  occur  from  the 
father,  excluding  any  transfer  of  spirochsetse  from  the  mother  through  the 
placenta.  This  question  is  particularly  suggested  by  the  fact  noticed  in 
1837  by  Colles,  that  a  woman  might  give  birth  to  a  syphilitic  child  and  nurse 
it  without  ever  showing  any  signs  of  syphilis  herself,  although  a  wet-nurse 
would  be  at  once  infected  by  the  child. 

This  is  the  so-called  Colles'  law,  and  it  seemed  to  show  that  the  mother 
was  immune  and  that  the  child  bore  the  whole  weight  of  the  infection  from 
the  father.  Recent  studies  show,  however,  that  the  mother,  even  though 
she  presents  no  lesions,  is  actually  infected  with  the  spirochsetae  and  that 
she  gives  a  positive  Wassermann  reaction.  The  so-called  exceptions  to 
Colles'  law,  in  which  such  a  mother  is  infected  with  syphilis  and  shows  the 
typical  symptoms,  must  be  examples  of  superinfection,  such  as  we  mentioned 
above.  More  difficult  to  explain  are  the  cases  in  which  a  mother  having 
given 'birth  to  a  syphilitic  child  byr  one  husband  produces  healthy  children 
by  another. 

Prof  eta's  law,  that  a  healthy  child  of  a  syphilitic  mother  is  immune,  is 
not  true — the  child  may  be  healthy,  but  it  is  susceptible  to  infection  from 
its  mother. 

The  weight  of  evidence  seems  to  be  in  favor  of  the  idea  that  if  a  syphilitic 
child  be  born  of  a  healthy  mother  and  a  syphilitic  father  it  is  because  the 
healthy  mother  has  been  infected  by  the  father  probably  by  way  of  the 
uterine  lining,  so  that  no  primary  lesion  is  observed  and  that,  after  all,  the 
placental  mode  of  transmission  may  play  the  important  part  in  the  infec- 
tion of  the  foetus. 

Immunity. — It  may  be  gathered  from  what  has  been  said  that  immunity 
in  syphilis  is  by  no  means  so  definite  as  in  such  diseases  as  smallpox  or 
yellow  fever,  but  that,  while  there  is  relative  insusceptibility,  a  new  infec- 
tion is  possible  at  any  stage.  Evidences  of  the  changed  reaction  of  the 
body  are  made  clear  in  various  ways,  however,  and  become  useful  in  making 
a  diagnosis.  Thus  the  so-called  Wassermann  reaction  depends  upon  the 
fact  that  the  complement  necessary  for  the  laking  of  a  sample  of  red  cor- 
puscles in  a  mixture  of  hsemolytic  amboceptor  and  corpuscles,  is  found  to 
have  been  used  up  if  it  is  first  treated  with  a  mixture  of  syphilitic  serum  and 
a  lipoid  antigen  represented  by  an  extract  of  a  known  syphilitic  organ  or 
even  an  alcoholic  extract  of  a  normal  heart,  whereas  when  treated  with 
normal  serum  and  this  antigen,  none  of  the  complement  is  absorbed  and 
haemolysis  proceeds. 

This  method  of  .deviation  of  complement  is  obviously  a  purely  empirical 
discovery,  although  it  seemed  at  first,  when  extracts  of  known  syphilitic 
organs  were  used  as  the  antigen,  to  be  a  very  purposeful  demonstration  of  a 
specific  relation.  Its  real  nature  is  yet  to  be  determined,  but  it  seems  to 
indicate  syphilitic  infection  very  accurately. 

Noguchi's  method,  the  luetin  reaction,  in  which  an  extract  of  a  sterilized 


696  TEXT-BOOK    OF    PATHOLOGY 

culture  of  spirochsetse  is  found  to  produce  an  inflammatory  reaction  in  the 
skin  of  syphilitics  and  none  in  normal  persons,  seems  to  depend  upon  an 
anaphylactic  sensitiveness  in  infected  persons.  It  is  positive  in  tertiary 
and  quaternary  stages  and  in  latent  forms,  but  seldom  so  in  the  primary  and 
secondary  stages. 

Zinsser  and  his  co-workers  have  attempted  to  produce  immunity  from 
the  spirochseta  in  rabbits  by  various  methods.  They  succeeded  in  de- 
veloping a  moderately  strong  agglutinating  serum  and  some  bactericidal 
effect  against  culture  spirocha3tse,  but  not  against  virulent  spirocha3tae. 

LITERATURE 

Noguchi:  Jour.  Exp.  Med.,  1911,  xiv,  557. 

Rietschel:  Ergeb.  d.  inn.  Med.  u.  Kinderheilk.,  1913,  xii,  160. 

Matzenauer:   Die  Vererbung  der  Syphilis,  Wien,  1903. 

Neisser:   Beitr.  z.  Path.  u.  Ther.  d.  Syphilis,  Berlin,  1911.     Also  in:   Arb.  a.  d.  Kais. 

Gesundheitsamt,  1911,  xxxvii. 

Finger:  Handbuch  d.  Geschlechtskrankheiten,  1912,  ii,  896. 
Finger  u.  Landsteiner:  Arch.  f.  Derm.  u.  Syph.,  1906,  Ixxviii,  335;  Ixxxi,  147. 
Landsteiner:   (Exp.  Syphilis)  Handb.  d.  Geschlechtskr.,  1912,  ii,  873. 
Herxheimer:  Ergeb.  d.  allg.  Path.,  1907,  xi,  1.  - 
Schaudinn,  Hoffman:  Arb.  a.  d.  Kais.  Gesundheitsamt,  1905,  xxii. 
Metschnikoff  et  Roux:  Ann.  Inst.  Pasteur,  1903,  xvii,  809. 
Uhlenhuth  u.  Mulzer:  Arb.  a.  d.  Kais.  Gesundheitsamt,  1913,  xliv,  307. 

Primary  Stage. — The  initial  lesion  or  chancre  arises,  as  mentioned  above, 
at  the  point  of  infection  one  to  four  or  more  weeks  after  exposure.  It  is 
nearly  always  dependent  upon  an  abrasion,  although  in  the  case  of  the 
mucous  surfaces  it  appears  that  infection  can  occur  directly.  The  abrasion 
in  the  skin  or  mucosa  usually  heals  after  a  few  days  without  leaving  any 
trace,  and  it  is  only  later  that  the  specific  lesion  appears  in  the  same 
place.  Nevertheless,  even  though  such  an  area  be  excised  and  cauterized 
a  few  hours  after  the  exposure,  it  is  frequently,  if  not  always,  found  that 
transportation  of  the  spirochsetae  has  already  occurred,  so  that  general 
infection  later  makes  itself  evident.  The  delay  in  the  appearance  of 
the  first  sign  of  the  initial  lesion  is  thought  to  be  due  to  the  fact  that  in 
the  process  of  accommodating  themselves  to  the  new  host  many  of  the 
spirochaetse  are  destroyed,  so  that  it  requires  time  for  those  which  sur- 
vive to  develop  the  lesion.  This  begins  sometimes  as  a  tiny  vesicle,  usually 
as  a  delicate  thickening  or  induration  of  the  surface  tissue,  over  which,  as 
time  passes,  the  epithelium  becomes  necrotic  and  converted  into  a  brownish 
crust  which  comes  off,  leaving  a  shallow  ulcer.  The  induration  extends 
and  becomes  a  flattened  hard  mass,  easily  rendered  bloodless  by  bending  or 
by  pressure,  and  easily  movable  in  the  surrounding  tissue  (Figs.  339  and 
340).  There  is  a  characteristic,  bacon-like  translucence  about  this  mass. 
The  ulceration  may  extend  and  become  quite  deep,  a  considerable  area  may 
be  involved,  and  the  chancre  may  persist  for  quite  a  time;  but  in  the  end 
it  heals  up,  the  induration  disappearing,  and  the  ulcer  leaving  a  scar. 


SYPHILIS  697 

Occasionally,  but  not  often,  considerable  distortion  and  loss  of  tissue  may 
be  produced. 

Histologically  (Fig.  341),  it  is  found  that  the  induration  is  produced  by 
a  great  accumulation  of  cells  in  the  skin  and  subcutaneous  tissue.  Ehr- 
mann has  shown  by  injections  that  great  numbers  of  new  blood-vessels  are 
formed  and  that  there  is  stasis  in  these  venules  from  the  pressure  of  the 
cells,  often  with  haemorrhages  and  the  formation  of  blood-pigment.  The 
accumulated  cells  are  in  part  polymorphonuclear  leucocytes,  which  are 


Fig.  339. — Primary  syphilitic  lesion  of  corona.     Early  stage  (Fordyce*). 

found  especially  in  the  base  of  the  ulcer,  but  predominantly  they  are  mono- 
nuclear  cells  of  the  type  of  lymphocytes,  plasma  cells,  and  larger  mono- 
nuclears.  They  are  assembled  in  great  numbers  about  the  blood-vessels 
whose  internal  layer  is  enormously  thickened,  and  extend  from  the  main 
mass  of  the  induration  in  the  form  of  thick  mantles  in  and  about  the  ad- 
ventitia  of  such  vessels.  Ehrmann  described  the  induration  as  largely  de- 

*  Professor  Fordyce  has  kindly  allowed  me  to  use  photographs  from  his  clinic  for 
Figs.  339,  340,  342,  343,  and  Dr.  Keidel  has  given  the  Figs.  344,  345,  350,  and  others 
from  the  Department  of  Syphilis  in  the  Johns  Hopkins  Hospital. 


698 


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pendent  upon  the  alterations  in  the  lymphatic  channels,  which  are  often 
choked  with  mononuclear  cells  or  with  proliferated  masses  of  their  own 
endothelial  cells.  In  our  preparations  it  is  difficult  to  see  any  such  pro- 
liferation of  the  endothelium  of  lymphatics  or  blood-vessels,  although  many 
of  them  are  packed  with  wandering  cells,  but  there  are  masses  of  tissue 
composed  of  large  pale  cells  of  irregular  and  indefinite  outline  with  large 
vesicular  nuclei.  These  are  seen  to  be  proliferated  fibroblasts,  and  they, 


Fig.  340. — Primary  syphilitic  lesion  of  prepuce.     Later  stage,  with  crust.     Secondary 
rash  of  macular  character  over  body  (Fordyce) 

together  with  the  abundant  wandering  cells,  doubtless  give  the  firmness 
and  translucence  to  the  tissue. 

Leading  away  from  the  chancre  are  lymph-channels  along  the  course  of 
which  little  nodular  accumulations  of  cells  may  be  found. 

The  chancre  may  develop  on  the  prepuce,  in  the  coronal  sulcus,  on  the 
glans  penis  or  the  frenulum,  or  about  the  orifice  of  the  urethra,  in  about  this 
order  of  frequency,  or  it  may  appear  on  the  skin  of  the  penis  or  of  the 
scrotum.  In  the  female  the  labia  majora  or  minora,  the  orifice  of  the  vagina, 
the  clitoris,  the  vault  of  the  vagina,  or  the  vaginal  portion  of  the  cervix  are 


SYPHILIS 


699 


the  commonest  sites.  But  the  lip,  tongue,  tonsil,  or  the  cheeks,  eyelids, 
breast,  fingers,  etc.,  may  also  be  infected  through  the  various  processes 
of  exposure  mentioned  above. 

A  short  time  after  the  appearance  of  the  chancre  the  regional  lymph - 


**^i  '-""^i^::  ;.  "£%' "'" .   *  :•"  ":  V"/\ 

*T£jv  :^ar-^:^,v'  -:     <:   '• 

-     '.--       -i^1 %        •!__  JLv^sLiiMI^F^  < 


•^^ 

Fig.  341. — Edge  of  chancre,  showing  ulceration  through  the  epidermis  and  great  ac- 
cumulation of  mononuclear  cells,  especially  about  the  vessels  and  lymphatics. 

glands  swell  and  become  hard.  The  inguinal  glands  are  most  commonly 
affected,  of  course.  In  them  the  spirochsetse  are  found  just  as  they  are  in 
the  chancre.  The  lymph-sinuses  are  filled  with  wandering  cells,  chiefly 
of  the  mononuclear  type,  and  later  there  is  a  proliferation  of  the  connective- 


700  TEXT-BOOK    OF    PATHOLOGY 

tissue  elements.  There  is  little  tendency  to  great  swelling  or  to  suppuration 
in  such  syphilitic  buboes  in  contrast  to  the  condition  following  infection 
with  Ducrey's  bacillus  (soft  chancre  or  chancroid),  and  that  in  gonorrhea. 

Chancroid  or  Soft  Chancre. — This  is  a  type  of  ulceration  of  the  genitalia  trans- 
mitted by  coitus  or  other  contact  and  caused  by  a  small  Gram-negative  strepto-bacillus 
which  was  described  by  Ducrey.  The  bacillus  is  easily  cultivated  and  often  grows 
in  short  chains.  It  is  capable  of  producing  a  similar  ulceration  on  inoculation  in  the  skin 
of  a  person  already  infected  or  an  uninfected  one.  The  ulcer  spreads  rapidly  and  has  a 
ragged  outline  with  undermined  edges  (Fig.  342).  There  is  no  induration  about  it,  but 
the  base  is  rough  and  covered  with  necrotic  material  and  bleeds  easily.  While  the  penis 
and  labia  are  most  commonly  affected,  the  ulceration  may  extend  to  the  skin  elsewhere. 
Red,  tender  lines  which  are  palpable  run  from  the  ulcers  toward  the  inguinal  region  and 
are  often  beaded  with  little  firm  nodules.  These  are  the  inflamed  lymph-channels,  and 
the  nodules  or  bubonuli  are  swollen  collections  of  lymphoid  tissue  which  may  become 
abscesses.  The  inguinal  lymph-glands  become  greatly  swollen  and  tender  (buboes}; 
on  incision  a  quantity  of  purulent  material  is  evacuated  and  the  glands  are  found  to  be 
matted  together  and  excavated  by  the  destructive  process  which  extends  from  one 
gland  to  another.  This  lesion,  like  the  ulcers,  finally  heals,  with  an  extensive  scar. 
There  are  no  general  symptoms  and  no  lesions  in  other  organs. 

Secondary  Stage. — In  rare  cases,  after  the  healing  of  the  chancre  no 
other  symptoms  appear,  and  this  may  be  true  if  vigorous  medication  be 
instituted  in  the  primary  stage.  But  usually  eight  or  ten  weeks  after  the 
infection,  that  is,  after  a  second  incubation  period,  the  secondary  lesions 
of  the  skin  and  mucosae  make  their  appearance  with  fever,  loss  of  appetite, 
muscular  pains,  etc.  No  brief  description  can  even  outline  satisfactorily 
the  extraordinary  variety  of  these  phenomena.  They  stimulate  every  kind 
of  skin  disease  and  may  be  mistaken  for  the  rashes  of  exanthematic  dis- 
eases (measles,  chickenpox,  etc.),  as  well  as  those  produced  by  various 
drugs  (Figs.  343,  344,  345).  They  have  a  tendency  to  heal  up  and  then 
to  recur,  but  although  they  may  produce  the  most  extensive  outbreak  all 
over  the  body,  they  are  seldom  destructive  and  leave  little  trace  of  their 
presence. 

The  simplest  rash  is  the  macular  syphilide,  which  begins  on  the  trunk 
and  may  quickly  appear  over  the  whole  body.  It  is  quite  like  the  rash  of 
measles  in  some  cases,  and  histologically  presents  chiefly  a  widening  of  the 
blood-vessels  with  slight  accumulation  of  cells.  Further  accumulation  of 
leucocytes  and  oedema  is  characteristic  of  the  papular  syphilide  in  which  the 
eruption  is  somewhat  raised.  With  the  fading  of  these  rashes  discoloration 
of  the  skin  may  remain  for  a  time.  Some  often  develop  superficial  crusts 
due  to  epithelial  necrosis  and  exudation,  while  others  are  definitely  pustular, 
little  abscesses  forming  in  each  lesion.  Many  of  these  syphilides  have  a 
tendency  to  heal  in  their  central  part  while  spreading  and  producing  new 
lesions  at  the  periphery.  Ring-formed  macular,  papular,  or  pustular  erup- 
tions arise  in  this  way.  Scaly  patches  resembling  psoriasis  appear  on  the 
palms  and  soles  at  a  later  stage,  and  still  later  there  may  be  found  the 


SYPHILIS 


701 


Fig.  342.— Chancroid  (Fordyce). 


Fig.  343. — Secondary  syphilitic  lesion  of  skin.     Papular  syphilide  (Fordyce). 


702 


TEXT-BOOK    OF    PATHOLOGY 


rounded,  terraced,  elevated  patches  with  necrotic  crusts — the  so-called 
rupial  eruption,  which  is  more  correctly  regarded  as  a  tertiary  lesion. 
Many  other  forms  and  combinations  occur,  descriptions  of  which  may  be 
found  in  text-books  of  dermatology.  Not  infrequent  are  pigmentary 
changes,  in  some  of  which  there  is  a  deepening  of  the  color  of  the  skin, 
in  others  a  complete  fading  away  of  pigment  in  certain  areas,  which  leaves 
them  white  in  contrast  with  the  surroundings  (leucoderma).  Patchy 
falling  out  of  the  hair  (syphilitic  alopecia)  is  also  characteristic  of  this 
stage  of  the  disease. 

Soreness  of  the  throat,  with  evident  though  slight  inflammation,  is  com- 
mon.    Most  characteristic,  however,  is  the  appearance  of  the  so-called 


Fig.  344.— Secondary  syphilis:  pustular  syphilide  (Keidel). 

mucous  patches  in  the  mouth  and  throat.  These  are  white  areas  in  the 
mucosa,  slightly  elevated  or  superficially  ulcerated  and  infiltrated  with 
fluid  and  cells  over  which  the  epithelium  is  proliferated.  They  discharge 
the  spirochsetae  and  are  a  ready  source  of  infection.  Similar  patches  may 
occur  in  the  vagina. 

Besides  these  lesions  of  the  skin  and  mucosse  in  the  secondary  stage, 
certain  others  are  very  prominent.  These  are  the  condylomata  and  moist 
papules,  which  as  inflammatory  elevations  loaded  with  spirochsetse  appear 
chiefly  about  the  genitals  or  on  the  inner  sides  of  the  thighs  or  anal  folds, 
or  elsewhere  where  skin  surfaces  touch  one  another,  so  that  sweat  or  other 
secretions  and  dirt  are  retained.  They,  too,  form  a  common  source  of  in- 


SYPHILIS 


703 


fection.  The  flat  condyloma  (to  be  distinguished  from  the  pointed  con- 
dyloma,  which  is  not  of  syphilitic  origin)  is  a  broad,  lobulated  elevation 
covered  with  greatly  thickened  and  somewhat  macerated  epithelium, 
infiltrated  with  leucocytes.  The  papillae  of  the  skin  are  enlarged  by  the 
widening  of  the  blood-vessels  and  especially  by  the  great  accumulation  of 
wandering  cells. 

Thus  during  the  secondary  stage  the  general  type  of  manifestation  of 
syphilis  appears  in  the  form  of  inflammatory  processes  often  leading  to  dis- 
tinct swelling  of  superficial  tissue,  with  some  tendency  to  necrosis  and  super- 


Fig.  345. — Secondary  syphilis:  follicular  syphilide  (Keidel). 


ficial  ulceration,  but  generally  healing  and  fading  away.  In  all  cases  the 
spirochsetaB  are  present  in  these  lesions,  and  especially  from  those  which 
are  kept  moist,  the  danger  of  transfer  is  great.  On  the  whole,  the  cells  of 
the  mononuclear  type  play  the  greatest  part  in  the  infiltration,  although 
the  polymorphonuclears  are  prominent,  especially  in  the  pustular  forms. 
Giant-cells  and  new-formed  fibroblasts  are  occasionally  seen.  The  dis- 
tribution of  the  secondary  lesions  gives  evidence  at  once  of  their  being  due 
to  the  spread  of  the  spirochsetse  by  the  blood-stream. 

The  Tertiary  Stage. — The  most  characteristic,  though  not  the  most 


704 


TEXT-BOOK   OF   PATHOLOGY 


common,  manifestation  of  the  effects  of  the  spirochsetse  in  this  stage  of  the 
disease  is  the  gumma,  which  received  its  name  from  its  elastic,  rubber-like 
consistency  ("Gummigeschwulst").  Most  commonly  such  nodules  are 
found  embedded  in  the  tissue  and  surrounded  on  all  sides  by  radiating 
fibrous  tissue,  which  in  itself  is  not  especially  peculiar.  But  the  central 
portion  is  firm,  elastic,  opaque,  and  yellowish  white,  like  hard  cheese. 
This  is  the  necrotic  caseous  part,  analogous  to  that  found  in  tubercles,  but 


Fig.  346. — Gumma  of  testicle,  showing  caseous  centre.     Atrophy  of  adjacent  tubules. 

different  in  its  elastic,  firm  consistency  and  in  the  slighter  tendency  to 
liquefy.  In  it  one  may  sometimes  discern  faint  outlines  of  pre-existent 
tissue  now  necrotic.  The  margin  or  capsule  is  often  not  specially  char- 
acteristic (Fig.  346),  being  made  up  of  a  rather  dense  tissue  rich  in  epi- 
thelioid  cells,  such  as  are  found  in  tubercles,  and  closely  infiltrated  with 
mononuclear  wandering  cells.  Giant-cells  with  multiple  nuclei  such 
as  are  found  in  tubercles  occur,  but  are  rarer  here.  Baumgarten  denies 


SYPHILIS  705 

their  existence  in  gummata,  claiming  that  they  are  characteristic  of 
tubercles,  and  that  if  they  do  occur  it  is  because  of  a  coincident  tuberculous 
infection.  Such  nodules  may  be  of  almost  any  size  from  minute  points 
as  small  as  the  smallest  tubercle  to  huge,  tumor-like  masses  easily  felt 
through  the  abdominal  walls  as  they  project  from  the  liver,  where  they 
seem  to  reach  their  greatest  size.  In  the  miliary  gummata  there  may 
be  no  caseation  or  coagulative  necrosis  and  the  nodule  is  seen  as  a  more  or 
less  concentrically  arranged  group  of  epithelioid  cells  richly  mingled  with 
mononuclear  wandering  cells  and  occasionally  with  giant-cells.  The 
arrangement  is  usually  indefinite  and  irregular,  lacking  the  sharpness  and 
precision  of  the  architecture  of  the  miliary  tubercle  (Figs.  347-349). 

Spirochaetse  have  been  demonstrated  by  animal  inoculation  in  larger 
gummata  by  Finger  and  Landsteiner,  but  they  are  not  easily  found  in  sec- 


Fig.  347. — Liver,  showing  several  fresh  miliary  gummata  and  small  caseous  areas. 

tions.  How,  then,  is  one  to  tell  a  gumma  from  a  tubercle  when  it  is  found 
at  the  autopsy?  Histologically  it  seems  almost  impossible  to  make  an 
absolute  differentiation  between  them.  A  section  through  a  gumma  in 
the  lung  tissue  might  have  exactly  the  appearance  of  one  from  a  large 
caseous  encapsulated  tubercle  in  the  same  condition.  A  miliary  gumma  in 
the  liver  might  correspond  exactly  with  some  types  of  tubercles  seen  there. 
Demonstration  of  the  presence  of  tubercle  bacilli  or  of  spirochsetse  would 
settle  the  matter,  but  these  searches  are  notoriously  uncertain.  Better 
would  be  the  inoculation  of  a  guinea-pig  with  the  material.  The  Wasser- 
mann  reaction  might  afford  decisive  evidence.  But,  as  a  rule,  the  gross  ap- 
pearance and  distribution  of  the  lesions  are  found  to  be  typical  enough  in 
each  disease  to  allow  one  to  discriminate — not  always  from  the  situation  of 
any  one  lesion,  but  from  its  relation  to  other  lesions  throughout  the  body. 
46 


706 


TEXT-BOOK    OF   PATHOLOGY 


Thus  gummata  are  commonly  found  in  the  periosteum  invading  the  bone; 
in  the  skull  they  are  frequently  found  involving  the  meninges  and  extending 
into  the  substance  of  the  brain.  Such  a  matting  together  of  periosteum, 
skull,  meninges,  and  brain  into  a  solid  caseous  mass  by  a  tuberculous  process 
would  be  rare.  In  the  brain  substance  they  occur  and  have  a  different 
consistence  from  that  of  the  very  similar  large  solitary  tubercles  which  are 
found  there  too,  but  the  tubercles  would  in  all  probability  be  associated 
with  readily  recognizable  tuberculosis  of  the  lungs,  etc.  This  is  most  often 
the  really  effective  aid  to  diagnosis,  for  it  is  not  difficult  to  recognize  well- 


Fig.  348. — Beginning  miliary  gumma  of  liver.     Necrosis  of  the  liver-cells  and  wandering 
in  of  mononuclears  is  followed  by  the  growth  of  epithelioid  cells. 

developed  and  wide-spread  tuberculosis.  In  the  liver  small  tubercles  and 
small  gummata  are  similar — the  condition  of  the  other  organs  will  generally 
decide  their  nature.  Large  tubercles  are  rare;  large,  partly  healed  gum- 
mata are  common.  Nevertheless  we  have  recently  had  a  case  in  which  a 
caseous  tubercle  7-8  cm.  in  diameter  occurred  in  the  liver.  Its  abundant 
content  of  tubercle  bacilli  and  the  wide  distribution  of  tuberculous  lesions 
elsewhere  made  the  diagnosis  pretty  clear.  In  the  testicle  gummata  are 
common,  while  tuberculous  infection  practically  always  begins  in  the 
epididymis,  and  only  later  may  extend  to  involve  the  testicle. 


SYPHILIS 


707 


Gummata  have  a  strong  tendency  to  heal,  so  that  they  are  commonly 
found  as  disappearing  centres  of  caseous  material  in  great  radiating  scars. 
This  is  far  less  often  true  of  tubercles.  Many  other  instances  might  be 
mentioned  in  which  the  attendant  circumstances  give  the  main  clue  to  the 
diagnosis.  The  history  of  the  case,  the  Wassermann  reaction,  the  bacterial 
findings,  the  distribution  of  the  lesions  and  their  relation  to  lesions  else- 
where, their  size,  consistence  and  gross  appearance,  their  tendency  to  heal 


Fig.  349. — Miliary  gummata  of  the  liver  with  occasional  giant-cells. 

or  to  break  down,  and  least  of  all  their  histological  structure — these  are 
the  things  upon  which  the  diagnosis  of  syphilis  in  the  tertiary  stage  may  be 
based. 

Not  all  tertiary  lesions  are  distinctly  gummatous,  however,  for  there 
frequently  arises  a  diffuse  infiltration  of  tissues  with  wandering  cells  and  a 
proliferation  and  new  formation  of  connective  tissue,  which  results  in  the 
formation  of  a  syphilitic  granulation  tissue  analogous  to  the  tuberculous 
granulation  tissue  which  plays  so  great  a  part  in  old  tuberculous  lesions. 


708  TEXT-BOOK    OF    PATHOLOGY 

In  places  this  tissue  may  have  a  gummatous  character  and  undergo  the 
same  retrogressive  changes  (coagulative  necrosis)  as  are  seen  there,  but 
here  again  the  tendency  is  toward  healing,  often  with  much  distortion. 
Here,  as  elsewhere,  in  syphilitic  processes  the  smaller  blood-vessels  generally 
show  thickening  of  the  intima  and  changes  in  the  endothelium,  which  may 
result  in  their  practical  obstruction.  About  these  vessels  there  accumulate 
mononuclear  wandering  cells  in  great  abundance. 

It  will  be  observed  in  considering  the  development  of  the  tertiary  syphi- 
litic lesions  that  they  often  arise  in  places  where  there  were  secondary 
lesions  which  had  healed,  and  it  has  been  suggested  that  they  are  the  effect 
of  the  further  growth  of  spirochsetse  which  had  been  left  behind  in  the  heal- 
ing of  the  secondary  syphilis.  The  evidence  is  not  entirely  convincing  in 
regard  to  this,  although  there  are  many  well-attested  cases  in  which  gum- 
mata  appeared  on  the  site  of  old  secondary  lesions.  It  is  difficult  to  say 
whether  this  holds  good  for  the  gummata  of  internal  organs. 

The  nature  of  all  these  processes  may  be  exemplified  in  describing  their 
occurrence  in  various  organs. 

Lymph-glands. — The  regional  lymph-glands,  as  has  been  said,  become 
infected  and  swell  slightly  a  few  days  after  the  appearance  of  the  initial 
chancre.  This  swelling  is  never  great  nor  does  suppuration  take  place 
unless  there  is  combined  with  the  syphilitic  infection  some  other,  such  as 
that  characteristic  of  the  soft  chancre.  Instead,  the  glands  remain  small 
and  firm  and  recede  after  a  time  to  their  former  size.  In  the  secondary 
stage,  that  is,  at  the  end  of  the  second  incubation  period,  the  lymph-glands 
become  enlarged  and  palpable  throughout  the  whole  body.  This  is  so 
characteristic  that  it  becomes  a  valuable  diagnostic  aid  in  this  stage  of  the 
disease.  Microscopically  in  both  these  stages  the  change  is  seen  to  be 
essentially  an  increase  in  the  number  of  lymphocytes,  and  especially  of 
larger  mononuclear  cells  which  fill  the  sinuses  and  are  often  phagocytic. 

These  large  cells  are  also  found  with  the  lymphocytes  in  the  lymph  cords 
and  are  looked  upon  by  most  writers  as  endothelial  or  reticulum  cells. 
Their  nature  is  questionable  in  this  case,  as  in  many  others  in  which  they 
appear  in  the  same  way.  The  connective-tissue  framework  of  the  glands 
seems  to  be  increased  after  a  time. 

In  the  tertiary  stage  a  similar  enlargement  of  the  glands  in  certain  lo- 
calities may  occur,  but  the  most  characteristic  change  is  in  the  develop- 
ment of  gummata  in  their  substance.  This  is  not  very  common  and  is 
usually  found  in  association  with  gummatous  lesions  in  the  neighboring 
organ.  Thus  large  gummatous  masses  in  the  bronchial  glands  were  found 
in  a  case  of  syphilitic  disease  of  the  lungs,  while  gummata  of  the  portal  and 
retroperitoneal  glands  accompanied  a  fresh  gummatous  cirrhosis  of  the  liver 
with  involvement  of  the  vena  cava  (Johns  Hopkins  Hosp.  Bull.,  1903,  xiv, 
88). 

The  spirochsetse  are  found  abundantly  in  the  swollen  glands  accompany- 
ing the  primary  and  secondary  stages. 


SYPHILIS 


709 


Blood  changes  in  syphilis  are  indefinite  and  not  thoroughly  studied;  there 
has  been  much  confusion  as  to  the  part  played  in  producing  them  by  mer- 
curial treatment,  but  it  seems  that  the  infection  by  itself  can  produce  a  rather 
severe  anaemia  in  the   secondary 
stage.     This  is  sometimes  spoken  f    ^ 

of  as  syphilitic  chlorosis.    A  mod- 
erate lymphocytosis  is  also  found. 

Alimentary  Tract. — The  Mouth. 
— It  has  already  been  mentioned 
that  primary  and  secondary  lesions 
occur  in  the  mouth,  chancres  upon 
the  tonsils,  lips  (Fig.  350),  and 
tongue  being  relatively  common 
among  the  forms  of  extragenital 
infection.  Histologically  and  in 
their  gross  appearance  they  resem- 
ble those  found  elsewhere,  and  the 
glands  which  drain  these  regions 
become  enlarged  and  very  hard 
during  the  existence  of  the  chancre. 

The  diagnosis  is  sometimes  diffi- 
cult, especially  in  the  case  of  the 
chancre  of  the  tonsil,  which  is  often 
anything  but  characteristic. 

The  tertiary  lesions  are  common 
and  important.  Gummata  some- 
times appear  on  the  lips,  but  more 
often  the  whole  lip  becomes  indu- 
rated by  the  formation  of  a  diffuse 
infiltration  throughout  it  of  the 
character  of  the  syphilitic  granu- 
lation tissue.  Ulceration  may  be 
most  extensive,  and  with  scarring 
the  mouth  is  extremely  distorted, 
so  that,  for  example,  the  whole 
upper  lip  is  destroyed,  the  gap  ex- 
tending into  the  nostrils  and  ex- 
posing the  teeth  and  gums.  With 
healing,  the  orifice  of  the  mouth  Fig  35o._Various  examples  of  chancre  of 
is  drawn  into  a  stiff,  triangular  the  lip  (Keidel). 

opening.     On   the    tongue    actual 

gumma  formation  is  more  common,  diffuse  infiltration  less  so.  The  gum- 
mata,  often  multiple,  arise  beneath  the  surface  and  extend  to  the  upper 
surface  of  the  tongue,  where  they  break  through,  forming  a  deep  ulcer  with 
steep  walls  and  stiff,  translucent  base.  Healing  leaves  a  distorting  scar. 


710  TEXT-BOOK    OF    PATHOLOGY 

It  is  important  to  distinguish  such  ulcerating  gummata  from  epitheli- 
omata  of  the  tongue  and  from  tuberculous  ulcers.  The  epithelioma  starts 
from  the  surface,  usually  at  the  margin,  and  extends  to  the  floor  of  the 
mouth,  growing  more  slowly  than  the  gumma.  Histologically  it  is,  of 
course,  easy  to  make  the  distinction. 

The  diffuse  infiltration  of  the  tongue  is  more  serious,  because  it  causes 
great  enlargement  and  rigidity  of  the  organ,  later,  in  healing,  leaving  the 
surface  deeply  fissured  but  otherwise  smooth.  This  smooth  atrophy  of  the 
villi  of  the  tongue  has  long  been  recognized  as  syphilitic.  Particularly 
harmful  is  the  rigidity  of  the  tongue  which  exposes  it,  especially  where  it  is 
enlarged,  to  all  kinds  of  injuries. 

Gummata  are  rare  in  the  tonsils,  but  are  more  common  in  the  hard  and 
soft  palate.  Beginning  usually  from  the  nasal  side  from  the  periosteum 
the  gummatous  nodule  projects  both  into  the  nose  and  mouth,  and,  soon 
ulcerating  and  discharging  its  contents,  it  produces  great  destruction  of 
the  bones  of  the  nose  and  an  open  perforation  from  the  nose  into  the  mouth. 
This  allows  of  a  nasal  speech  (rhinolalia)  and  also  of  the  passage  of  food  and 
fluids  through  the  nose.  It  is  even  worse  when  the  soft  palate  is  in  the 
same  way  partly  destroyed,  for  the  necessary  opening  and  closing  off  of  the 
posterior  nares  is  impossible.  Gummatous  ulcerations  of  the  pharynx 
usually  heal  with  less  distortion,  but  the  healing  of  the  lesions  of  the  soft 
palate  and  fauces  is  likely  to  produce  a  sort  of  stenosis  or  great  narrowing 
of  the  buccopharyngeal  and  nasopharyngeal  passages. 

(Esophagus  and  Stomach. — Primary  and  secondary  lesions  of  the  oesopha- 
gus are  practically  unknown.  Tertiary  or  gummatous  changes  have  been 
described — gummata  arising  in  the  submucosa  and  rupturing  to  produce 
ulcers  which  in  healing  give  rise  to  stricture  of  the  canal. 

In  the  stomach  there  have  been  found  diffuse  infiltrative  processes  in  the 
submucosa  and  mucosa  and  also  gummatous  formations  which  on  break- 
ing down  produce  extensive  ulcers,  easily  enough  distinguished  from  the 
ordinary  round  ulcer  of  the  stomach.  Such  lesions  may  sometimes  extend 
into  the  duodenum. 

Intestine. — Tertiary  lesions  of  the  small  intestine  are  usually  localized 
in  the  jejunum,  or  the  upper  ileum,  where  they  appear  as  flat  eleva- 
tions of  the  character  of  a  syphilitic  granulation  tissue  involving  submucosa 
and  mucosa.  Multiple  ulcers  are  found  which  extend  in  the  form  of  rings 
round  the  gut,  and  which  in  healing  may  produce  strictures.  There  is  a 
remarkable  example  of  this  in  the  Pathological  Museum  of  Columbia  Uni- 
versity; but  the  condition  must  be  very  rare.  Indeed,  the  only  syphilitic 
lesions  of  the  intestinal  tract  which  are  common  are  those  found  in  the 
rectum.  There,  especially  about  the  anus,  chancres  may  appear,  and 
secondary  lesions  in  the  form  of  moist  papules  and  flat  condylomata  are 
extremely  common.  Various  other  secondary  lesions  involving  cellular 
infiltration  of  the  mucosa,  abscess  formation,  and  even  fistula  production 
occur  at  this  stage. 


SYPHILIS 


711 


But  the  tertiary  lesions  arising  often  very  late  in  the  disease,  after  all 
evidence  of  the  earlier  stages  of  the  infection  have  disappeared,  are  the 
cause  of  the  most  disturb- 
ing changes.  Anatomic- 
ally they  are  analogous 
to  those  found  elsewhere 
and  are  peculiar  only  in 
their  mechanical  effects. 
Gummata  appear  in  the 
submucosa  of  the  rectum 
and  are  soon  exposed  to 
the  lumen  by  ulceration, 
and  surrounded  by  abun- 
dant scar  tissue.  With- 
out actual  gumma  form- 
ation there  may  be  diffuse 
and  wide-spread  infiltra- 
tion of  the  whole  wall  of 
the  gut  and  especially 
of  the  submucosa,  with 
mononuclear  and  epithe- 
lioid  cells  and  this  infil- 
trated tissue  soon  breaks 
down  into  extensive  ul- 
cers which  partly  or 
completely  surround  the 
lumen.  A  foul  discharge 
accompanies  such  ulcer- 
ation and  the  passage  of  faeces  is  painful.  This  is  especially  so  when  the 
ulceration  becomes  very  extensive,  and  when,  with  secondary  infections, 
fistulse  are  found  running  into  the  adjacent  tissues  or  communicating  with 
the  vagina.  Later  the  dense  scar  formation  about  the  healing  and  still 
progressive  ulcers  constricts  the  lumen  of  the  gut  (Fig.  351).  Then,  in 
addition  to  the  pain  and  tenesmus,  actual  obstruction  arises;  there  is  alter- 
nate constipation  and  diarrhoea  and  the  intestine  above  the  stricture  is 
dilated  and  hypertrophied,  and  ulcerated  from  the  stagnation  of  faeces. 
Tbe  patient  usually  dies  from  some  intercurrent  infection,  for  which  the 
poisoning  caused  by  this  slow  intestinal  obstruction  prepares  the  way.  As 
in  other  cases  of  syphilis  of  long  standing,  amyloid  infiltration  of  the  organs 
is  often  found. 

The  Liver. — Little  is  known  of  any  secondary  syphilitic  lesions  in  the 
liver.  The  recognized  changes  are  essentially  characteristic  of  the  tertiary 
stage  and  consist  in  the  formation  of  gummata,  often  with  extensive  in- 
flammatory infiltration  of  the  liver  substance,  and  scarring.  It  is  not  usual 
to  find  fresh  gummata  at  autopsy,  but  in  the  case  illustrated  in  Figs.  347 


Fig.  351. — Syphilitic  stricture  of  the  rectum. 


712  TEXT-BOOK   OF   PATHOLOGY 

to  349  there  were  numerous  groups  of  miliary  and  submiliary  gummata 
which,  in  some  places,  were  beginning  to  be  caseous  and  in  others  were  sur- 
rounded by  scars.  The  formation  of  these  lesions  involves  the  destruction 
of  the  liver  substance  and  to  a  less  extent  the  pushing  aside  of  the  tissue. 
They  are  usually  numerous,  but  sometimes  they  coalesce  into  a  great 
tumor-like  mass  (Fig.  352).  In  one  instance  which  I  saw  there  was  a 
great  nodular  tumor  projecting  from  under  the  edge  of  the  liver  so  as  to  be 
palpated  through  the  abdominal  wall.  It  melted  away  rapidly  under 
energetic  antisyphilitic  treatment,  which,  after  all,  with  the  history,  was 
the  chief  proof  of  its  gummatous  nature. 

Iodides  as  well  as  mercury  were  given  in  this  case,  as  has  been  done  for  many  years. 
Jobling  and  Petersen  have  recently  explained  the  action  of  iodides  as  follows.    The  sof ten- 


Fig.  352. — Large  gumma  of  liver. 

ing  and  removal  of  caseous  necrotic  material  from  a  gumma  is  due  to  a  tryptic  ferment. 
The  gumma,  however,  persists  and  remains  firm  because  it  contains  large  quantities  of 
antitryptic  substances  which  are  of  lipoid  nature,  being  combinations  of  unsaturated 
fatty  acids.  Their  power  of  antagonizing  the  ferment  depends  upon  their  unsatura- 
tion,  which  in  turn  can,  as  is  well  known,  be  satisfied  by  iodine,  this  forming  the  basis 
of  the  well-known  index  used  in  estimating  unsaturated  fatty  acids.  Administration  of 
iodine  by  saturating  the  antitryptic  substances,  destroys  their  power  over  the  tryptic 
ferments,  which  then  dissolve  the  caseous  material. 

Probably  the  most  common  condition  is  that  in  which  numerous  distinct 
gummata  of  the  consistence  of  Swiss  cheese  are  formed  throughout  the  liver, 
and  are  found  as  the  centres  of  extensive  radiating  scars.  In  one  such 


SYPHILIS 


713 


liver  (Fig.  353),  in  a  case  which  presented  evidences  of  syphilis  elsewhere, 
the  organ  was  decreased  in  size  and  roughly  and  very  coarsely  nodular. 
On  cutting  through  it,  it  was  found  to  be  permeated  by  a  network  of  coarse 
bands  of  gray  fibrous  tissue  which  separated  large  masses  of  relatively 
normal-looking  liver  tissue,  into  which,  however,  finer  bands  extended. 
At  three  or  four  places  on  the  cut  surface  there  were  at  the  nodal  points  of 
the  scars  firm,  yellowish-white  masses  of  caseous  material  up  to  1  cm.  in 
diameter.  Further,  as  it  penetrated  the  diaphragm,  the  inferior  vena  cava 
was  surrounded  by  a  large  gumma  originating  in  the  liver  and  projecting 
through  the  diaphragm.  It  involved  the  wall  of  the  vein  and  almost 


Fig.  353. — Gummata  in  the  liver  with  extensive  scarring.     There  is  one  large  gumma  in 
the  wall  of  the  vena  cava,  as  it  passes  behind  the  liver,  with  thrombosis  of  the  vein. 


occluded  its  lumen,  the  closure  being  completed  below  by  a  great  thrombus 
which  extended  down  into  the  renal  veins. 

Such  are  the  relatively  fresh  conditions,  but  generally  only  the  broad 
scars  remain  (Fig.  354),  and  one  finds  the  liver  greatly  distorted  by  the  re- 
placement of  whole  areas  of  liver  substance  by  these  scars,  which  have 
retracted  into  the  organ  as  though  cords  had  been  tightly  tied  about  it, 
cutting  deep  into  its  substance.  The  rest  of  the  liver  is  normal  or,  more 
usually,  enlarged  by  a  compensatory  hypertrophy.  Many  of  the  features 
characteristic  of  cirrhosis  of  the  liver,  the  regenerative  processes,  and  the 
distortion  of  the  circulation  as  well  as  of  the  liver  tissue,  may  be  found  in 


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these  cases.  Ascites,  portal  stagnation,  splenic  enlargement,  and  jaundice 
may  occur,  but  they  vary  with  the  varying  mechanical  conditions,  and  the 
presence  of  large  gummata  and  scars  about  the  portal  region  and  bile-ducts 
naturally  plays  an  important  part  in  this  regard. 

Such  a  deeply  lobed,  distorted  liver  (Fig.  355)  is  almost  always  the  result 
of  syphilitic  infection.     It  is  not,  however,  the  only  effect  which  can  be 


Fig.  354. — Old  scar  in  a  syphilitic  liver.     In  the  centre  is  a  large  vein  which  has  become 
partly  recanalized  after  obliteration. 


produced  by  that  disease,  since  in  other  instances  one  may  find  a  much 
finer  scarring,  evidently  due  to  a  more  diffuse  affection. 

In  the  salivary  glands,  particularly  the  parotid,  and  in  the  pancreas 
gummatous  and  diffuse  syphilitic  lesions  have  been  described  in  a  few 
cases. 

Warthin  has  studied  the  pancreas  in  old  cases  of  syphilis,  and  found  that 
it  oftens  show  scarring,  and  that  the  scars  are  frequently  the  site  of 


SYPHILIS 


715 


definite  infiltrations  of  plasma  and  lymphoid  cells,  such  as  he  has  found 
to  be  characteristic  effects  of  syphilis  in  other  organs.  This  chronic 
interstitial  pancreatitis,  so-called,  is  often  accompanied  by  diabetes,  and, 
indeed,  in  two  cases  he  found  the  spirochsetse  in  the  areas  of  cellular  in- 
filtration. Warthin  will  not  say  that  diabetes  is  dependent  upon  syphilis 
as  its  common  cause;  this  demonstration  is  rather  part  of  his  general 
thesis  that  syphilis  produces  wide-spread  injury  and  cellular  infiltration 
of  many  organs,  which  is  generally  overlooked. 


Fig.  355. — Old  syphilitic  cirrhosis  with  deep  constrictions  where  there  are  scars. 


In  the  kidney  gummata  are  sometimes  met  with  and  changes  leading  to 
diffuse  scarring  and  contraction  of  the  kidneys  due  to  syphilis  have  been 
said  to  occur.  Probably  they  depend  upon  intimal  lesions  in  the  renal 
arteries. 

The  Respiratory  Tract. — Syphilitic  lesions  are  found  in  the  upper  air- 
passages,  larynx,  and  trachea,  and  rather  less  commonly  in  the  bronchi 
and  lungs. 

In  the  nose,  chancres  are  not  uncommon,  appearing  at  the  orifices  of  the 


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nostrils,  or  the  alse  nasi,  or  even  in  the  interior,  on  the  septum.  They  are 
caused  as  a  rule  by  infection  from  the  fingers  or  from  handkerchiefs. 

In  the  secondary  stage  the  most  common  manifestation  is  a  syphilitic 
erythema,  or  reddening,  which  appears  in  flecks,  sometimes  later  covered 
by  a  necrotic  layer  of  epithelium  and  occasionally  giving  rise  to  nosebleed. 
This  is  the  basis  of  the  coryza  which  is  a  common  accompaniment  of  this 
stage  of  the  disease.  Papules  and  actual  condylomata  sometimes  arise  in 
the  nose.  Far  more  important  and  quite  common  are  the  lesions  of  the 
tertiary  stage,  which,  as  elsewhere,  are  diffuse  syphilitic  infiltrations  or 
gummata.  The  former  may  produce  thickening  of  the  mucosa  over  the 
septum  or  turbinates,  generally  with  ulceration,  which  may  penetrate  to 

the  cartilage  or  bone,  and,  often  through 
the  aid  of  secondary  infections,  leads  to 
destructive  perichondritis  and  periostitis. 
Naturally  this  process  involves  the  risk 
of  extension  upward  to  the  ethmoid  and 
sphenoid  bones,  and  meningeal  infection 
may  follow.  Sometimes  great  tumor-like 
masses  are  formed  at  the  base  of  the 
septum  or  elsewhere.  Similarly,  definite 
gummatous  lesions  appear  in  the  mucosa 
or  in  the  perichondrium  or  periosteum  of 
the  bones  which  constitute  the  interior 
of  the  nose.  Extensive  deep  ulcerations 
follow,  and  whole  bones  become  necrotic 
sequestra.  The  septum  may  be  com- 
pletely destroyed,  as  well  as  the  turbin- 
ates, and  large  portions  of  the  vomer  and 
the  nasal  bones.  The  nose  is  in  this  way 
hollowed  out  into  a  great  cavity,  the  lining 
of  which  is  a  scarred  and  atrophic  mucosa. 
The  process  is  accompanied,  so  long  as 
necrotic  bone  is  present,  by  the  most 
nauseating  f oetor.  At  times,  as  has  been 

mentioned  above,  perforation  of  the  hard  palate  or  destruction  of  the  soft 
palate  occurs.  In  the  course  of  healing,  the  most  extensive  adhesions  and 
strictures  of  the  air-passages  develop,  so  that  sometimes  the  nasal  cavity 
may  be  quite  shut  off  from  the  pharynx.  Great  deformities  of  the  face 
result,  since,  with  the  collapse  of  the  nasal  bones,  the  nose  sinks  into  the 
opening  produced.  The  mildest  form  of  this  is  perhaps  the  saddle-nose  so 
often  seen  in  the  streets  and  so  common  in  late  cases  of  congenital  syphilis, 
in  which  the  bridge  of  the  nose  is  sunken  and  the  tip  turns  upward,  expos- 
ing the  nostrils  in  front  (Fig.  356).  But  in  countries  like  Morocco,  where 
the  disease  is  neglected,  one  sees  the  most  extreme  deformities,  produced 
by  ulceration  through  the  skin,  so  that  the  whole  nasal  cavity  is  open 


Fig.  356. — Late  congenital  syph- 
ilis showing  "saddle  nose,"  inter- 
stitial keratitis,  and  leucoderma. 


SYPHILIS  717 

to  the  outside  and  into  the  mouth,  and  all  semblance  of  a  face  has  disap- 
peared. 

In  the  nasopharynx  the  same  series  of  lesions  may  appear,  and  there  are 
instances  of  chancre  of  the  Eustachian  tube  having  been  caused  by  the 
use  of  an  infected  Eustachian  catheter. 

Larynx. — The  lesions  of  the  larynx  might  be  inferred  from  what  has 
been  said  of  the  nose.  Although  secondary  changes  occur  there,  the  ter- 
tiary phenomena  are  most  important.  In  a  case  recently  seen  at  autopsy 
there  was  a  diffuse  syphilitic  infiltration  of  the  whole  interior  of  the 
larynx  with  ragged  ulceration  extending  to  the  perichondrium  and  involv- 
ing both  sides  of  the  cavity. 

Gummatous  lesions  involve  the  arytenoid  cartilages  and  epiglottis  most 
commonly,  but  may  affect  any  other  part.  The  deep  precipitous  ulcers 
with  abundant  yellow  secretion  are  capable  of  destroying  the  vocal  cords 
and  of  leading  to  necrosis  of  the  cartilages.  They  must  be  distinguished 
from  tuberculous  and  cancerous  ulcers  in  the  same  places.  Healing  leads 
to  great  deformity  and  stricture  formation  in  the  larynx,  for  which  trache- 
otomy is  sometimes  necessary. 

We  have  observed  at  autopsy  one  case  in  which  the  obstruction  of  the 
larynx  was  extreme,  the  vocal  cords  being  converted  into  great  scarred 
masses  which  could  not  be  much  separated.  One  effect  was  the  dilatation 
of  the  trachea  and  bronchi  and  an  extensive  secondary  infection  of  the 
lung  with  the  formation  of  huge  abscesses. 

Trachea,  Bronchi,  and  Lungs. — Tertiary  lesions  in  the  trachea  and 
bronchi  are  usually  in  the  form  of  syphilitic  granulation  tissue,  although 
sometimes  definite  gummata  may  arise  in  the  wall  or  extend  from  outside. 
The  process  causes  much  thickening  of  the  wall  with  ulceration  which 
lays  bare  and  softens  or  destroys  the  cartilage  rings. 

In  such  a  case  the  trachea  and  bronchus  may  collapse  at  an  angle  or  be 
compressed.  Usually  healing  takes  place  with  the  formation  of  a  scar 
which  causes  a  stenosis  of  the  canal.  Almost  any  part  of  the  trachea  may 
be  involved,  but  it  seems  that  the  region  of  the  bifurcation  is  most  com- 
monly affected,  the  stricture  narrowing  one  main  bronchus.  This  was  the 
condition  found  in  a  case  studied  in  Baltimore,  and  the  effect  upon  the  lung, 
as  might  have  been  foretold,  was  to  produce  most  extensive  bronchiectasis. 
The  reasons  for  this  are  discussed  elsewhere. 

The  clinical  signs  in  such  a  case  are  rather  definite,  since  the  harsh  stridor 
of  the  air  passing  the  obstruction,  and  the  prolonged  expiratory  sound  on 
that  side,  indicate  clearly  the  existence  of  a  stenosis.  When  the  stenosis 
appears  in  a  branch  of  the  main  bronchus  there  are  localized  changes  in 
the  breath  sounds,  and  the  bronchial  dilatation  and  emphysematous 
alterations  in  the  lung  are  limited  to  the  area  which  is  supplied  with  air 
by  that  bronchus. 

In  the  lung  itself,  aside  from  the  congenital  changes,  the  lesions  due  to 
syphilis  are  not  very  clearly  nor  surely  recognized.  Gummata  of  various 


718  TEXT-BOOK    OF   PATHOLOGY 

sizes  up  to  tumor-like  masses  occur  anywhere  in  the  lung.  They  are 
grayish  or  reddish-gray  nodules,  sharply  outlined,  and  radiating  fibrous 
strands  into  the  rest  of  the  lung.  One  occasionally  sees  these  masses,  which 
in  the  absence  of  obvious  tuberculosis  and  when  other  signs  of  syphilis 
exist,  it  seems  proper  to  diagnose  as  gummata;  but  doubtless  many  of 
those  described  may  have  been  localized  encapsulated  tubercles.  About 
the  large  vessels  at  the  hilum  of  the  lung  and  the  large  bronchi  gummatous 
indurative  processes  occur,  with  great  thickening  of  the  adventitial  walls 
of  the  vessels  and  some  constriction  of  the  bronchi.  Great  scars  extend 
out  into  the  remainder  of  the  lung  and  bronchiectasis  follows  the  obstruc- 
tion. This  has  been  called  the  indurative  bronchiectatic  type  of  pulmonary 
syphilis.  Whether  pneumonic  or  ulcerative  forms  of  syphilis  with  cavity 
formation  really  exist  is  uncertain.  The  confusion  with  tuberculosis,  and 
especially  the  fact  that  syphilitics  are  very  prone  to  tuberculosis,  makes 
this  point  difficult  to  settle  (Flockemann:  Centrbl.  f.  allg.  Path.,  1899, 
x,  469). 

LITERATURE 

Ehrmann:    Handb.  d.  Geschlechtskr.,  1912,  ii,  959-1130.     Arch.  f.  Dermatol.,  1899, 

xlviii,  256. 

Lang:  Pathologic  u.  Therap.  der  Syphilis,  2te  Aufl.,  Wiesb.,  1896. 
Neumann:  Nothnagel's  spez.  Path.,  1899,  Bd.  xxiii.     Exhaustive  treatment  of  the  whole 

subject  of  syphilis  by  Gerber,  Pal,  Benda,  Nobl,  Ebstein,  Jesionek,  Seifert,  Hart- 

tung,  Braun  and  others  in  Handb.  d.  Geschlechtskr.,  1913,  iii,  1-951. 
Nonne:  Syphilis  u.  Nervensystem,  1915,  3te  Aufl.,  Berlin. 
Adami:  N.  Y.  Med.  Jour.,  1899,  549. 

Jobling  and  Petersen:  Action  of  Iodides,  Arch.  Int.  Med.,  1915,  xv,  286. 
v.  Baumgarten:   Verh.  Deutsch.  Path.  Gesellsch.,  1901,  iii.  107  (Histology  of  gumma, 

with  discussion). 

v.  Werdt:  Frankf.  Ztschr.  f.  Pathol.,  1913,  xii,  177  (Liver  gummata). 
Warthin:  Harvey  Lecture,  1918,  Amer.  Jour,  of  Syphilis,  1918,  ii. 
Fordyce:  Harvey  Lecture,  1914-15,  Series  X,  221. 
Zinsser,  Hopkins,  and  McBurney:  Jour.  Exp.  Med.,  1915,  xxi,  576;  1916,  xxiii,  323, 

329,341;  1916,  xxiv,  561. 

Bones  and  Joints. — It  is  said  that  periosteal  inflammation  may  form  a 
part  of  the  secondary  stage  of  syphilis,  but  there  is  as  yet  very  little  ana- 
tomical evidence  with  regard  to  this.  Secondary  lesions  of  the  joints  are 
also  mentioned.  But  the  later  lesions  of  both  bones  and  joints  are  far  more 
frequently  met  with  and  far  more  serious. 

Tertiary  lesions  of  the  bones  seem  to  affect  most  commonly  the  skull, 
the  tibia,  the  fingers,  and  other  bones  which  are  very  superficially  situated, 
while  less  is  known  of  those  which  occur  in  the  more  protected  bones. 
Possibly  this  is  due  to  the  influence  of  trauma  in  determining  the  site  of 
gummatous  affections.  Part  of  the  anatomical  changes  due  to  syphilis 
are  distinctly  and  characteristically  gummatous,  while  there  are  others 
which  are  quite  like  the  results  of  chronic  inflammation  of  the  bone  produced 
by  other  causes,  except  perhaps  in  their  history  and  in  their  association 


SYPHILIS  719 

with  other  syphilitic  lesions.  Probably,  however,  the  study  of  these 
chronic  inflammations  for  spirochsetse  will  show  more  clearly  their  syphilitic 
character.  Although  the  bone  is  soon  involved,  these  are  at  first  essen- 
tially affections  of  the  periosteum,  which  is  torn  from  the  bone  by  an  in- 
flammatory infiltration  composed  chiefly  of  mononuclear  wandering  cells. 
With  rupture  of  the  periosteum  the  overlying  skin  may  be  broken  through, 
after  which  the  place  is  exposed  to  further  infections.  Such  an  ulceration 
often  exposes  the  underlying  bone,  parts  of  which  become  necrotic  and 
separate  from  the  rest  as  a  sequestrum  which  may  be  discharged.  Syphilitic 
ulcers  of  this  type  are  long  in  healing  (Fig.  357).  By  no  means  all  such  in- 
flammations end  in  ulceration ;  instead,  they  produce  a  great  new  growth  of 
spongy  bone  on  the  surface  of  the  old  cortex,  forming  in  this  way  a  convex 


Fig.  356A. — Tertiary  syphilis:  ulcerated  gumma  of  leg  (Keidel). 

layer  which,  when  the  bone  is  macerated  and  dried,  has  something  of  the 
appearance  of  rough  pumice  stone.  Sometimes  it  is  much  denser  and 
may  even  be  very  hard  and  solid  (Fig.  357A).  Such  osteophytes  often  rise 
in  a  sort  of  wall  about  the  area  of  most  intense  inflammation  where  necrosis 
has  actually  occurred.  It  is  this  process  which  gives  origin  to  many  of 
the  thickenings  with  rough,  irregular  surface  which  one  finds  so  com- 
monly on  the  shafts  of  long  bones  in  any  collection,  but  it  must  be  recog- 
nized that  these  are  not  all  syphilitic — other  non-specific  forms  of  peri- 
ostitis can  produce  the  same  thing.  In  another  form  the  new  production 
of  bone  is  more  extensive  still,  and  no  longer  limited  to  the  activity  of  the 
periosteum;  it  is  laid  down  in  each  Haversian  system  and  through  the 
cancellous  bone  in  the  interior,  so  that  the  shaft  of  the  bone  becomes  dense 


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and  ivory-like  and  the  whole  bone  is  much  heavier  than  normal.  There 
is  no  special  localization  for  these  processes,  although  it  is  true  that  thick- 
enings of  the  long  bones,  the  clavicles,  the  sternum,  etc.,  are  particularly 
common. 

Somewhat  more  easily  recognized  and  characteristic  of  syphilis  are  the 
gummatous  lesions  which  may  arise 
in  connection  with  the  periosteum  or 
in  the  interior  of  the  bone.  In  the 
first  case  the  gummatous  tissue  ex- 
tends along  the  blood-vessels  into 
the  bone,  enlarging  their  canals  and 
eroding  the  bone  to  a  peculiar  worm- 
eaten  appearance.  Sometimes,  as 


Fig.  357. — Tertiary    syphilis:  syphilitic 
ulcers  over  shins  (Keidel). 


Fig.  357A. — Syphilitic  periostitis  and  os- 
teophyte  formation. 


in  the  skull,  the  periosteum  can  be  torn  off,  pulling  out  of  their  canals  a 
lot  of  these  great  cellular  extensions  and  leaving  a  coarsely  corroded  sur- 
face. Complete  destruction  of  the  bone  is  easily  produced  by  their  con- 
fluence, and  it  is  common  in  these  cases  to  find  the  skull  penetrated  by  a 
ragged  hole  filled  by  the  gummatous  mass  which  generally  extends  to 
involve  the  dura  mater  and  often  enough  the  underlying  brain.  But 


SYPHILIS 


721 


there  are  many  cases  in  which  the  dura  limits  the  process  and  the  necrotic 
debris  is  discharged  externally.  Osteophytes  from  the  periosteum  sur- 
round such  an  area  and  make  the  defect  seem  deeper.  The  same  gum- 
matous  nodes  are  often  found  on  the  shins,  extending  into  the  cortex 
and  marrow  cavity,  and  often  circumscribing  and  causing  the  necrosis  of 
fragments  of  the  bone.  The  most  extensive  destruction  may  occur  in  the 
skull  (Fig.  358),  and  especially  in  old  specimens  derived  from  long  untreated 
cases,  one  sees  great  gaps  in  the  cranium  with  ragged  margin  and  sur- 
rounded by  rough  osteophytes.  In  all  these  processes  the  simultaneous 
existence  of  rarefaction  and  condensation  or  sclerosis  of  the  bone  is  to  be 


Fig.  358. — Old  syphilitic  erosion  of  the  skull.     The  margins  in  this  case  are  smoothed  off 

by  a  healing  process. 

observed.  In  this  respect  the  syphilitic  changes  stand  in  contrast  to  the 
tuberculous,  where  rarefaction  of  the  bone  is  accompanied  by  very  little 
new  formation. 

Gummata  formed  in  the  marrow  cavity  are  of  sufficiently  frequent  oc- 
currence, although  they  were  practically  overlooked  until  Chiari  demon- 
strated their  existence.  They  are  gelatinous  patches,  often  bright  yellow 
from  their  content  of  fat,  which  may  occur  singly  or  in  such  numbers  and 
continuity  as  to  involve  the  whole  marrow  cavity.  Generally  there  is  no 
outward  evidence  of  their  existence,  but  the  cortex  may  be  attacked  and 
eroded  and  the  periosteum  outside  produce  a  new  layer  of  bone  to  corre- 
spond. In  this  way  there  may  be  a  spindle-shaped  dilatation  of  the  bone; 
47 


722  TEXT-BOOK   OF   PATHOLOGY 

canals  or  fistulse  are  formed  through  the  cortex,  and,  except  for  the  absence 
of  sequestra,  the  bone  comes  to  look  like  the  end-result  of  an  ordinary 
osteomyelitis. 

Gummatous  osteoperiostitis  with  enlargement  and  rarefaction  and  in- 
ternal destruction  of  the  bone  in  the  phalanges,  is  found  in  the  so-called 
syphilitic  dactylitis.  The  finger  swells  and  sometimes  there  is  fracture  of 
the  weakened  bone  or  the  gummatous  material  is  discharged  through  a 
fistula. 

These,  then,  are  the  usual  syphilitic  affections  of  the  bone :  (a)  periosteal 
gumma  formation  with  necrosis  of  the  underlying  bone,  followed  by  ulcera- 
tion  and  exposure  through  the  skin  or  by  extensive  osteophyte  growth,  and 
(6)  gummatous  osteitis  or  osteomyelitis  with  necrosis  and  erosion  of  the 
directly  affected  part  and  rarefaction  or  sclerosis  of  the  surrounding  bone. 

All  these  things  may  make  their  appearance  fairly  early  in  the  disease 
or  only  after  long  years  of  apparent  health. 

As  in  the  case  of  the  bones,  the  joints,  bursse,  and  tendon-sheaths  often 
reveal  a  susceptibility  to  syphilis  only  after  many  years  of  the  disease. 
There  may  be  an  accumulation  of  watery  exudate  only,  or  the  formation 
in  the  synovial  membrane  of  a  syphilitic  granulation  tissue  with  ulceration, 
and  great  proliferation  of  the  adjacent  unaffected  membrane  and  synovial 
villi.  Probably  in  many  cases  the  joint  affection  is  secondary  to  the  ap- 
pearance of  gummatous  infiltration  of  the  epiphysis. 

This  lifts  up  and  destroys  the  cartilage,  and  healing  takes  place  after 
much  loss  of  time  through  the  obliteration  of  the  cavity  by  fibrous  tissue. 
In  the  bursse  and  tendon-sheaths  painless  swellings  due  to  the  appearance 
of  a  lining  of  gummatous  granulation  tissue  persist  for  a  long  time  but 
yield,  as  do  the  joint  affections,  to  specific  treatment. 

LITERATURE 

Churchman:  Am.  J.  Med.  Sc.,  1909,  cxxxviii,  371. 
Levin:  Med.  Record,  1908,  Ixxiv,  836. 
Schmidt,  M.  B.:  Ergeb.  d.  allg.  Path.,  1900-01,  vii,  221. 
Harttung:  Handb.  d.  Geschlechtskr.,  1912,  iii. 

Heart  and  Blood-vessels. — Syphilis  of  the  blood-vessels  has  already  been 
described  (page  350).  There  it  was  stated  that  in  the  case  of  such  large 
vessels  as  the  aorta,  gummatous  or  diffuse  syphilitic  infiltration  affects  the 
adventitia  and  media,  being  localized,  almost  as  in  the  case  of  the  bone, 
along  nutrient  vessels  and  that  the  extreme  hyperplastic  changes  in  the 
intima  arise  in  response  to  the  destruction  thus  produced.  In  smaller 
vessels,  such  as  those  of  the  meninges,  practically  the  same  thing  occurs 
except  that  the  gummatous  mass,  beginning  in  the  adventitia  and  extending 
through  the  media  to  the  intima,  is  relatively  very  large  and  produces  a 
distinct  nodule  on  the  vessel. 

Quite  analogous  changes  occur  in  the  small  vessels  in  the  interior  of 
organs,  although  there  it  is  by  no  means  so  easy  to  recognize  the  stages  of 


SYPHILIS    OF   THE    GENITAL    ORGANS  723 

the  process,  and  the  proliferation  of  the  intima  and  occlusion  of  the  vessel 
is  likely  to  be  the  most  conspicuous  thing. 

In  the  heart,  tertiary  syphilitic  lesions  may  assume  the  form  of  distinct 
gummata  or  myocardial  scars.  Doubtless  the  latter  may  be  due  in  part 
to  narrowing  of  the  coronary  vessels  by  specific  changes  in  their  walls,  and 
then,  of  course,  they  are  only  an  accompaniment  of  the  vascular  disease. 
Indeed,  it  seems  that  the  proof  of  the  direct  syphilitic  nature  of  the 
myocardial  scars  is  not  easy,  but  Warthin  describes  a  long  series  in  which 
all  transitions  from  fresh  lymphoid  and  plasma  cell  infiltrations  occur, 
and  in  which  he  has  demonstrated  the  spirochsetae  in  many  cases. 

Mention  has  already  been  made  of  the  aneurysmal  dilatations  of  the 
apical  region  of  the  left  ventricle  of  the  heart,  which  is  now  fairly  clearly 
shown  to  be  of  syphilitic  origin,  all  stages  being  demonstrable  between 
the  fresh  gumma  of  the  septum  and  wall  of  the  heart  and  the  distended 
scarred  sac. 

The  gummata  may  occur  anywhere  in  the  muscle,  but  they  have  a 
peculiar  tendency  to  appear  in  and  about  the  conducting  bundle  of  His, 
and  especially  at  the  point  in  the  septum  behind  the  tricuspid  and  below 
the  aortic  valves,  where  it  is  most  concentrated.  A  number  of  proven 
cases  of  gumma  formation  in  this  situation  have  been  described,  with 
studies  of  the  interruption  of  conduction  which  they  cause.  The  dis- 
sociation of  the  rate  of  beat  of  the  ventricles  from  that  of  the  auricles 
(Stokes-Adams'  disease,  or  heart  block)  which  results  in  this  way  has  been 
described  elsewhere  (p.  500).  Syphilitic  endocarditis  is  a  vaguely  under- 
stood process  except  in  connection  with  the  aortic  valves,  where,  as  stated 
(p.  254),  the  deformities  produced  are  the  cause  of  most  of  the  cases  of 
aortic  insufficiency. 

LITERATURE 

Chiari:  Verb.  Deutsch.  path.  Gesellsch.,  1904,  vi,  137. 
Benda:  Ibid.,  164  (Syphilis  and  blood-vessels). 
Marchand:   Ibid.,  197  (Discussion). 

Robinson:    Bull.  Ayer  Clin.  Lab.,  1907,  iv,  1  (Gumma  of  heart). 
Bridgman  and  Schmeisser:  Johns  Hopkins  Hospital  Reports,  1916,  xviii,  90. 

SYPHILIS  OF  THE   GENITAL  ORGANS 

Of  the  syphilitic  lesions  of  the  male  or  female  genitalia,  aside  from  the 
primary  chancres  and  the  condylomatous  and  other  affections  of  the 
secondary  stage  which  have  already  been  mentioned,  the  gummatous  and 
interstitial  changes  in  the  testicle  are  the  most  common  and  important. 
Gummatous  and  other  lesions  have  been  described  in  the  vagina,  uterus, 
tubes,  and  ovaries,  and  also  in  the  vas  deferens,  seminal  vesicles,  etc.,  but 
these  are  such  rare  occurrences  and  so  imperfectly  studied  that  we  may 
turn  at  once  to  the  testicular  affections. 

Most  characteristic  are  those  in  which  a  definite  gumma  arises  in  the 
testis,  taking  its  origin  in  the  interstitial  tissue  and  pushing  aside  the 


724 


TEXT-BOOK   OF   PATHOLOGY 


testicular  tubules.  In  this  respect  it  differs  from  the  tuberculous  process, 
which  begins  usually  in  the  epididymis,  and  which,  if  it  does  affect  the  testis, 
does  so  by  causing  the  formation  of  tubercles  within  or  in  direct  relation 
to  the  tubules.  The  elastic  tissue  elements  are  destroyed  thereby,  al- 
though in  the  gummatous  orchitis  they  remain  intact.  The  gumma  has 
the  characters  seen  elsewhere  and  often  shows  the  presence  of  giant-cells 
in  the  marginal  portions.  Such  gummata,  at  first  grayish-red  on  section, 
later  become  opaque,  yellowish,  and  caseous  (Fig.  359).  They  may  extend 


Fig.  359. — Gumma  of  testicle.  The 
firm  caseous  nodules  are  surrounded  by 
scar  tissue. 


Fig.  360. — Syphilitic  fibrous  orchitis. 


to  and  through  the  tunica  albuginea  and  sometimes  reach  a  great  size,  so 
as  to  be  mistaken  for  tumors,  and  excised.  With  antisyphilitic  treatment 
they  disappear,  leaving  an  extensive  scar.  In  a  specimen  before  me,  while 
the  gumma  is  at  the  height  of  its  course,  the  surrounding  testicular  tissue 
is  very  cedematous,  the  tubules  being  spread  wide  apart  not  only  by  this 
accumulation  of  fluid,  but  also  by  the  infiltration  of  great  numbers  of 
mononuclear  wandering  cells.  In  nearly  every  tubule  there  are  evidences 
of  degeneration  and  disappearance  of  the  spermatogenic  cells,  and  in  most 
there  is  already  great  thickening  and  hyaline  degeneration  of  the  connec- 


SYPHILIS   OF   THE    GENITAL   ORGANS  725 

tive-tissue  wall.     Undoubtedly  these  tubules  would  have  lost  their  func- 
tional activity  and  merged  later  into  a  scar. 

The  other  form,  the  so-called  orchitis  fibrosa  (Fig.  360),  has  long  been 
regarded  as  definitely  syphilitic,  and  clear  evidence  of  syphilis  when  found  at 
autopsy.  Except  in  such  stages  as  described  above,  in  connection  with 
active  gummata  it  seems  to  be  known  in  the  form  of  extensive  scars  through 
the  testicle,  which  shine  on  section  as  pearly  white  streaks  against  the  dull 
brown  of  the  remaining  testicular  substance.  In  these  scars  are  found  the 
hyaline,  thickened  remnants  of  testicular  tubules  and  some  infiltration  of 
wandering  cells.  But,  as  Chiari,  Hansemann,  and  others  pointed  out  in 
discussing  Baumgarten's  paper,  there  is  no  real  proof  that  all  such  scars 
are  syphilitic.  They  may,  as  well,  result  from  the  orchitis  which  follows 
trauma,  gonorrhoea,  mumps,  and  many  other  things.  The  literature  is 
contradictory  on  the  validity  of  the  evidence  of  the  syphilitic  nature  of 
these  scars,  but  perhaps  with  the  newer  surer  methods  of  diagnosis  the 
matter  will  soon  be  made  clear. 

Warthin's  recent  studies  show  that  in  many  cases  the  lesion  is  to  be 
found  in  the  form  of  loose  intertubular  scars  which  show  in  places  accumu- 
lations of  plasma  cells  and  lymphocytes,  and  among  these  spirochaetes 
are  sometimes  found. 

LITERATURE 

Baumgarten,  Chiari,  Orth,  Hansemann,  and  others:  Verh.  Deutsch.  path.  Gesellsch., 
1900,  iii,  107  (Syphilis  of  Testicle). 


CHAPTER  XXXVI 
TYPES  OF  INJURY.— SPIROCILETAL  INFECTION  (Continued) 

Syphilis:  Syphilitic  lesions  of  nervous  system.  Syphilitic  meningitis.  Tabes  dorsalis. 
General  symptoms.  Lesions  of  the  nervous  system,  theories  concerning  it.  Dementia 
paralytica,  its  relation  to  tabes;  symptoms.  Anatomical  changes  in  brain  and  cord.  Con- 
genital syphilis.  General  relations.  Lesions  in  respiratory  organs,  liver,  pancreas,  bones, 
etc.  Late  forms  of  congenital  syphilis. 

Nervous  System. — Syphilitic  disease  in  the  nervous  system  is  essentially 
of  the  tertiary  stage,  unless  we  accept  the  fourth  or  quaternary  stage  for 
those  so-called  parasyphilitic  conditions  which  we  now  know  to  be  so  truly 
syphilitic — dementia  paralytica  and  tabes.  From  an  anatomical  point 
of  view  there  are  three  main  types,  of  which  one  includes  the  cases  of  gum- 


Fig.  361. — Gumma  of   brain  distorting  cerebral  convolutions   and   adherent  to  the 

meninges. 

matous  encephalitis  or  meningo-encephalitis,  myelitis,  or  neuritis;  the 
second,  the  various  forms  of  syphilitic  meningitis,  and  the  third  the  diffuse 
processes  described  above  as  quaternary.  But  between  the  first  two  there 
are  various  gradations,  and,  further,  it  is  difficult  to  distinguish  sharply 
between  them  and  others  which  begin  in  the  cranial  periosteum  and  extend 
into- the  brain. 

The  most  common  are  those  cases  in  which  a  gummatous  mass  is  found 
in  the  cortex  of  the  brain  connected  through  the  pia  arachnoid  with  the 
dura  and  even  penetrating  through  the  skull  (Fig.  361).  Such  a  gumma 
may  be  as  large  as  a  filbert,  or  an  irregular  conglomeration  of  caseous  masses 
may  be  much  larger. 

726 


SYPHILIS   OF   THE    NERVOUS    SYSTEM  727 

A  great  deal  of  translucent  gray  or  grayish-red  material  forms  the  outer 
portions  and  radiates  into  the  surrounding  tissue,  especially  along  the  blood- 
vessels. Parts  of  it  may  be  reddish-gray,  but  the  central  part  is  usually 
yellow  and  very  opaque  and  firm.  The  difficulties  in  being  sure  as  to 
whether  such  a  lesion  is  tuberculous  or  gummatous  have  been  mentioned. 
From  the  point  where  the  gumma  extends  to  involve  the  dura,  that  mem- 
brane may  be  greatly  thickened  on  all  sides  by  a  syphilitic  granulation 
tissue,  rich  in  cells  and  showing  in  places  a  tendency  to  caseation. 

The  brain  is  not  merely  pushed  away — it  is  invaded  and  infiltrated  in 
this  process,  and  along  the  vessels  there  is  a  great  accumulation  of  mono- 
nuclear  wandering  cells.  It  has  been  thought  generally  that  such  a  gumma 


Fig.  362. — Part  of  a  gumma  of  the  lenticular  nucleus,  showing  central  caseation. 

may  not  spring  from  the  brain  substance  itself,  but  only  from  the  walls  of 
the  blood-vessels  or  the  meninges.  This,  however,  offers  no  limitation,  and 
one  discovers  gummata  growing  deep  in  the  corpus  callosum,  or  in  the  basal 
ganglia,  or  the  pons.  The  medulla  and  substance  of  the  spinal  cord  may  be 
their  seat,  but  it  must  be  said  that  these  deep-seated  gummata  are  less  com- 
mon than  those  which  are  superficial  and  connect  with  the  meninges. 

A  gumma  localized  in  the  lenticular  nucleus  and  appearing  as  a  fairly  sharply  outlined 
mass  to  the  naked  eye  affords  a  good  example  of  the  histological  characters  of  these 
lesions.  Under  the  microscope  it  appears  not  nearly  so  sharply  outlined  nor  so  uniform 
in  its  makeup;  caseous  patches  are  scattered  here  and  there  in  a  kind  of  network  in  a 
diffuse  mass  of  very  cellular  tissue  (Fig.  362).  On  approaching  from  the  normal  brain 


728  TEXT-BOOK   OF   PATHOLOGY 

substance  the  blood-vessels  in  the  outskirts  are  found  surrounded  by  lymph-spaces  which 
are  packed  with  loose  cells.  Not  all  of  these  are  plasma  cells.  Many  of  them  seem  much 
larger  with  protoplasm  which  stains  red;  many  others  are  lymphocytes.  The  intima  of 
these  vessels  is  often  so  thickened  by  new-formed  cells  as  nearly  to  obstruct  the  lumen. 
Advancing,  one  reaches  a  tissue  in  which  little  brain  substance  is  to  be  recognized;  it 
is  rich  in  new  capillary  blood-vessels  and  overrun  by  hordes  of  mononuclear  cells  of  the 
same  varieties  of  form  as  are  seen  in  the  walls  of  the  blood-vessels.  Plasma  cells  of 
typical  form  are  there;  but  most  of  the  cells  are  lymphocytes  or  else  much  larger  cells, 
with  granular  or  vacuolated  cell-body  and  large  vesicular  nucleus.  In  places  there  is 
a  condensation  of  the  ground  tissue  in  which  the  most  prominent  cells  are  like  the 
epithelioid  cells  of  the  tubercle,  with  long,  pale,  vesicular  nuclei.  Often,  among  these 
are  found  beautiful  giant-cells  with  many  nuclei.  These  border  on  the  areas  of  necrosis, 
and  round  them  the  epithelioid  cells  along  the  edge  of  the  caseous  material  have  become 
distorted  and  twisted  into  a  radiate  position  pointing  toward  the  caseation. 

These  caseous  areas  show  throughout  the  shadowy  remains  of  the  continuation  of  the 
vascular  infiltrated  tissue  which  has  simply  been  rendered  necrotic.  It  will  be  seen 
that  in  no  particular  is  this  process  absolutely  distinguishable  from  tuberculosis,  but  at 
least  it  is  more  diffuse  and  one  has  less  the  impression  of  the  formation  of  firm  nodules 
which  push  aside  tissue  before  they  become  caseous.  This  is  rather  an  infiltrating  granu- 
lation tissue,  parts  of  which  undergo  caseation. 

Very  small  or  miliary  gummata  may  be  scattered  all  through  the  brain. 
Diffuse  syphilitic  infiltration  or  granulation  tissue  formation  seems,  how- 
ever, to  be  very  rare,  although  Bechterew  described  multiple  sclerosing 
foci  in  the  spinal  cord  in  one  case. 

On  the  other  hand,  gummata  encroach  upon  the  cranial  and  spinal  nerves 
at  their  roots,  in  some  cases,  and,  extending  from  epi-  to  endoneurium,  in- 
volve the  nerve-fibres  in  their  necrosis.  Paralysis  and  degeneration  of  the 
nerve  follow.  In  the  peripheral  nerves,  gummata  occur  in  the  same  way. 
One  case  observed  at  autopsy  in  which  the  nerves  of  the  upper  arm  were 
matted  together  in  a  caseous  gumma,  with  degeneration  of  the  distal  por- 
tions, was  described  by  Remsen. 

The  meningeal  form,  which  is  so  apt  to  extend  to  involve  the  brain,  affects 
the  dura  or  the  pia.  Aside  from  the  gumma  formation  just  described  the 
dura  may  present  rather  diffuse  layers  of  granulation  tissue  densely  in- 
filtrated with  lymphocytes  and  sometimes  hsemorrhagic.  More  char- 
acteristic are  the  affections  of  the  pia  and  arachnoid,  in  which  one  finds 
small  gray  nodules  along  the  course  of  the  pial  blood-vessels  (Fig.  363). 
These  sometimes  have  opaque  whitish  centres  and  prove  to  be  minute  gum- 
mata which  begin  in  the  adventitia  and  quickly  invade  the  media,  inciting 
a  similar  proliferation  in  the  intima,  which  is  often  enough  to  narrow  very 
greatly  or  completely  close  the  lumen.  In  cross-sections  the  tiny  lumen  is 
found  at  one  side,  and  in  the  excentric  mass  the  internal  lamella,  wrinkled 
on  the  thin  side  of  the  vessel  wall,  is  stretched  out  thin  and  straight  through 
the  most  affected  part. 

Sometimes  the  lumen  is  divided  into  two  or  more  channels  and  a  new 

elastic  lamella  may  form,  more  closely  placed  about  one  or  more  of  these. 

Strassmann  has  demonstrated  the  spirochsetae  in  these  adventitial  gummata. 

Outside  the  vessels  the  pia  is  thickened  and  rendered  opaque  and  yellow- 


LOCOMOTOR  ATAXIA,  OR  TABES  DORSALIS 


729 


ish  by  a  dense  infiltration  of  wandering  cells,  mostly  mononuclear.  This 
exudate  is  generally  most  abundant  over  the  base  of  the  brain,  and  espe- 
cially in  such  regions  as  that  of  the  optic  chiasma.  The  cranial  nerves 
passing  through  it  were,  in  the  case  we  studied  (Goldsborough),  roughened 
and  swollen  from  the  presence  of  small  gummata  which  in  their  caseation 
involved  the  nerve-fibers. 

It  is  manifest  that  all  this  must  produce  the  most  varied  symptoms, 
partly  the  result  of  the  general  meningeal  inflammation,  partly  due  to 
direct  irritation  or  paralysis  of  the  affected  nerves.  Disturbances  of  the 
functions  of  the  eye  muscles,  of  speech,  etc.,  are  especially  common. 

Verse  found  the  same  process  affecting  the  meningeal  veins  rather  than 
the  arteries,  and  demonstrated  the  spirocheetae  in  great  numbers  in  their 


.:, 


Fig.  363. — Gumma  of  pial  blood-vessel.      Syphilitic  meningitis. 

walls  and  in  the  adjacent  tissue,  or  even  in  some  cases  in  thrombi  which 
occluded  the  veins. 

LITERATURE 

Nonne:   Syphilis  and  Nervensystem,  3te  Aufl.,  Berlin,  1915. 
Strassmann:    Ziegler's  Beitrage,  1910,  xlix,  430. 
Verse:  Ibid.,  1913,  Ivi,  580. 
Remsen:  Johns  Hopkins  Hosp.  Bull.,  1903,  xiv,  280. 

LOCOMOTOR  ATAXIA,  OR  TABES  DORSALIS 

We  may  consider  this  disease  here,  together  with  the  general  paralysis  of 
the  insane,  even  though  it  has  not  been  absolutely  proven  to  be  of  syphilitic 
origin.  Statistical  study  has  given  figures  which  point  in  an  unmistakable 
manner  to  syphilis  as  its  cause.  Erb  found  syphilis  in  89.5  per  cent,  of 
the  cases  and  others  have  found  a  similar  percentage.  Recently  Noguchi 


730  TEXT-BOOK   OF   PATHOLOGY 

found  the  spirochseta  in  the  cord  in  one  case  out  of  twelve,  and  it  seems  only 
a  question  of  further  study  to  prove  the  constancy  of  the  relationship. 

The  disease  is  in  large  part  an  affection  of  the  lower  sensory  neurons, 
although  we  shall  find  that  these  are  unequally  altered  in  different  parts,  and 
that  while  many  of  the  phenomena  are  to  be  explained  as  the  result  of  this 
lesion,  there  are  others  which  are  not. 

The  clinical  aspect  of  the  disease  is  extremely  variegated,  though  most 
of  the  symptoms  are  the  result  of  disturbances  of  the  sensory  apparatus, 
partly  irritative,  partly  paralytic.  Reflexes  and  movements  depending  on 
muscle  sense,  and,  consequently,  coordination,  are  much  disturbed. 

Violent  stabbing  pains  in  the  limbs  or  elsewhere  (lightning  pains)  occur 
especially  at  night;  sudden  attacks  of  cramp-like  pain  in  some  internal 
organ — stomach,  larynx,  bladder,  etc.,  are  known  as  gastric  or  laryngeal 
or  vesical  crises.  A  period  of  sexual  excitement  is  followed  by  impotence. 
The  tendon  reflexes  are  abolished;  the  pupils  become  inactive  and  fixed. 
Sensation  is  dulled  or  perverted;  the  patient  no  longer  feels  the  floor  he 
walks  on,  or  feels  it  like  so  much  wool.  He  loses  his  sense  of  the  position 
of  his  extremities  and  must  watch  his  feet  in  order  to  set  them  in  the  right 
place;  inattention  may  result  in  a  fall.  The  gait  becomes  peculiar  and 
slapping.  This  ataxia,  which  has  given  rise  to  one  of  the  names,  may 
affect  any  or  all  of  the  muscles. 

So-called  trophic  changes  arise  in  various  places.  Half  of  the  tongue 
atrophies;  an  ulcer  appears  in  the  foot  and  proceeds  to  grow  deeper,  pain- 
lessly, until  it  perforates  the  foot.  The  bones  become  fragile  and  break, 
and  fail  to  heal  again.  Joints  loosen  and  become  disorganized;  the  car- 
tilage softens  and  the  bone  is  eroded,  or  great  dislocation  may  occur.  Dis- 
turbed nutrition  of  the  tissues  in  general  seems  to  arise  and  the  patient  dies 
of  an  intercurrent  infection,  although  seizures,  simulating  apoplexy  and 
epileptiform  convulsions,  may  have  been  survived.  The  details  of  these 
symptoms  must  be  read  elsewhere,  most  clearly  perhaps  in  Marie's 
"Lecons  sur  les  maladies  de  la  Moelle." 

Lesions. — At  the  autopsy  the  lesions  depend  upon  the  stage  of  the  disease. 
If  the  patient  dies  at  an  early  period,  it  may  be  necessary  to  search  with 
the  microscope  for  any  change,  but  if  it  has  lasted  a  long  time  the  spinal 
cord  with  its  posterior  nerve-roots  shows  a  characteristic  appearance.  The 
meninges  (pia  arachnoid)  may  be  thickened  and  cloudy  in  part  or  quite 
normal  looking,  but  the  posterior  columns  are  sunken  and  the  dorsal  roots 
look  gray  and  smaller  than  normal.  On  section,  the  dorsal  columns  are  gray 
and  translucent  in  contrast  to  the  remaining  pinkish,  opaque,  white  matter. 
It  is  rarely  possible  to  distinguish  with  the  naked  eye  the  exact  distribution 
of  this  gray  material  in  the  dorsal  columns,  but  with  certain  stains  the 
microscope  shows  it  well.  The  grayness  and  translucence  are  due  to  the  dis- 
appearance of  the  lipoid  myeline  sheaths,  as  well  as  the  axis-cylinders  of  the 
nerve-fibres  and  their  replacement  by  an  overgrowth  of  neuroglia.*  If  the 

*  Observations  of  which  Dr.  Tilney  has  told  me  seem  to  show  that  much  of  the 
material  employed  to  replace  the  lost  nerve-fibres  may  be  of  connective-tissue  origin. 


LOCOMOTOR  ATAXIA,  OR  TABES  DORSALIS 


731 


process  were  fresh  enough,  the  myeline  might  not  have  disappeared  entirely, 
but  its  remnants  could  be  made  visible  as  black  globules  by  the  use  of  osmic 
acid,  which  does  not  blacken  the  normal  myeline  sheath.  After  a  week  or 


Fig.   364A. — Tabes  dorsalis.     Dorsal  region  of  cord.     Moderate  sclerosis  of  posterior 

columns  (Fordyce). 


Fig.  364B.  —  Tabes  dorsalis. 


Dorsal  region  of  cord  with  extreme  sclerosis  of  the  posterior 
columns  (Fordyce). 


two,  however,  these  fat-globules  disappear  and  then  the  injured  area  can 
best  be  made  apparent  by  the  Weigert  stain,  which  colors  blue-black  all 
the  normal  myeline  sheaths  and  leaves  the  wasted  and  scarred  area  un- 


732  TEXT-BOOK    OF    PATHOLOGY 

stained.     It  is  usually  this  unstained  area  which  one  can  demonstrate  in 
tabes  (Fig.  364). 

It  will  be  recalled  that  the  posterior  roots  are  largely  made  up  of  central  processes  of 
the  dorsal  root  ganglion-cells,  which  were  at  one  era  of  development  bipolar  and  still 
are  in  certain  cranial  ganglia,  but  which  now  have  one  T-shaped  process,  one  branch  of 
the  T  coming  from  the  periphery,  while  the  other  enters  the  cord.  On  entering  the 
cord  in  the  posterior  root  the  fibres  swerve  a  little  to  the  median  side  of  the  end  of  the 
posterior  horn  of  the  gray  matter,  which  does  not  quite  reach  the  surface.  They  pass 
through  the  zone  of  Lissauer,  which  is  made  up  of  fine  fibres  which  also  come  in  as  part 
of  the  nerve,  and  turning  upward  a  short  way,  sweep  along  with  the  other  fibres  into  the 
posterior  column  and  into  the  posterior  horn.  The  fibres  entering  by  the  posterior  root 
bifurcate,  sending  a  short  branch  downward,  a  longer  branch  upward.  Three  main 


Fig.  364C. — Tabes  dorsalis.    Degenerative  changes  in  the  posterior  nerve-root  (Fordyce) . 

groups  are  generally  distinguished  in  the  distribution  of  these  upward  branches:  a  short 
group  which  quickly  turns  into  the  gray  matter  of  the  posterior  horn,  a  median  group 
which  runs  up  in  the  column  of  Burdach — sometimes  all  the  way,  but  often  leaving  it  to 
turn  into  the  gray  matter  and  end  about  a  cell  there — and  a  long  group  which  passes 
into  the  column  of  Goll  and  runs  up  to  'the  nucleus  of  that  column  in  the  medulla  or 
even  further.  It  is  the  column  of  Goll  which  brings  fibres  even  from  the  lower  lumbar 
region. 

The  fibres  of  the  dorsal  root,  which  enter  the  gray  matter,  end  in  arborizations  about 
ganglion-cells  of  that  side,  a  great  many  of  them  .constituting  the  fibre  reticulumof  the 
column  of  Clarke;  or  they  pass  forward  to  terminate  about  a  ganglion-cell  of  the  anterior 
horn,  or  cross  by  the  posterior  commissure  to  end  similarly  in  the  gray  matter  of -the 


LOCOMOTOR   ATAXIA,    OR   TABES   DORSALIS  733 

opposite  side.  Each  fibre  gives  off  many  fine  branches  or  collaterals  which  terminate  in 
quite  similar  ways  about  the  ganglion-cells  of  the  gray  matter,  and  thus  forms  abundant 
incidental  connections  at  every  stage  in  its  progress  upward  in  the  cord,  which  are 
doubtless  of  fundamental  importance  in  the  establishment  of  reflex  arcs. 

Flechsig,  Trepinski,  and  others  have  shown  that,  according  to  this  distribution  of  the 
fibres,  and  according  to  the  varying  time  at  which  they  are  matured  by  receiving  their 
medullary  sheaths,  one  may  distinguish  various  subdivisions  or  tracts  in  the  column  of 
Burdach — a  posterior,  a  middle,  and  an  anterior  root  zone  as  well  as  a  median  zone  which 
lies  within  the  column  of  Goll  against  the  median  line. 

In  the  middle  root  zone  two  types  of  fibres  can  be  distinguished  by  their  different 
time  of  myelinization,  etc.  Naturally  these  fields  seen  in  any  cross-section  are  only  the 
expression  of  the  currents  of  fibres  at  that  particular  level  and  so  must  change  as  one 
ascends  the  cord,  except  inasmuch  as  the  incoming  fibres  deport  themselves  in  the  same 
way  at  successive  levels.  But  if  a  group  of  fibres  entering  the  cord  becomes  recognizable 
by  any  degenerative  change  it  need  not  be  expected  that  those  fibres  will  occupy  the 
same  position  in  the  field  higher  up ;  on  the  contrary,  they  assume  a  new  position  or  dis- 
appear because  they  have  turned  into  the  gray  matter  to  end. 

Consequently,  it  could  only  be  through  an  exact  repetition  of  the  same  degenerative 
change  in  each  successive  root  that  anything  like  the  same  distribution  of  degenerated 
fibres  would  be  found  at  different  levels,  and  even  then  in  the  higher  levels  the  scarred 
remains  of  those  entering  far  down  and  continued  upward  to  that  point  would  be  added 
to  those  newly  entering  from  a  higher  root. 

The  statement  is  generally  made  that  in  tabes  dorsalis  the  beginning 
of  the  sclerosis  or  scarring  is  first  seen  in  the  "bandelettes  externes,"  or 
parts  of  Burdach's  column  lying  against  the  posterior  horn;  that  the 
middle  root  zone  is  early  involved  and  also  the  zone  of  Lissauer  and  the 
column  of  Goll,  but  that  the  anterior  or  ventral  root  zone  is  found  in- 
tact until  very  late  in  the  disease.  While  this  is  true,  it  must  be  true 
in  any  given  case  in  different  degree  in  different  parts  of  the  cord.  The 
complete  escape  of  a  whole  entering  root,  or  of  a  series  of  them,  from 
the  effects  of  the  disease  at  a  point  higher  in  the  cord,  allows  intact 
fibres  to  appear  in  these  situations,  so  that  at  those  levels  the  areas 
of  sclerosis  are  reduced  to  the  upward  prolongations  which  still  con- 
tinue from  those  below.  And  it  is  true  that  such  escape  of  the  roots 
may  occur,  just  as  it  is  true  that  the  lesion  need  not  be  symmetrical 
on  the  two  sides.  But  all  this  merely  emphasizes  the  fact  that  the 
degenerative  lesion  in  tabes  is  not  like  that  produced  by  the  cutting 
of  a  single  dorsal  root  between  its  ganglion  and  the  cord.  The  result  of 
that  would  fade  away  into  the  gray  matter,  except  in  so  far  as  a  few  de- 
generated fibres  might  be  recognized  continuing  up  the  column  of  Bur- 
dach or  in  the  column  of  Goll  all  the  way  to  the  medulla.  Instead,  in 
tabes  there  is  a  nearly  constant  and  nearly  symmetrical  addition  of  the  re- 
sults of  degeneration  with  the  advent  of  each  succeeding  dorsal  root.  And, 
nevertheless,  the  irregularities  show  that  the  process  is  not  to  be  regarded 
as  the  complete  degeneration  of  a  column  or  system,  but  as  a  succession  of 
segmental  degenerations  accumulating  their  results  in  the  cord  as  one  passes 
upward.  It  would  be  most  instructive  to  have  a  reconstruction  of  this 
lesion  from  an  early  case  of  tabes,  before  the  whole  posterior  tracts  had  be- 


734  TEXT-BOOK   OF   PATHOLOGY 

come  fused  in  the  sclerotic  band,  to  show  the  topography  of  these  repeated 
additions  of  sclerotic  tissue  in  the  cord  and  their  relation  to  the  changes  in 
the  roots. 

It  is  with  regard  to  the  nature  of  the  changes  in  the  roots  that  the  most  persistent 
dispute  has  raged.  It  is  agreed  that  while  the  roots  are  pathologically  altered,  the 
change  in  the  portion  between  the  dorsal  root  ganglion  and  the  cord  is  more  extreme  than 
that  in  the  peripheral  nerves  or  in  the  ganglion-cells  themselves,  and  consequently  nearer 
to  that  seen  in  the  cord  itself.  The  following  views  have  been  expressed,  most  of  which 
will  doubtless  disappear  in  the  light  of  the  simple  explanation  which  must  finally  come 
some  day. 

The  whole  lesion  is  due  to  vascular  obstruction;  it  is  the  effect  of  injury  or  destruction 
of  peripheral  ganglionic  elements,  which  may  also  be  responsible  for  ascending  degenera- 
tions after  amputations  (Marie);  ft  is  a  systemic  degeneration  of  tracts  in  the  cord  itself 


Fig.  365. — Charcot  joint.  Syphilitic  arthropathy  involving  knee,  with  erosion 
and  new  formation  of  a  lower  articular  surface.  Extensive  destructive  changes  in  sur- 
rounding tissues  with  fistulse. 

corresponding  with  their  developmental  characters  (Flechsig,  Trepinski) ;  it  is  the  effect 
of  destruction  of  the  cells  of  the  spinal  root  ganglia;  it  is  the  effect  of  meningeal  inflam- 
mation about  the  entering  roots  which  causes  their  compression  and  destruction  (Na- 
geotte) ;  it  is  the  effect  of  direct  or  indirect  action  of  the  syphilitic  poison  on  the  nerve 
roots,  affecting  less  the  ganglia,  but  producing  the  degenerative  changes  described  (Red- 
lich,  Obersteiner).  This  is  partly  based  on  analogy  with  similar  affections  found  in 
ergot  poisoning  and  pellagra. 

Of  all  these,  the  last  seems  most  likely  to  prevail,  in  view  of  the  intimate  relation  of  the 
disease  to  syphilis  and  the  finding  of  the  spirochaetse  in  at  least  one  case  in  the  spinal 
cord.  But,  as  can  be  seen,  the  pathogenesis  of  the  disease  is  far  from  clear  and  must  be 
much  more  precisely  worked  out  before  we  can  accept  any  view  as  final. 

In  the  end  one  finds  practically  all  of  the  posterior  columns  in  the  lumbar 
and  dorsal  regions  reduced  to  a  scar-like  mass  of  neuroglia,  the  only  ex- 


DEMENTIA   PARALYTICA  735 

ceptions,  up  to  an  advanced  stage,  being  the  ventral  root  zone  and  the 
medial  zone.  Lissauer's  zone,  the  column  of  Clarke  in  the  gray  matter  and 
the  column  of  Goll,  with  most  if  not  all  of  the  column  of  Burdach,  are  thus 
degenerated.  In  the  cervical  region  the  lesion  is  less  extensive  and  reduces 
itself  toward  the  column  of  Goll.  Since  these  tracts  are  so  intimately  con- 
cerned with  muscle  sense  and  with  the  reflex  arcs  it  is  not  surprising  that 
ataxia,  the  loss  of  the  sense  of  position,  failure  in  the  discrimination  of 
weights,  etc.,  should  be  prominent  features  of  the  disease. 

Tactile  sensation,  temperature  sense,  etc.,  which  are  so  largely  concerned 
in  the  short  relayed  tracts  in  the  cord  and  in  the  other  ascending  tracts 
not  involved  in  this  process,  are  less  affected.  The  cells  of  Clarke's  column 
connecting  with  the  cerebello-spinal  tract  must,  however,  lose  some  of 
their  relations,  since  the  fibres  entering  with  the  dorsal  roots  which  arborize 
round  them  are  destroyed. 

It  is  difficult  to  explain  the  various  "trophic"  disturbances  which  are 
found  in  the  tissues,  such  as  the  bone  and  joint  changes  mentioned  above 
and  the  alterations  in  nails,  skin,  etc.,  which  are  so  frequent.  It  seems  quite 
possible,  however,  with  regard  to  the  "Charcot's  joints,"  or  tabetic  arthro- 
pathy  (Fig.  365) ,  that  this  is  directly  a  syphilitic  lesion,  as  held  by  Strum- 
pell,  Stargardt,  and  others,  rather  than  a  trophic  disturbance  dependent 
upon  the  nervous  affection.  For  a  discussion  of  this  disease  the  student  is 
referred  to  the  following: 

LITERATURE 

Zoepffel:  Berl.  klin.  Woch.,  1911,  xlviii,  2032. 

Stargardt:  Arch.  f.  Psychiatric,  1912,  xlix,  936. 

Redlich:  Pathol.  d.  tabischen  Hinterstrangserkrankungen,  Jena,  1897 

Schseffer,  K.:  Handb.  d.  Neurologic,  Lewandowski,  1911,  vol.  ii. 

Marie,  P.:  Mai.  de  la  Moelle,  Paris,  1892. 

Schmaus  and  Sacki:  Ergeb.  d.  allg.  Path.,  1900,  v,  268;  1904,  ix,  217. 

DEMENTIA  PARALYTICA  (GENERAL  PARESIS,  PROGRESSIVE  PARALYSIS 

OF  THE  INSANE) 

Another  affection  long  known  to  be  in  some  way  associated  with  syphilis 
and,  like  tabes,  spoken  of  as  parasyphilitic,  is  now  shown  by  the  aid  of  the 
Wassermann  reaction  and  by  the  demonstration  of  the  spirochsetse  in  the 
brain  to  be  definitely  a  syphilitic  disease.  It  has  been  suggested  by  Mobius 
and  others  that  this  is  a  disease  practically  identical  with  tabes  dorsalis 
except  in  that  it  is  localized  in  the  brain;  and  it  seems  that  in  a  sense  this 
is  true,  although  the  difference  in  localization  makes  a  great  difference  in 
the  disease  as  far  as  the  manifestations  are  concerned;  indeed,  the  lesions 
of  the  spinal  cord  in  this  condition  are  rather  different  from  those  found  in 
tabes,  and  the  symptoms  resulting  from  them  are  also  different. 

Clinically,  dementia  paralytica  is  a  most  dramatic  illness  whose  mental 
symptoms  vary  somewhat  with  the  character  of  the  individual.  It  is  remark- 
able, however,  to  observe  how,  under  this  infection,  all  minds  are  planed 


736  TEXT-BOOK   OF   PATHOLOGY 

down  to  the  same  low  level.  It  usually  begins  insidiously,  with  drowsi- 
ness, lapses  of  attention,  peculiarities  of  conduct,  and  accentuation  of  pre- 
dominant personal  characteristics,  and  proceeds  to  graver  departures  from 
civilized  custom  which  are  often  shown  in  their  true  light  in  the  police 
court. 

Confusion  of  ideas  and  failure  of  memory,  together  with  loss  of  self- 
restraint,  are  soon  accompanied  by  delusions  of  grandeur  in  which  the  pa- 
tient becomes  most  extravagant  in  his  belief  in  his  own  powers  and  pos- 
sessions. 

Even  at  the  beginning  of  this  stage  his  condition  may  not  have  been 
recognized,  and  he  is  at  the  risk  of  committing  mistakes  in  business  or 
otherwise  which  may  cost  him  dear. 

In  later  stages  memory  is  lost  to  an  astounding  degree;  the  patient  lives 
only  in  the  moment,  totally  forgetful  of  what  happened  an  hour  ago;  writ- 
ing becomes  characteristically  disturbed  and  finally  impossible;  speech  is 
slow,  blurred,  and  full  of  mistakes,  the  delusions  take  the  place  of  everything 
else  and  are  occasionally  interrupted  by  violent  maniacal  outbreaks  or  by 
apoplectiform  or  epileptoid  convulsions,  from  which  the  patient  usually 
recovers  without  any  after-effects.  With  all  this,  and  to  the  end  of  life 
in  the  most  miserable  bodily  and  mental  disruption,  he  is  in  a  state  of  glow- 
ing content.  This  euphoria,  or  sense  of  well-being,  is  enough  to  compensate 
for  most  of  the  horror  of  the  disease,  but  in  other  cases  there  is  deep  de- 
pression or  complete  mental  dulling. 

Aside  from  the  mental  derangement  there  are  bodily  evidences  of  the  ail- 
ment— the  pupils  are  irregular  in  form  or  size  and  usually  rigid,  as  in  loco- 
motor  ataxia.  Paresis  of  many  muscles  may  appear,  and  after  the  disease 
is  well  advanced  contractures  in  these  muscles  hold  the  extremities  in  a 
helpless  rigidity,  so  that  the  patient  is  permanently  bedridden.  Bed-sores 
of  great  extent  are  likely  to  appear  in  such  cases.  Loss  of  tactile  and  pain 
sense  is  common  and  readily  results  through  inattention,  in  injuries  such  as 
burns  and  lacerations.  The  so-called  trophic  disturbances  are  found  here 
as  in  tabes — perforating  ulcers  of  the  foot,  great  haemorrhages  in  the  outer 
ear  following  a  slight  injury,  disorganization  of  the  joints,  great  porosity 
and  fragility  of  the  bones,  with  fractures  after  trifling  blows.  Extreme 
emaciation  alternates  with  periods  of  obesity,  but  in  the  end  the  weight 
usually  goes  down  until,  at  death,  the  patient  seems  almost  a  skeleton. 

Death  occurs  after  one  to  three  years,  though  sometimes  there  are  re- 
missions during  which  mental  and  bodily  health  seems  pretty  good  and 
death  comes  only  six  or  eight  years  after  the  onset.  It  may  be  the  result 
of  great  emaciation  and  gradual  exhaustion,  but  most  commonly  it  is 
brought  about  by  an  intercurrent  infection,  especially  bronchopneumonia, 
to  which  these  demented  people,  with  their  dulled  sensation  and  disturbed 
reflexes,  are  particularly  exposed  from  the  aspiration  of  saliva  or  food  into 
the  bronchi.  In  any  case  they  are  more  than  usually  susceptible  to  infec- 
tion in  their  state  of  disturbed  nutrition. 


DEMENTIA   PARALYTICA 


737 


At  autopsy  the  most  striking  changes  are  in  the  brain  and  meninges. 
The  dura  is  often  lined  over  one  or  both  halves  of  the  brain  with  a  thick, 
blood-stained  layer  of  new  tissue,  which  it  is  often  possible  to  separate  into 
several  sheets,  the  deeper  of  which  are  stained  a  dull  rusty  brown  by  the 


Fig.  366. — Chronic  haemorrhagic  internal  pachymeningitis. 


Fig.  367. — General  paresis.     Surface  of  the  brain  showing  atrophy  of  the  convolutions 

(from  Weygandt). 

pigment  formed  from  the  extravasated  blood  (Fig.  366).  This  hsemor- 
rhagic  pachymeningitis  is  not  peculiar  to  general  paresis,  but  is  found  in 
many  other  conditions. 

The  pia  arachnoid  is  usually  opaque  and  grayish  white  or  very  cedematous. 

48 


738  TEXT-BOOK   OF   PATHOLOGY 

Not  infrequently  it  stretches  across  quite  wide  sulci,  which  are  then  partly 
filled  with  fluid,  and  sometimes  the  surface  of  the  brain  presents  a  great 
depression  full  of  yellowish  fluid,  through  and  over  which  the  arachnoid 
stretches.  All  these  things  are  the  result  of  the  atrophy  and  shrinkage  of 
the  cerebral  substance,  the  decrease  in  the  bulk  of  the  convolutions  throw- 
ing wide  the  sulci  (Fig.  367).  The  whole  brain  is  a  good  deal  decreased 
in  size — on  an  average  by  150  grams,  but  the  two  sides  may  be  asymmetrical. 
The  cerebral  ventricles  are  often  widened  and  contain  an  excess  of  fluid. 
Their  lining  is  roughened  by  the  appearance  of  minute  gray,  sand-like 
nodules  which  are  outgrowths  of  neuroglia  which  push  the  ependyma  before 
them.  This  "ependymitis  granularis"  also  occurs  in  other  conditions. 

Microscopically,  alterations  are  found  especially  in  the  more  anterior 
portions  of  the  cerebral  cortex.  The  meninges  are  found  to  be  thickened 
and  infiltrated  with  mononuclear  wandering  cells,  among  which  plasma 
cells  are  prominent.  They  are  often  intimately  adherent  to  the  brain 
substance.  The  vascular  prolongations  are  accompanied  by  mantles  of 
the  same  plasma  cells  and  other  smaller  mononuclears,  and  even  about 
the  smallest  vessels,  which  seem  dilated  and  increased  in  number,  the  spaces 
are  filled  with  these  cells. 

The  nerve-cells  of  the  cortex  are  in  all  stages  of  degeneration,  shrinkage, 
and  disintegration,  and  great  numbers  of  them  have  disappeared.  Those 
which  remain  have  lost  their  protoplasmic  processes  in  many  cases  and 
often  their  axone  fibre.  They  are  also  greatly  disarranged,  so  that  the 
normal  layers  and  vertical  rows  are  no  longer  to  be  made  out,  but  the  cells 
lie  confused  and  sparsely  scattered  in  the  cortex.  Naturally  the  fibres, 
and  especially  the  tangential  association  fibres  and  collaterals,  are  greatly 
reduced  in  number.  The  radial  fibres  seem  more  resistant,  but  even  they 
are  markedly  diminished.  In  consequence  of  these  losses  the  cerebral 
convolutions  shrink  and  fall  apart.  But  in  the  place  of  the  lost  cells  and 
fibres  a  great  new  growth  of  neuroglia  springs  up.  Abundant  neuroglia 
cells,  including  the  so-called  spider  cells,  appear,  together  with  a  relatively 
dense  network  of  neuroglia  fibres.  This  is  especially  concentrated  on  the 
exposed  surface  and  in  those  places  where  the  brain  substance  is  invaginated 
by  the  nutrient  vessels.  Every  vessel  is  thus  surrounded  by  a  network  of 
fibres.  Sometimes  there  are  even  projecting  brush-like  masses  on  the  outer 
surface,  which  aid  in  causing  the  adhesion  of  the  meninges.  The  superficial 
layer,  normally  rather  indistinct,  here  becomes  a  dense  felt-work  of  neu- 
roglia fibres  extending  a  little  way  into  the  cortex  and  devoid  of  nerve-cells. 

The  spirochsetse  found  by  Noguchi  and  Moore  in  paretic  brains  were 
scattered  in  the  cerebral  substance,  not  particularly  in  association  with  the 
vessels  and  not  in  this  external  neuroglial  layer.  The  cerebrospinal  fluid  is 
rich  in  lymphocytes  and  contains  also  plasma  cells.  It  is  rich  in  globulins 
and  gives  the  Wassermann  reaction  in  extreme  dilution. 

In  the  remainder  of  the  brain  the  lesions  are  very  similar,  with  wide- 
spread loss  of  nerve-cells  and  fibres.  This  is  well  seen  in  the  basal  ganglia, 


CONGENITAL   SYPHILIS  739 

the  pons  and  medulla,  as  well  as  in  the  cerebellum,  whose  peculiar  cortical 
cells  may  be  greatly  reduced. 

In  the  spinal  cord,  tract  degenerations  are  found  in  limited  areas  of  the 
posterior  column,  generally  together  with  descending  degenerations  of  the 
pyramidal  tracts.  Doubtless,  while  the  posterior  tract  degeneration  de- 
pends upon  the  same  setiological  factor  as  the  changes  in  the  brain,  the 
descending  degenerations  may  be  due  to  lesions  in  the  motor  cortex. 
These  are  the  changes  in  the  so-called  tabo-paresis,  which,  as  has  been  said, 
does  not  correspond  precisely  with  tabes  in  symptoms  or  anatomical  basis. 

LITERATURE 
Kraepelin:  Lehrb.  d.  Psychiatrie,  Leipzig,  1909,  General  Paresis  (Translation  Nerv. 

and  Mental  Dis.,  Monogr.,  1913,  series  No.  14). 
Alzheimer:    Histol.  Stud.  z.  Differential  Diag.  d.  Prog.  Paralyse,  Habilitationschrift, 

1904. 

Weygandt:  Psychiatrie,  Miinchen,  1902. 
Noguchi  and  Moore:  Jour.  Exp.  Med.,  1913,  xvii,  232 

CONGENITAL  SYPHILIS 

The  term  congenital  syphilis  is  to  be  preferred  to  hereditary  syphilis  inas- 
much as  it  appears  that  the  disease  is  not  transmitted  as  a  hereditary  char- 
acteristic (dependent  upon  the  chromosomes  of  the  uniting  germ  cells), 
but  rather  as  an  infection  transmitted  to  the  fcetus  in  the  course  of  its  de- 
velopment, either  by  spirochaBta?  which  accompany  the  sperm  cell  and 
probably  infect  the  mother,  or  by  spirochaBtaB  from  the  tissues  of  the  mother, 
herself  previously  infected.  In  all  these  cases,  except  perhaps  in  late 
postconceptional  syphilis,  in  which  both  placenta  and  child  may  possibly 
escape,  the  placenta  is  the  seat  of  syphilitic  alterations  which  are  of  rather 
vague  character,  since  actual  gummata  are  only  unconvincingly  described 
and  are  at  least  rare.  There  are  found  diffuse  infiltrations  of  the  placenta 
with  wandering  cells,  vascular  changes  both  in  the  placenta  and  in  the 
umbilical  cord,  distinguished,  as  elsewhere,  by  thickening  of  adventitia 
and  intima,  and,  thirdly,  curious  modifications  of  the  villi,  consisting  of 
new  formation  of  loose  connective  tissue  about  the  central  blood-vessels, 
such  as  to  cause  a  great  bulbous  swelling  of  each  villus  and  hence  a  marked 
enlargement  of  the  placenta.  On  this  account,  a  striking  disproportion 
between  the  size  of  the  placenta  and  that  of  the  child  is  always  suggestive 
of  syphilis. 

None  of  these  changes  is,  however,  of  absolutely  diagnostic  importance. 

Evidently  the  spirochsetse  can  enter  the  fcetal  blood  readily  enough  from 
such  diseased  placenta?,  and  finding  in  the  fcetal  tissues  a  specially  suitable 
medium  for  growth,  proceed  to  multiply  to  an  extent  never  approached  in 
the  tissues  of  the  adult  in  acquired  syphilis.  They  are  to  be  demonstrated 
in  perfectly  astounding  numbers  by  the  Levaditi  method  of  silver  staining 
in  most  of  the  tissues  of  the  syphilitic  new-born,  where  they  lie  scattered 
everywhere  among  the  cells,  generally  without  producing  any  very  evident 
change  about  them.  The  lesions  which  they  produce  are  essentially  like 


740  TEXT-BOOK    OF    PATHOLOGY 

those  of  the  tertiary  stage,  although  some  are  evidently  of  the  secondary 
type.  Primary  lesions  do  not  occur.  These  tertiary  lesions  consist  most 
commonly  of  diffuse  inflammation,  with  the  formation  of  a  great  deal  of 
scar-like  connective  tissue  throughout  the  organ;  rarely  there  are  actual 
gummata,  and  often  the  effect  seems  to  be  shown  in  the  retardation  and 
impairment  of  the  normal  growth  and  development  of  the  organ. 

The  effects  of  syphilitic  infection  in  the  parents  upon  the  children  seem 
to  become  somewhat  weakened  with  the  advance  of  time  and  with  succes- 
sive pregnancies.  The  first  pregnancies  after  infection  end  as  a  rule  in 
early  miscarriages;  often  the  foetus  is  found  in  an  extreme  state  of  macera- 
tion, as  though  it  had  been  dead  a  long  time.  In  the  later  pregnancies  the 
child  may  be  born  alive  with  lesions  of  syphilis,  and  die  soon.  Still  later 
it  may  survive  and  even  show  no  sign  of  disease  at  first,  but  pretty  surely 
in  childhood  or  adolescence  or  even  in  later  life  the  stigmata  or  character- 
istic and  destructive  marks  of  the  disease  appear  somewhere,  either  in  the 
form  of  a  finished  process,  or  as  a  progressive  disease  which  may  lead  to  the 
deformity  or  death  of  the  patient.  It  is  evident  that  this  so-called  "  syphi- 
lis tardive"  forms  an  interminable  subject  with  quite  as  many  variegated 
possibilities  as  in  the  acquired  form. 

Indeed,  practically  all  of  the  effects  of  acquired  syphilis  appear  in  the 
congenital  retarded  form,  even  including  tabes  and  general  paresis,  and 
none  of  them  shall  be  discussed  again  here.  The  following  concerns  those 
which  are  peculiar  to  the  congenital  form. 

The  new-born  syphilitic  child  or  dead  foetus  commonly  shows  some 
affections  of  the  skin,  such  as  the  plantar  and  palmar  pemphigus,  in  which 
the  skin  of  the  palms  and  soles  is  lifted  up  in  bullse  or  blisters  filled  with 
fluid;  another  type  shows  extensive  scaling  off  of  the  epidermis,  sometimes 
over  great  areas  (specific  ichthyosis). 

There  may  be  ulcerative  lesions  over  the  buttocks  and  thighs  which  later 
heal  to  form  inconspicuous  scars.  Papules  and  areas  of  infiltration  on  the 
lips,  especially  at  the  angles  of  the  mouth,  burst  later  and  ulcerate,  healing 
afterward  to  form  radiating  scars — the  so-called  rhagades.  The  same  thing 
happens  in  the  peri-anal  region. 

Coryza  or  " snuffles"  is  a  practically  constant  accompaniment  and  is 
extremely  serious  to  the  nursing  child,  since  it  cannot  breathe  through  its 
nose  while  it  suckles.  On  this  account  it  may  practically  starve  to  death. 
In  still-born  infants,  or  in  those  which  die  shortly  after  birth,  the  lungs  show 
in  many  cases  a  peculiar  change,  generally  spoken  of  loosely  as  white 
pneumonia  or  pneumonia  alba.  There  has  been  much  dispute  about  the 
nature  of  this,  and  while  some  have  tried  to  separate  a  desquamative  from 
an  interstitial  form,  others  have  found  these  two  processes  combined. 

The  lungs  are  enlarged  and  heavy,  the  consolidation,  usually  patchy, 
is  smooth,  pale,  and  elastic.  Microscopically  (Fig.  368),  in  all  the  cases  I 
have  seen,  there  has  been  a  combination  of  great  thickening  of  the  alveolar 
septa  with  some  desquamation  of  the  epithelium  and  in  places  an  infiltra- 


CONGENITAL   SYPHILIS 


741 


tion  with  leucocytes  and  mononuclear  wandering  cells.  The  epithelial 
lining  cells  are  cubical  in  form  from  the  lack  of  distension,  and  while  many 
are  desquamated  into  the  air-cells,  there  seems  to  be  no  very  great  multi- 
plication on  their  part.  On  the  other  hand,  the  connective  tissue  of  the 
lung  is  enormously  increased  in  bulk  about  vessels  and  bronchi  and  in  the 
alveolar  walls  themselves.  These  are  so  thick  that  the  alveoli  look  like 


-aL 


Fig.  368. — Congenital  syphilis  of  the  lung:  pneumonia  alba.  There  is  great  interstitial 
growth  of  connective  tissue  with  infiltration  of  wandering  cells  and  thickening  of  the 
alveolar  epithelium. 

glandular  spaces  in  a  solid  tissue;  the  capillaries  are  wide  and  seem  very- 
abundant  as  they  run  from  side  to  side  of  the  septa.  The  connective  tissue 
forms  a  loose  network,  evidently  rather  cedematous,  in  which  the  connective- 
tissue  cells  are  scattered,  sparsely  mingled  with  a  good  number  of  mono- 
nuclear  wandering  cells.  In  rather  rare  cases  distinct  gummata  have  been 
seen  in  the  lungs. 

In  the  liver  there  occurs  a  variety  of  lesions.  The  organ  is  generally 
enlarged  and  firm,  sometimes  it  has  a  normal  dark-red  appearance  on  sec- 


742 


TEXT-BOOK    OF    PATHOLOGY 


tion,  sometimes  it  is  pale  grayish-brown  and  rather  translucent,  with 
numerous  scattered  foci  of  opaque  yellow.  Perhaps  the  commonest 
change  is  a  general  retardation  of  its  development,  so  that  at  birth  it  still 
appears  as  an  organ  actively  engaged  in  blood  formation.  Bullard  thinks 
of  this  as  a  compensatory  myeloid  activity  on  account  of  the  general 
fibrosis  of  the  bone-marrow.  The  capillaries  are  wide  and  in  places  dis- 
tended with  groups  of  blood-cells  of  all  sorts,  myelocytes,  lymphocytes, 


'" 


vH*      *:.  /•-       :»:  :'v';'^  Av.:Vf, 
^^ 


Fig.  369. — Congenital  syphilis  of  the  liver.  The  liver-cell  strands  are  separated  by 
fibrous  tissue,  and  there  are  accumulations  of  wandering  cells  in  places.  Such  foci  may 
later  become  caseous. 

eosinophiles,  and  particularly  nucleated  red  corpuscles.  In  other 
places  the  liver-cell  columns  are  widened  into  bulbous  masses  of  pro- 
toplasm in  which  are  grouped  numerous  large  nuclei,  evidently  indi- 
cating a  continued  new  formation  of  liver-cells.  There  is  nothing  clearly 
specific  about  such  an  anatomical  picture — the  same  thing  may  be  found  in  a 
normal  f cetus  of  a  rather  earlier  stage  of  development,  but  the  abundant  dis- 
tribution of  spirochsetae  through  the  tissue  determines  its  syphilitic  nature. 


CONGENITAL   SYPHILIS  743 

More  distinctive  are  the  cases  in  which  the  whole  lobular  arrangement 
of  the  liver-cells  is  rendered  indefinite  by  the  diffuse  new  growth  of  fibrous 
tissue  everywhere  through  the  organ.  The  liver-cell  strands  are  reduced 
to  small  distorted  bands  of  protoplasm  containing  many  nuclei,  sometimes 
clustered  almost  as  in  a  giant-cell,  and  separated  everywhere  by  a  loose 
fibrous  tissue  in  which  run  the  isolated  capillaries.  In  the  case  illustrated 
(Fig.  369)  there  are  numerous  foci  of  necrosis,  in  which  there  are  crowded 
abundant  leucocytes  and  fragmented  nuclei.  These  evidently  form  one 
type  at  least  of  what  are  called  miliary  gummata,  although  there  is  nothing 
very  specific  in  their  appearance.  They,  like  the  rest  of  the  liver,  contain 


Cv;;;^vt:.;;;; 


Fig.  370. — Congenital  syphilis.  Pancreas  of  child  with  excessive  interstitial  con- 
nective tissue  separating  acini.  The  island  of  Langerhans  is  still  in  connection  with  a 
duct. 

quantities  of  spirochsetse.  Occasionally  one  finds  more  definite  concen- 
trically arranged  miliary  gummata,  like  small  tubercles  in  the  liver,  and 
these  have  been  well  described  by  Hecker.  More  rarely  there  are  larger 
caseous  gummatous  nodules  surrounded  by  scar  tissue  and  ending  in  a 
lobulated  cirrhotic  deformity  of  the  liver. 

The  pancreas,  so  rarely  involved  in  acquired  syphilis,  is  commonly 
affected  by  the  congenital  form.  Again  there  are  rarely  gummata  of 
definite  form,  but  very  commonly  diffuse  granulation  tissue  growth  and  re- 
tardation of  development  (Fig.  370).  One  finds  the  pancreas  slightly 
enlarged  and  gray  and  firm.  On  section  the  acini  are  spread  apart  and 
apparently  incompletely  differentiated,  the  islands  of  Langerhans  often 


744 


TEXT-BOOK   OF   PATHOLOGY 


appearing,  as  in  the  foetus,  in  persistent  connection  with  the  branches  of 
the  pancreatic  duct.  Focal  necrosis  of  a  more  or  less  suggestive  gummatous 
character  is  often  found  in  the  interstitial  tissue. 

Similarly,  congenital  syphilitic  disease  in  the  kidneys  produces  rarely 
definite  gummata,  but  often  patches  of  atrophy  and  destruction  of  tubules 
and  glomeruli  with  scarring.  The  same  peculiarity  is  true  of  the  testicle, 
in  which  the  gumma  common  in  the  acquired  form  is  replaced  by  atrophy 
or  maldevelopment  of  the  tubules,  often  with  interstitial  connective-tissue 
formation,  which  leaves  the  organ  distorted,  small,  and  hard. 

In  the  bones  the  syphilitic  osteochondritis  first  described  by  Wegner  is  a 
most  definite  and  characteristic  lesion  found  practically  always  in  the 
syphilitic  new-born,  although  it  does  not  affect  equally  all  the  bones,  being 
most  distinctly  developed  in  the  epiphyseal  ends  of  the  long  bones  about 
the  knee.  The  epiphyseal  line,  which  ordinarily 
forms  a  perfectly  even,  thin,  pearly  gray  line  be- 
tween cartilage  and  bone,  loses  this  delicate  aspect 
and  becomes  thick,  jagged  and  opaque  yellowish- 
white  (Fig.  371).  Often  it  has  a  granular,  mortar- 
like  appearance  and  it  is  seen  that  it  no  longer 
marks  the  line  of  continuity  of  the  cartilage  with 
the  bone,  but  that  instead  it  is  really  a  cleft  be- 
tween the  two,  filled  with  a  fine  yellowish  gritty 
substance.  Sometimes  the  epiphysis  is  quite  dis- 
located and  separated  from  the  bone  along  this 
line. 

Microscopically  (Figs.  372,  373)  the  reasons  for 
this  are  seen:  Along  the  line  of  ossification  on  the 
side  of  the  bone  there  is  developed  a  layer  of 
granulation  tissue  essentially  gummatous  in  its 
character,  and  prone  to  necrosis  and  disintegra- 
tion; it  involves  the  most  recently  formed  bone, 

and  stops  the  process  of  bone  formation  by  causing  the  necrosis  of  this 
layer,  all  of  which  collapses  together  in  a  debris  of  minute  bony  fragments 
(Fig.  374).  Round  about,  from  the  periosteum  and  perichondrium,  there  are 
reparatory  new  growths  of  slight  extent,  and  later,  if  the  child  survives, 
all  this  debris  is  removed  and  healing  takes  place  in  such  a  way  as  to  read- 
just lamellated  bone  to  cartilage  and  allow  bone  formation  to  proceed  as 
before,  although  one  may  imagine  that  in  all  such  cases  a  good  deal  of 
disturbance  in  the  development  of  the  bone  must  result. 

Bullard  finds  by  actual  measurement  of  large  numbers  of  syphilitic  in- 
fants and  children  that  growth  of  the  bones  in  length  is  distinctly  retarded 
as  compared  with  that  of  normal  controls.  The  blood-forming  functions 
of  the  bone-marrow  are  almost  annihilated  by  the  conversion  of  the  tissue 
into  a  sort  of  granulation  tissue  with  few  remains  of  myeloid  elements. 


Fig.  371. — Syphilitic  os- 
teochondritis. The  line  of 
ossification  is  irregular  and 
is  conspicuously  opaque. 


CONGENITAL   SYPHILIS 


745 


There  are  many  other  lesions  to  be  found  in  such  newborn  syphilitic 
children,  but  they  all  proceed  on  the  same  principles  and  these  may  suffice 
to  illustrate. 

Late  Forms  of  Congenital  Syphilis.— Very  important  and  difficult  to 
comprehend  are  the  syphilitic  lesions  which  appear  after  the  lapse  of  months 
or  years  in  children  born  of  syphilitic  parents,  which  at  birth  may  not  have 
shown  any  signs  of  disease. 


ISf 


Fig.  372. — Syphilitic  osteochondritis,  showing  slight  distortion  of  the  line  of  ossification. 


Fournier,  in  his  book  on  "La  Syphilis  Tardive,"  includes  practically  every 
ailment  that  flesh  is  heir  to  under  this  heading,  so  that  at  first  it  must  seem 
fanciful;  but  while  one  remains  skeptical  about  some  of  the  phenomena 
referred  to  syphilis,  good  proof  is  brought  for  most  of  them. 

The  scars  and  deformities  or  stigmata  of  syphilis  are  recognizable,  as 
well  as  the  active  progressive  disease,  and  often  serve  to  indicate  the  cha- 


Fig.  373.-- Syphilitic  osteochondritis.  Section  showing  the  changes  mentioned,  and 
also  separation  of  the  epiphysis  (a).  About  the  comminuted  fragments  of  calcined 
cartilage  and  bone  is  a  cellular  granulation  tissue  (c)  with  extensive  necrosis  (6)  toward 


CONGENITAL   SYPHILIS 


747 


acter  of  some  other  more  obscure  process  which  is  still  going  on.  Various 
deformities  due  to  retardation  of  development  leading  even  to  dwarfism 
are  regarded  as  syphilitic.  These  as  they  affect  the  skull  produce  irregu- 
larities of  form  and  asymmetries,  or  a  hydrocephalic  dilatation  which 
might  seem  due  to  other  possible  causes. 

Perfectly  distinct,  however,  are  the  malformations  of  the  nose,  gum- 
matous  destruction  of  the  nasal  bones  producing  saddle-nose,  while  even 


Fig.  374.  —  Syphilitic  osteochondritis.     Another  section  from  the  same  case,  showing 
extensive  efforts  at  healing,  with  the  formation  of  new  cartilage  and  cancellous  bone 


greater  deformity  is  caused  by  collapse  of  the  cartilaginous  part  of  the 
septum,  which  allows  the  tip  of  the  nose  to  telescope  into  the  rest,  so  that 
there  is  a  fold  of  skin  on  each  side. 

Various  changes  in  ears  and  eyes  occur  with  deafness  and  impairment  of 
vision.  Of  these,  the  commonest  and  most  easily  recognized  is  the  inter- 
stitial keratitis,  which  gives  a  steamy  opacity  to  the  cornea  and  which 
may  obstruct  vision  very  completely,  or  finally  clear  away  entirely. 


748  TEXT-BOOK    OF    PATHOLOGY 

In  the  teeth  there  are  many  deformities  ascribed  to  syphilis,  all  rather 
difficult  to  explain  and  none  surely  indicative  of  syphilis  unless  it  be  pos- 
sibly the  true  Hutchinson's  teeth.  The  change  that  Hutchinson  described, 
affecting  most  obviously  the  upper  incisors,  is  such  that  the  teeth  are  rather 
tapered,  usually  stand  wide  apart,  and  have  a  single  semicircular  recess  in 
the  biting  edge  (Fig.  374A). 

In  the  skeleton  the  lesions  of  late  congenital  syphilis  are  practically 
those  of  the  tertiary  stage  of  the  acquired  form,  including  chronic  forms  of 
periostitis,  arthritis,  etc.  But  the  atrophy,  or  rather  maldevelopment,  of 
bones  which  produces  the  extreme  delicacy  and  small  size  of  the  skeleton 
in  some  of  these  cases  is  rather  different,  as  is  also  the  extraordinary  local 
or  partial  gigantism,  which  is  of  similar  origin  and  follows  the  great  local 
overgrowth  of  bone. 

Lesions  of  the  nervous  system  and  of  the  various  other  organs  of  the  body 
are  like  those  of  acquired  syphilis,  except  that  they  seem  to  be  intensified 


Fig.  374A. — Hutchinson's  teeth. 

in  these  patients,  inasmuch  as  the  infection  has  begun  with  the  beginning 
of  their  lives  and  affected  their  resistance  throughout. 

LITERATURE 

Volk:   Placentarsyphilis,  Ergeb.  d.  allg.  Path.,  1904,  viii,  509. 
Schwab:  La  Syphilis,  1905,  Juli. 
Fournier,  E. :   L'heredosyphilis  tardive,  Paris,  1907: 
Herxheimer,  G.:  Ergeb.  d.  allg.  Path.,  1908,  xii,  499. 
Hecker:  Deutsches  Arch.  f.  klin.  Med.,  1898,  Ixi,  1. 

Hochsinger:   Studien  uber  hered.  Syphilis,  Leipzig  u.  Wien,  1898  and  1904. 
Warthin:  Amer.  Jour.  Med.  Sci.,  1911. 


OTHER   SPIROCKLETAL  INFECTIONS 

Space  will  allow  only  the  briefest  mention  of  certain  other  diseases  known 
or  thought  to  be  caused  by  various  spirochsetse,  which  are  of  very  great 
importance  in  the  tropics,  but  unfamiliar  here. 


CONGENITAL   SYPHILIS 


749 


Yaws  or  framboesia  is  a  disease  resembling  syphilis  in  some  respects, 
which  is  caused  by  the  Spirochseta  or  Treponema  pertenue  as  shown  by 
Castellani.  It  is  not  a  venereal  disease,  but  is  apparently  transmitted  by 
contact,  for  the  primary  lesion  may  be  found  in  positions  which  suggest 
this.  It  is  extremely  common  in  the  tropics,  and  most  of  the  children  in 
the  islands  of  the  Pacific,  in  the  East  and  West  Indies,  and  elsewhere 
seem  to  acquire  the  infection.  It  is  less  common  in  adults.  It  is  thought 
to  give  rise  to  primary,  secondary,  and  tertiary  lesions,  as  in  the  case  of 
syphilis,  but  the  primary  lesions  are  not  very  different  from  the  secondary, 


Fig.   374B. — Yaws      Secondary   erup- 
tion in  florid  stage  (Fiji  Islands). 


Fig.  374C. — Yaws.  Showing  exten- 
sive spread  of  crusted  lesions  (Tonga 
Islands) . 


and  the  connection  of  the  distorting,  destructive  processes  which  are  said 
to  be  tertiary  lesions  with  the  others  is  not  entirely  convincing,  although 
pretty  generally  accepted.  The  primary  lesion,  generally  shown  as  such, 
is  usually  a  vesicle  or  pustule,  developed  on  the  hand  or  on  the  hip  of  a 
mother,  where  the  skin  came  into  contact  with  the  infected  child  she  was 
carrying,  or  on  the  breast.  The  secondary  lesions  appear  as  a  great  crop 
of  large  flattened  vesicles,  which  quickly  become  changed  into  honey  yel- 
low pustular  elevations  (Figs.  374B,  374C).  These  on  section  show  a  great 


750 


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thickening  of  the  epithelium  and  a  dense  infiltration  of  plasma  cells  be- 
neath (Fig.  374D).  The  spirochsetae  are  most  readily  found  in  the  early 
stages,  before  the  breaking  of  the  crust  allows  of  secondary  infection  of  the 
pustule.  The  tertiary  lesions  are  found  in  the  bones  and  other  tissues  of 
the  extremities  or  of  the  face  and  upper  respiratory  passages,  and  there 
they  produce  the  most  extensive  losses  of  tissue,  with  scarring  and  extra- 
ordinary distortions.  The  secondary  lesions  disappear  in  a  magical  way 
under  salvarsan  treatment. 


Fig.  374D. — Yaws.     Deeper  layers  of  skin  in  a  secondary  lesion  showing  the  great  ac- 
cumulation of  plasma  cells. 

Spirochaetosis  Icterohsemorrhagica  (Weil's  Disease). — This  disease,  long 
known  as  Weil's  disease,  occurs  in  endemic  and  S9metimes  epidemic  form 
in  Japan,  and  has  recently  affected  large  numbers  of  soldiers  in  the  trenches 
in  France,  Belgium,  and  elsewhere  in  Europe.  It  is  an  affection  which 
begins  suddenly  with  fever,  headache,  general  aching  pains,  and  nosebleed, 
and  is  often  marked  by  the  vomiting  and  coughing  up  of  blood,  and  by  the 
passage  of  blood  with  the  stools.  After  about  five  days  the  fever  passes 


CONGENITAL   SYPHILIS  751 

off  and  jaundice  appears.  After  five  or  six  days  more  the  fever  reappears 
and  lasts  for  about  a  week.  It  has  been  shown  by  Inada  and  his  co- 
workers  that  the  cause  is  a  spirochaete  which  also  infects  rats,  the  Spiro- 
chaeta  icterohaemorrhagica,  and  that  it  is  probably  transferred  through  the 
skin  of  human  beings  from  the  infected  urine  of  the  rats.  This  does  not 
seem  altogether  convincing,  and  it  has  been  suggested  that  it  may  possibly 
be  transmitted  by  some  biting  insect.  During  the  first  days  of  the  illness 
it  is  found  in  the  circulating  blood,  after  the  fifteenth  day  in  the  urine. 
It  seems  that  a  certain  amount  of  immunity  is  developed  and  may  be  pro- 
duced artificially  in  animals.  Relapsing  fever  and  rat-bite  fever  are  other 
diseases  of  a  very  similar  character,  concerning  which  references  are  given 
below. 

Yellow  fever  was,  of  course,  one  of  the  most  dreaded  plagues  of  mankind 
a  few  years  ago,  but  now,  since  the  epoch-making  studies  of  Reed  and  his 
colleagues,  and  the  very  effective  application  of  these  principles  by  General 
Gorgas,  it  is  being  rapidly  exterminated.  It  is  a  very  grave,  febrile  disease 
with  vomiting  of  blood,  jaundice,  haemorrhages  in  the  skin  and  elsewhere, 
and  extensive  necroses  in  the  liver  with  disturbance  of  its  function.  Reed 
showed  that  it  is  transmitted  by  the  bite  of  an  infected  mosquito,  Stego- 
myia  fasciata,  but  only  after  the  lapse  of  twelve  days  after  the  mosquito 
had  bitten  a  person  ill  of  the  fever  and  become  infected.  Evidently  it 
requires  twelve  days  for  the  development  in  the  body  of  the  mosquito,  of 
enough  virus  to  infect  a  man,  or  else  the  virus  must  go  through  a  twelve- 
day  cycle  of  development  in  the  mosquito.  This  is  a  mosquito  which  is 
very  domestic  in  its  habits,  living  about  houses  and  laying  its  eggs  in 
water  found  in  receptacles  there.  Since  in  cities  like  Guayaquil  there  is 
no  other  water-supply  than  tanks  and  cisterns  about  the  houses,  it  is  not 
easy  to  destroy  the  mosquitos,  but  otherwise  it  is  only  necessary  to  empty 
out  the  water  from  these  receptacles  once  a  week  to  prevent  all  larvae 
from  hatching.  Gorgas  has  shown  that  it  is  not  necessary  to  destroy  every 
mosquito,  but  merely  to  reduce  their  numbers  to  a  point  below  that  at 
which  their  presence  has  a  reasonable  chance  of  spreading  infection.  In 
Guayaquil  and  in  Payta  and  Piura  in  northern  Peru  he  has  accomplished 
this  during  the  past  summer,  and  apparently  ended  the  infection.  No- 
guchi  has  recently  published  the  results  of  studies  which  show  that  a 
spirochaete,  indistinguishable  morphologically  from  the  icterohaemorrhag- 
ica,  is  present  in  cases  of  yellow  fever,  as  shown  first  by  the  inoculation  of 
guinea-pigs,  and  thinks  that  this  is  the  cause  of  yellow  fever.  Various 
criticisms  have,  of  course,  been  offered,  but  it  is  to  be  hoped  that  these 
results  will  prove  correct.  He  has  named  the  organism  Leptospira  ic- 
teroides. 

LITERATURE 

Yaws: 

Castellani  and  Chalmers:  Manual  of  Tropical  Medicine,  London,  1910. 


752  TEXT-BOOK   OF   PATHOLOGY 

*     Spirochcetosis  Icterohcemorrhagica: 

Inada,  Ido,  Hoki,  Kaneko,  and  Ito:  Jour.  Exp.  Med.,  1916,  xxiii,  377;  1916,  xxiv,  471, 

485;  1917,  xxvi,  325,  341,  355. 

Nolf  and  Firket,  J. :  Archives  Med.  Beiges,  Avril,  1918. 
Stokes  and  Ryle:  Brit.  Med.  Jour.,  1916,  ii,  413. 

Gamier  and  Reilly:  Arch,  de  med.  exp.  et  d'anat.  path.,  1918,  xxviii,  228. 
Martin,  C.  J.:  Jour.  Royal  Army  Med.  Corps,  1918,  xxx,  102. 

Rat-bite  Fever: 

Futaki  and  others:  Jour.  Exp.  Med.,  1916,  xxiii,  249;  1917,  xxv,  33. 

Kaneko  and  Okuda:  Ibid.,  1917,  xxvi,  363,  377. 

Blake:  Ibid.,  1916,  xxiii,  39. 

Yellow  Fever: 

Reed,  Carroll,  Lazear,  and  Agramonte:  Amer.  Public  Health  Assoc.,  1900,  xxviii.    Jour. 

Amer.  Med.  Assoc.,  Feb.  16,  1901. 
Noguchi:  Jour.  Exp.  Med.,  1919,  xxix,  547,  563,  585;  1919,  xxx,  1,  9,  13,  87,  95,  401; 

1920,  xxxi,  135,  159. 


CHAPTER  XXXVII 
TYPES  OF  INJURY.-EXANTHEMATIC  DISEASES 

Introduction.  Measles:  Susceptibility,  aetiology,  course  of  the  disease  and  pathological 
anatomy.  Scarlet  fever:  ^Etiology;  complicating  streptococcus  infection,  transmission- 
course  and  pathological  anatomy.  Scarlatinal  nephritis. .  Smallpox:  Relation  to  vaccinia; 
vaccination;  ostiology;  symptoms  and  pathological  anatomy. 

EXANTHEMATIC  DISEASES 

THERE  follows  some  description  of  the  more  important  of  a  series  of  dis- 
eases which  we  recognize  as  extremely  easily  communicable  and  therefore 
undoubtedly  due  to  an  infection,  but  in  which,  in  spite  of  the  most  earnest 
efforts,  no  living  organism  has  been  demonstrated  with  the  certainty  which 
we  demand.  It  is  true  that  many  supposed  parasites  have  been  found,  as, 
for  example,  the  cytorhyctes  in  the  skin  in  small-pox,  which  are  looked  upon 
with  confidence  by  their  discoverers  as  the  specific  factors,  but  their 
descriptions  do  not  carry  conviction.  It  has  been  well  said  that  if  there  is 
any  doubt  about  a  parasite  when  you  see  it,  it  is  usually  not  a  parasite. 
Whatever  the  nature  of  these  organisms,  they  must  multiply  with  great 
rapidity  and  disseminate  themselves  quickly  through  the  body  by  way  of 
the  blood-stream.  Indeed,  the  diseases  can  probably  be  transmitted  in 
each  case  by  inoculation  of  blood,  as  has  been  shown  by  Hektoen  to  be 
true  for  measles.  Doubtless,  too,  the  organisms  are  very  small  and  per- 
haps, in  most  cases,  capable  of  going  through  a  porcelain  filter.  The  dis- 
eases have  in  common  the  occurrence  of  an  eruption  on  the  skin,  or 
exanthem,  which  no  doubt  indicates  the  presence  of  the  organism  there, 
but  since  such  eruptions  are  found  in  other  infectious  diseases  and  even  in 
various  intoxications  it  does  not  really  form  a  good  basis  for  their  classifica- 
tion. There  are  many  such  diseases,  including  chicken-pox,  rubeola  or 
German  measles,  Duke's  fourth  disease,  erythema  infectiosum,  etc.,  but 
the  most  important  are  those  which  follow.  Doubtless  before  long  their 
aetiology  will  be  cleared  up  and  we  shall  be  able  to  form  a  better  idea  of  the 
way  in  which  the  lesions  are  produced. 

MEASLES 

This  is  a  disease  of  childhood  because  susceptibility  is  practically  universal 
and  the  opportunity  for  infection  so  general  that  few  children  escape. 
There  are  few  adults  to  infect,  since  nearly  all  have  had  the  disease  in  child* 
hood.  In  this  is  implied  the  fact  that  one  attack  confers  immunity.  The 
disease  may  be  transferred  in  utero  if  the  mother  is  ill  with  it  when  the  child 
is  about  to  be  born.  The  child  of  a  mother  who  has  never  had  measles 
]49  753 


754  TEXT-BOOK    OF    PATHOLOGY 

may  contract  it  almost  immediately  after  birth,  while  the  child  of  an  im- 
mune mother  is  born  with  an  immunity  which  lasts  one  or  two  months. 
The  mother's  milk  confers  no  protection.  While  such  a  situation  prevails 
in  most  civilized  countries,  it  is  well  known  that  in  isolated  lands,  such  as 
the  South  Sea  Islands,  where  the  disease  was  unknown,  the  advent  of  the 
infection  with  early  explorers  was  followed  by  terrific  epidemics  which 
killed  off  many  of  the  natives. 

In  the  winter  of  1917-18  the  concentration  of  troops  in  training  camps 
brought  together  great  numbers  of  young  men  who  had  never  had  measles, 
and  very  great  epidemics  occurred.  It  was  noted  that  the  men  from  rural 
districts  of  the  more  sparsely  inhabited  states  of  the  South  were  espe- 
cially affected,  while  those  from  cities  escaped. 

Although  under  ordinary  conditions  in  which  patient's  live  separately 
in  their  homes  measles  is  not  considered  a  serious  disease,  secondary 
infection  with  a  hffimolytic  streptococcus  occurs  when  many  cases  are 
housed  together  and  produces  a  very  fatal  pneumonia.  This  can  be 
avoided  by  rigidly  isolating  those  cases  which  show  the  streptococcus 
infection,  but  the  history  of  all  great  epidemics  of  measles  reveals  the  prev- 
alence of  this  type  of  pneumonia,  and  I  could  demonstrate  in  the  ancient 
museum  specimens  from  that  which  occurred  during  the  Civil  War  in  1864 
and  1865  not  only  the  character  of  the  pneumonia,  but  the  streptococci 
in  chains  in  the  lungs.  Secondary  infection  with  the  tubercle  bacillus  or 
the  aggravation  of  tuberculosis  already  existing  has  always  been  empha- 
sized. We  saw  none  of  these  cases  in  the  camp  epidemics,  and  it  has  even 
been  suggested  that  the  nodular  form  of  bronchopneumonia  has  been 
mistaken  for  tuberculosis,  but  this  seems  scarcely  probable,  and  the  older 
observations  may  doubtless  be  accepted. 

Nothing  is  known  of  the  nature  of  the  causative  agent.  The  experi- 
ments of  Hektoen  consisted  in  incubating  the  blood  taken  during  the  erup- 
tive stage  in  ascitic  broth  and  injecting  it  into  two  non-immune  persons, 
both  of  whom  developed  the  disease.  Anderson  and  Goldberger  stated 
that  they  could  produce  measles  in  monkeys  by  inoculation  of  blood  from 
early  stages,  that  the  virus  would  pass  a  Berkefeld  filter,  and  that  they 
could  carry  it  on  from  monkey  to  monkey.  Sellards,  however,  after  in- 
oculating eight  apparently  non-immune  volunteers  in  every  way  he  could 
devise  failed  to  transfer  the  disease.  His  paper  discusses  the  whole  sub- 
ject. 

Transmission  is  ordinarily  direct  from  person  to  person,  probably  by 
means  of  the  respiratory  tract,  the  infection  presumably  being  carried  in 
a  spray  from  the  coughing  child. 

The  period  of  incubation  is  eight  to  nine  days;  the  rash  appears  after 
about  fourteen  days.  There  are  thus  several  days  in  which  prodromal 
symptoms  of  headache,  malaise,  and  nasal  and  bronchial  catarrh  prevail. 
Conjunctivitis,  intense  coryza  with  reddening  of  the  pharynx  and  larynx, 
and,  a  little  later,  bronchitis,  are  characteristic  and  constant  features. 


MEASLES  755 

The  so-called  Koplik's  spots  in  the  mouth  are  minute  white  flecks  sur- 
rounded by  bluish  and  then  red  zones.  They  appear  early  and  have  a 
diagnostic  importance. 

The  exanthem  or  rash  appears  first  on  the  face  and  then  spreads  over 
the  rest  of  the  body.  It  is  slightly  elevated,  grayish-red,  and  distributed  in 
flecks  which  are  sometimes  very  small  but  usually  conglomerated  into  larger 
patches  which  reach  1  cm.  in  diameter.  It  is  common  to  observe  a  cres- 
centic  form  in  these  patches.  There  are  fever  and  leucocytosis  and  the 
catarrhal  symptoms  continue.  With  the  lapse  of  a  few  days  the  rash  fades 
and  there  may  be  desquamation  of  branny  scales.  The  bronchitis  clears 
up  also  unless  there  are  further  complications  in  the  form  of  lobular  pneu- 
monia or  other  secondary  infection. 

Pathological  Anatomy. — Sections  of  the  skin  which  pass  through  the 
macules  show  a  moderate  oedema  and  hyperaemia  with  some  accumulation 
of  lymphocytes  about  the  blood-vessels.  But  there  is  no  necrosis  nor  in- 
tense inflammatory  reaction.  The  lobular  pneumonia  which  is  an  ex- 
tremely common  complication  in  the  late  stage  of  measles  has  been  described 
in  connection  with  streptococcal  infections.  It  is  essentially  the  result  of 
an  infection  with  the  hsemolytic  streptococcus,  although  other  organisms 
were  occasionally  found  associated.  It  is  characterized  by  its  peribronchial 
and  interstitial  distribution,  forming  nodules  of  dense  tissue  and  exudate 
about  the  terminal  bronchioles,  with  spread  of  the  bacteria  by  way 
of  the  lymphatics  through  the  interlobular  septa  to  the  pleura.  The 
lymphatics  are  thrombosed  and  all  the  skeletal  structures  of  the  lung 
become  thickened  by  new  formation  of  tissue.  The  pleural  cavity  is 
quickly  filled  with  a  thin  fluid  full  of  bacteria  and  organization  of  the 
exudate  on  the  surface  is  rapid.  While  this  is  the  usual  condition,  there 
are  other  cases  in  which  low  resistance  allows  the  streptococci  to  produce 
extensive  necrosis  through  the  lung  with  hemorrhage  and  little  response 
of  a  protective  character. 

The  other  organs,  besides  the  lungs  and  skin,  are  not  characteristically 
affected  in  measles.  There  is  usually  a  moderate  acute  splenic  tumor  and 
general  enlargement  of  the  lymphoid  apparatus.  The  conjunctivitis, 
rhinitis,  etc.,  are  probably  caused  by  the  specific  agent,  but  bacteria  are 
so  regularly  associated  that  the  affection  is  not  peculiar.  Otitis  media  is  a 
not  infrequent  sequel. 

LITERATURE 

von  Jiirgensen  and  von  Pirquet:  Masern,  NothnagePs  Handb.,  Wien,  1911,  iv. 
Briicker:  Jahrb.  f.  Kinderheilk.,  1902,  Ivi,  725. 
Koplik:  Archives  of  Pediatrics,  1896,  xiii,  918. 
Hektoen:  Jour.  Infect.  Dis.,  1905,  ii,  238. 

Goldberger  and  Anderson:  Jour.  Amer.  Med  Assoc.,  1911,  Ivii,  971. 
Levy  and  Alexander:   Ibid.,  1918,  Ixx,  1827. 
Sellards:   Johns  Hopkins  Hosp.  Bull.,  1919,  xxx,  257. 
MacCallum:   Monograph,  Rockefeller  Institute,  1919,  No.  10. 


756  TEXT-BOOK   OF   PATHOLOGY 

SCARLET  FEVER 

This  is  generally  looked  upon  as  a  more  serious  disease  than  measles,  not 
only  in  itself  but  because  of  the  complications  which  accompany  it  and  the 
secondary  affections  which  appear  after  recovery  seems  well  established. 
It  is  very  readily  transmitted  from  one  person  to  another  and  therefore 
occurs  in  epidemics. 

Etiology. — Nothing  whatever  is  known  of  the  infectious  agent  which 
causes  this  disease.  It  is  true  that  Mallory  has  described  peculiar  rosette- 
like  bodies  in  the  skin  and  that  Gamaleia  and  others  have  seen  similar 
things,  but  these  cannot  be  found  in  skin  excised  from  the  living  patient, 
and,  on  the  other  hand,  they  can  be  found  in  the  skin  at  autopsy  in  persons 
who  have  died  of  other  diseases.  Their  setiological  relation  to  scarlet  fever 
is  at  least  doubtful. 

Further,  it  is  known  that  there  is  always  an  intense  infection  of  the  throat 
with  virulent  streptococci  or  pneumococci,  and  there  are  those  who  main- 
tain that  scarlet  fever  is  nothing  more  than  a  streptococcus  infection.  In- 
deed, one  sees  not  infrequently  intense  streptococcus  septicaemias  which, 
beginning  in  the  throat,  develop  all  the  prominent  symptoms  of  scarlatina. 
Two  such  cases  have  been  mentioned  in  another  chapter,  and  in  one  of  them 
there  remains  even  yet  uncertainty  as  to  whether  the  patient  died  of  scarlet 
fever  or  of  a  streptococcus  infection.  But  while  infection  with  the  strep- 
tococcus confers  no  immunity  from  another  attack,  and  rather  predisposes 
toward  reinfection,  one  attack  of  scarlet  fever  results  in  a  lasting  immunity. 
Besides,  scarlet  fever  is  not  the  only  disease  which  is  so  intimately  associated 
with  a  streptococcus  infection — the  same  situation  occurs  with  measles, 
small-pox,  etc.,  and  it  would  be  equally  reasonable  to  insist  that  they  too  are 
merely  forms  of  streptococcus  infection.  There  are  other  considerations, 
too,  which  make  it  seem  certain  that  the  cause  of  this  disease  is  a  special 
animate  virus,  which  is  quite  different  from  the  streptococcus. 

The  disease  may  be  transmitted  by  the  nasal  and  pharyngeal  secretion 
or  by  objects  soiled  with  it  or  with  the  scales  from  the  skin.  Of  course, 
this  is  the  traditional  guesswork,  since  the  organism  is  not  known,  but  at 
least  those  modes  of  transmission  seem  likely,  and  Stickler  actually  pro- 
duced the  disease  by  subcutaneous  injection  of  pharyngeal  mucus  in  the 
attempt  to  imitate  inoculation  as  then  practised  in  smallpox.  Krum- 
wiede,  Nicoll  and  Pratt  were  unable  to  transmit  the  disease  to  monkeys 
in  this  way  or  even  by  the  injection  of  blood  from  scarlatina  patients. 
On  the  other  hand,  scarlatinal  infections  in  surgical  incisions,  or  in  cuts  or 
scratches  received  during  an  autopsy  on  the  body  of  a  person  dead  of  scarlet 
fever,  are  well  known,  and  the  case  of  Leube,  who  thus  infected  himself, 
is  famous. 

The  infectious  agent  seems  to  cling  to  clothing  and  other  objects  and  to 
remain  alive  for  a  long  time.  Hence  the  cases  of  infection  from  apparel 
which  has  been  stored  for  years  in  a  trunk. 

Course  of  the  Disease. — The  disease  begins  suddenly,  after  three  or 


SCARLET   FEVER  757 

four  days  of  incubation,  with  sore  throat,  fever  and  swelling  of  the  lymph- 
glands  at  the  angle  of  the  jaw  and  of  the  tonsils.  With  increase  in  the  in- 
tensity of  the  angina  and  the  appearance  of  whitish  flecks  of  exudate  on 
the  red  background  there  comes  vomiting.  Soon  there  appears  on  the  face, 
and  later  over  the  whole  body,  the  characteristic  red  rash  which  is  made  up 
of  flecks  much  finer  than  in  the  case  of  measles  and  more  closely  set;  the 
whole  face  and  skin  has  a  flushed  red  color.  In  all  cases  the  angina  repre- 
sents a  streptococcus  infection,  but  there  are  some  which  proceed  to  re- 
covery without  much  further  evidence  of  bacterial  infection,  while  in  other 
cases  there  are  phenomena  of  the  most  intense  sort  which  appear  to  be 
largely  due  to  the  streptococci.  Escherich,  therefore,  divides  the  cases 
into  toxic  and  infectious  types.  In  the  more  severe  cases  the  angina  be- 
comes far  more  intense.  The  tonsils  swell  to  the  point  of  meeting  in  the 
mid-line  and  become  partly  necrotic.  Considerable  areas  of  mucosa  of  the 
fauces  and  the  walls  of  the  pharynx  become  covered  with  a  false  membrane 
of  greenish  color,  the  removal  of  which  reveals  deep  ulcerations  with  foul 
base.  The  scarlatinal  angina  is  thus  an  extremely  destructive  process. 
The  neighboring  lymph-glands  in  the  neck  are  swollen  to  a  great  size  and,  if 
incised,  sometimes  exude  a  greenish  pus,  sometimes  show  their  central  parts 
as  firm,  necrotic  masses  which  are  later  discharged.  Such  scarlatinal 
buboes  may  occur  in  this  way  in  the  early  stages  of  the  disease  or  appear 
much  later  after  the  acute  symptoms  have  passed. 

Pathological  Anatomy. — Laryngeal  and  tracheal  inflammation  is  found 
only  in  the  severest  cases  and  then  the  occurrence  of  bronchopneumonia 
is  likely.  This  lobular  pneumonia  commonly  becomes  confluent  and  leads 
to  the  production  of  abscesses  in  the  lung.  Extension  into  the  pleural 
cavity  results  in  empyema  which  may  readily  end  fatally. 

In  the  heart  there  may  be  no  evident  gross  lesions  even  though  the  child 
die  with  signs  directly  indicating  its  involvement. 

Stegemann  shows  that  even  in  the  early  days  of  the  disease  there  are  changes  in  the 
heart  ganglia,  including  degeneration  and  necrosis  of  the  nerve-cells  and  infiltration  with 
lymphocytes,  and  ascribes  paralysis  of  the  heart  to  these  lesions.  Later,  in  more  pro- 
tracted cases,  there  is  similar  infiltration  of  the  heart-muscle  and  conduction  bundle. 

There  are  no  specific  changes  in  the  nervous  system  nor  indeed  can  any 
be  recognized  in  the  other  organs  during  the  acute  stage.  It  is  true  that 
necroses  have  been  found  in  the  liver,  which  is  commonly  the  seat  of  cloudy 
swelling,  and  it  is  thought  that  these  necroses  may  sometimes  lead  to  a  form 
of  cirrhosis.  The  spleen  is  moderately  swollen,  markedly  so  only  in  cases 
where  the  streptococcus  infection  is  predominant.  There  are  occasionally 
acute  inflammations  of  the  joints,  with  effusion  of  sterile  fluid  into  the, 
synovial  cavities;  but  these  disappear  without  leaving  any  disabilities. 

Rach  has  studied  the  histology  of  the  skin  rash  and  has  shown  that  in 
each  fleck  there  is  a  focus  of  acute  inflammatory  exudation,  with  outpouring 
of  polynuclear  leucocytes  and  red  corpuscles  into  the  substance  of  the  skin 


758  TEXT-BOOK    OF    PATHOLOGY 

about  the  blood-vessels.  This  extends  into  the  epidermis,  where  there 
may  appear  small  blebs  filled  with  leucocytes.  Later  there  occurs  a  thick- 
ening and  dislocation  of  the  epidermis  which  forms  the  well-known  chaffy 
scales.  A  similar  influence  disturbing  the  growth  of  the  nails  produces  a 
transverse  groove  which,  with  the  passage  of  time,  gradually  advances  to 
the  free  edge  of  the  nail. 

There  is  a  definite  leucocytosis  with  a  rather  high  percentage  of  eosino- 
phile  cells.  The  red  corpuscles  decrease  for  a  time  to  about  3,000,000 
per  c.mm.  Death  may  occur  in  the  acute  stage  from  general  intoxication, 
with  cardiac  collapse,  or  from  various  lesions  produced  in  the  respiratory 
tract  by  the  streptococcus  in  association  with  the  main  infectious  agent, 
or  the  patient  may  recover  and  progress  to  complete  health. 

Nevertheless,  in  many  cases  in  which  the  symptoms  have  passed  away 
and  recovery  is  apparently  well  established,  new  symptoms  appear  in  about 
the  third  week.  Of  these,  a  fresh  swelling  of  the  lymph-glands  and  signs 
of  acute  nephritis  are  the  most  prominent.  These  are  not  due  to  a  second 
complicating  disease,  as  is  the  case  with  the  tuberculosis  which  so  commonly 
follows  measles,  but  are  late  manifestations  of  the  scarlatina  itself.  They 
appear  to  have  about  the  same  relation  to  the  acute  phenomena  as  the 
secondary  lesions  of  syphilis  bear  to  the  primary  lesions  (Escherich),  and 
evidently  indicate  the  latent  presence  of  the  organism  in  the  body  during 
the  period  of  apparent  recovery.  The  enlargement  of  the  lymph-glands 
seems  independent  of  that  which  occurred  in  the  primary  stage  and  appears 
suddenly  with  pain.  Usually  it  lasts  only  a  short  time  and  recedes  after 
a  few  days,  rarely  ending  in  suppuration. 

The  nephritis  is  more  serious.  This  has  already  been  discussed  in  the 
chapter  on  Nephritis,  but  it  may  be  pointed  out  again  that  there  appear  to 
be  two  forms — one  in  which  the  function  of  the  kidney  is  not  very  greatly 
disturbed,  except  in  the  more  severe  cases,  and  in  which  the  lesion  consists 
essentially  in  the  exudation  of  many  wandering  cells,  chiefly  of  the  character 
of  lymphocytes  and  plasma  cells,  into  the  interstices  between  the  tubules. 
This  is  the  so-called  acute  interstitial  nephritis  which  has  been  described 
by  Councilman  and  others.  The  second  form  is  predominantly  a  glo- 
merulonephritis  in  which  the  kidneys  are  found  to  be  swollen  and  pale  or 
mottled,  often  with  opaque  yellowish  flecks.  On  section  the  glomeruli 
project  as  grayish  translucent  dots.  There  may  be  ecchymoses  in  the  sub- 
stance of  the  kidney.  Microscopically  there  are  to  be  found  all  the 
changes  previously  described,  which  lead  to  obliteration  of  the  glomerulus, 
by  haemorrhage  into  the  capsule  with  organization,  proliferation  of  the 
capsular  epithelium,  and  occlusion  of  the  capillaries  of  the  tuft  by  thrombi 
or  by  massed  endothelial  cells.  It  is  in  the  scarlatinal  forms  that  the  pro- 
duction of  crescentic  masses  of  capsular  epithelium  about  the  glomerular 
tuft  is  well  seen,  although  of  course  this  occurs  in  other  types  of  nephritis. 
Degenerative  changes  in  the  tubular  epithelium  with  destruction  and  des- 
quamation  of  cells  accompany  the  glomerular  changes.  Later,  with  the 


SMALL-POX  759 

collapse  of  tubules,  much  loose  connective  tissue  appears  between  the  ele- 
ments of  the  cortex,  and  in  time  the  kidney  may  be  extensively  scarred. 
But  in  many  cases  complete  recovery  from  all  these  injuries  occurs,  and  if 
there  is  opportunity  to  examine  the  kidney  of  such  a  person  much  later  in 
life,  it  is  probable  that  only  isolated  scars  may  be  found  as  the  remains  of 
the  early  injury.  In  other  words,  it  is  by  no  means  inevitable  that  the 
occurrence  of  an  acute  scarlatinal  nephritis  should  result  in  the  production 
of  a  progressive  chronic  diffuse  nephritis.  The  contrary  is  rather  more 
probable.  During  such  an  acute  and  subacute  scarlatinal  nephritis  the 
function  of  the  kidney  may  be  intensely  disturbed.  The  secretion  of  chlor- 
ides and  of  water  is  diminished  and  there  is  generalized  oedema.  There  is 
usually  marked  albuminuria  and  generally  blood  is  passed  in  the  urine.  The 
blood  pressure  is  quickly  heightened,  and  hypertrophy  of  the  heart  appears 
rapidly.  Ursemic  symptoms  frequently  occur,  and  may  be  severe  enough 
to  cause  death. 

LITERATURE 

Escherich  and  Schick:  Scharlach,  Wien,  1912  (Excellent  paper  with  literature). 
Stegemann:  Jahrb.  f.  Kinderheilk.,  1914,  Ixxx,  491. 
Krumwiede  and  others:  Archives  of  Int.  Med.,  1914,  xiii,  909. 
Williams,  A.  W.:  Amer.  Jour.  Obst.,  1908,  Iviii,  152. 
Rach:  Ziegler's  Beitr.,  1910,  xlvii,  455. 
Schridde:  Ibid.,  1913,  Iv,  345. 
Mallory:  Jour.  Med.  Res.,  1904,  x,  483. 
Field:  Jour.  Exp.  Med.,  1905,  vii,  343. 

SMALL-POX 

Small-pox  is  allied  to  measles  and  scarlet  fever  in  the  sense  that  it  is  a 
febrile  disease  strikingly  characterized  by  the  appearance  of  an  exanthem 
or  skin  eruption.  This,  however,  is  scarcely  a  satisfactory  basis  for  classi- 
fication, and  it  may  well  be  that  when  we  learn  the  nature  of  the  atiological 
factors  in  these  diseases  their  relations  will  seem  less  intimate.  Chicken- 
pox  or  varicella  is  a  disease  of  milder  character,  but  resembles  small-pox 
much  more  closely  than  do  the  other  exanthemata.  A  disease  of  cattle 
closely  resembling  small-pox,  and  known  as  cow-pox,  is  very  rarely  seen 
any  longer,  but  is  artificially  preserved  in  the  form  of  vaccinia.  The  re- 
lation of  the  diseases  small-pox  and  vaccinia  is  not  yet  clear,  since  vaccinia 
inoculated  in  human  beings  produces  only  a  local  lesion  which  protects 
against  small-pox,  while  human  small-pox  inoculated  into  cattle,  rabbits, 
and  other  animals  produces  vaccinia  and  not  small-pox.  If  small-pox  be 
inoculated  into  human  beings,  as  was  done  at  the  instance  of  Lady  Mary 
Wortley  Montague,  before  the  discovery  of  vaccinia,  a  mild  and  localized 
affection  is  produced  which  protects  against  a  severer  attack  of  small-pox, 
but  may  sometimes  be  transmitted  to  other  persons  as  true  and  severe 
small-pox. 

The  disease  has  occurred  in  extensive  and  very  fatal  epidemics,  and  when 
introduced  into  countries  where  it  had  not  existed  before,  has  in  some  cases 


760  TEXT-BOOK    OF    PATHOLOGY 

exterminated  the  whole  population.  Even  yet  it  rages  at  times  with  ex- 
treme violence.  In  1798  Jenner  published  his  observations  on  the  disease 
of  cows  (cow-pox)  which  was  often  accidentally  transmitted  to  milkmaids 
and  others  and  which  protected  against  the  rather  prevalent  small-pox. 
He  instituted  vaccination,  with  the  life-saving  results  which  are  so  well 
known  to-day.  Even  yet,  however,  there  are  many  persons  of  meagre 
intelligence  who  oppose  the  use  of  vaccination,  and  on  account  of  their  in- 
fluence there  are  always  unvaccinated  individuals  who  are  susceptible  and 
thus  make  possible  the  occurrence  of  the  disease. 

Etiology. — We  are  not  definitely  informed  as  to  the  cause  of  small-pox. 
Numerous  writers  have  recognized  in  the  epithelial  cells  of  the  pocks 
minute  bodies  which  they  have  regarded  as  protozoan  parasites.  They 
were  first  seen  by  Weigert  and  then  described  by  others.  Guarnieri  named 
them  Cytoryctes  variolce,  and  Councilman  and  his  co-workers  have  described 
them  more  fully,  having  found  them  in  all  their  cases.  Calkins  has  worked 
out  a  life-history  by  comparing  the  various  stages,  but  tells  me  that  he 
would  now  modify  some  of  these  conclusions.  The  details  must  be  read 
in  their  papers,  but,  in  brief,  they  find  a  minute  form  in  the  cytoplasm 
of  the  epithelial  cell  which  grows  to  a  large  size  and  finally  splits  up  into 
many  small  forms  which  invade  the  cytoplasm  of  another  epithelial  cell. 
Some  of  these  small  forms  gain  entrance  into  the  nuclei  of  other  cells  and 
there  pass  through  more  complex  stages  of  development  which  are  thought 
to  produce  sexual  forms,  and  finally  from  these  sporoblasts  which  dis- 
seminate multitudes  of  small  spores  that  may  transmit  the  infection. 
Much  has  been  written  in  opposition  to  the  assumption  that  these  living 
parasites  are  the  cause  of  the  disease,  just  as  in  the  case  of  the  Negri  bodies 
in  rabies,  but  the  authors,  who  have  had  much  experience  with  the  disease, 
are  confident  of  this  relation.  The  matter  must  await  further  study  of  a 
biological  nature.  It  is  possible  to  transmit  the  infection  through  any 
number  of  generations,  and  Lambert  and  Steinhardt  have  shown  that  the 
virus  of  vaccinia  may  be  propagated  in  culture  in  connection  with  pieces 
of  skin  and  greatly  increased  in  amount. 

Noguchi  has  subsequently  modified  the  ordinary  method  of  vaccine 
propagation  by  inoculating  it  into  the  testicles  of  animals  where  it  is  not 
exposed  to  bacterial  infection. 

In  all  cases  of  small-pox,  except  perhaps  the  very  mild  or  abortive  forms, 
there  is  an  accompanying  infection  with  streptococci.  It  will  be  remem- 
bered that  this  associated  streptococcus  infection  is  characteristic  of  scarlet 
fever  and  of  diphtheria  also,  so  that  it  by  no  means  excludes  the  idea  of 
a  separate  and  specific  setiological  factor.  Many  of  the  lesions  of  small-pox, 
especially  in  the  internal  organs,  are  ascribed  to  the  effects  of  the  strepto- 
cocci. 

Symptoms. — The  disease  begins  abruptly  with  a  chill  or  with  headache 
and  malaise  and  in  a  short  time  becomes  recognizable  by  the  appearance  of 
shotty  nodules  in  the  skin  which  develop  rapidly  and  reach  their  acme 


SMALL-POX 


761 


about  the  tenth  day  (Fig.  375).  These  at  first  feel  like  little  firm  points, 
but  soon  become  vesicular,  and  from  that  quickly  assume  the  yellowish 
opacity  which  reveals  their  pustular  character.  Practically  all  of  them 
show  depression  or  dell,  but  occasionally  this  is  obliterated,  for  reasons  to 
be  discussed.  The  pocks,  or  pustules,  are  usually  about  3  mm.  in  diam- 
eter, but  they  may  become  confluent  into  irregular  patches.  They  develop 
in  no  particular  relation  to  hairs  or  sweat-glands.  After  the  height  of  their 
growth  is  reached  they  do  not  burst  spontaneously,  but  dry  up  into  crusts 
which  adhere  for  a  time  and  finally  fall  off. 

Pathological  Anatomy. — Microscopical  study  in  various  stages  shows  that 
the  lesions  begin  in  the  lower  layers  of  the  epidermis  itself,  just  above  the 
lowermost  or  Malpighian  layer.  The  corium  underneath  is  at  first  not 
affected  and  may  escape  completely. 
The  epithelial  cells  of  the  prickle-cell 
layer  swell  up  and  become  greatly 
vacuolated.  Their  nuclei  swell  and 
become  distorted  or  shriveled,  only 
the  margin  remaining.  The  periph- 
ery of  the  cell  becomes  compact 
and  fuses  with  that  of  the  next  cell. 
The  vacuoles  rupture  into  one  an- 
other and  soon  the  area  is  occupied 
by  a  reticulum  of  fibers  which  are 
derived  from  remains  of  the  periph- 
eral parts  of  the  cells  and  extend 
from  the  uplifted  roof  to  the  under- 
lying base  of  the  cavity  thus  formed 
(Fig.  376).  Such  is  a  vesicle,  due  to 
the  death  and  degeneration  of  the 
epithelial  cells  and  the  accumulation 
of  fluid  among  their  remains.  Fibrin 
is  to  be  found  in  the  later  stages,  but 
at  this  period  leucocytes  are  few  in  Fig.  375.— Small-pox.  Tenth  day  of  erup- 
the  exudate.  Later  they  appear  and  tion  (Welch  and  Schamberg). 

give  the  purulent  character  to  the 

fluid  exudate.  It  is  the  reticulum  of  fibrils  left  from  the  degenerating 
epithelial  cells  which  holds  down  the  middle  of  the  roof  of  the  pustule 
and  gives  the  appearance  of  the  dell.  If,  with  the  rapid  accumulation 
of  exudate,  the  fibrils  are  ruptured,  the  surface  of  the  pock  may  become 
convex. 

After  the  height  of  the  process  is  over,  new  epithelium  grows  from  the 
sides  over  the  remaining  Malpighian  layer  which  usually  forms  the  bottom 
of  the  pustule,  or  over  the  exposed  corium  if  that  layer  has  been  destroyed, 
but  also  along  the  under  side  of  the  uplifted  roof  of  the  pock.  Shortly, 
it  happens  that  the  exudate  enclosed  now  between  two  layers  of  epidermis 


762 


TEXT-BOOK   OF   PATHOLOGY 


of  which  the  upper  becomes  completely  dried  up,  also  dries  up  and  is  rubbed 
off  as  a  crust  with  the  adherent  upper  layer  of  epithelium.  A  depression 
is  thus  left  lined  with  epidermis.  If  the  Malpighian  layer  has  remained 
intact,  no  deep  pitting  results,  but  if  the  necrosis  has  extended  into  the 
corium,  the  healing  of  the  pock  leaves  a  pit. 

Various  modifications  in  the  eruption  occur  and  the  disease  is  roughly 
divided  accordingly  into  mild  forms,  in  which  there  are  hardly  any  skin 
lesions  or  symptoms;  abortive  forms,  in  which  the  lesions  of  the  skin  quickly 
recede  and  disappear;  haemorrhagic  pustular  forms,  in  which  haemorrhage 
occurs  in  and  about  the  pustules;  and  purpuric  forms,  in  which  more  ex- 


Fig.  376. — Small-pox  pustule.    The  pustule  is  formed  in  the  substance  of  the  epidermis. 
Strands  of  persistent  epithelial  cells  cross  it  (Dr.  James). 

tensive  haemorrhage  into  the  skin  forms  a  feature  more  conspicuous  even 
than  the  pustules.  The  last  is  an  extremely  severe  form  in  which  death 
may  occur  before  the  eruption  is  well  developed. 

In  the  internal  organs  the  changes  are  partly  due  to  the  specific  cause  of 
the  disease,  but  are  partly  the  effect  of  the  accompanying  streptococcus 
infection. 

In  the  mucosae  of  the  mouth  and  other  body  orifices  and  in  that  of  the 
trachea  and  digestive  tract,  there  occur  specific  lesions  of  the  character  of 
those  in  the  skin  and  with  the  same  degeneration  and  necrosis  of  the  epi- 
thelium, but  since  there  is  no  protective  horny  layer  to  allow  of  the  develop- 


SMALL-POX  763 

ment  of  definite  pocks,  they  result  in  the  separation  of  the  epithelial  cells, 
the  infiltration  of  the  tissue  with  leucocytes,  and  the  production  of 
indefinite  small  ulcers. 

In  the  testes  and  bone-marrow  more  readily  recognizable  specific  lesions 
occur.  In  the  testes  these  are  found  as  nodules  in  the  substance,  more 
numerous  just  under  the  tunica  albuginea.  They  are  formed  by  a  focal 
infiltration  of  wandering  cells  among  the  tubules.  After  a  time  the  tubules 
involved  become  necrotic  and  invaded  by  the  mononuclear  cells.  Such 
nodules  appear  in  section  as  opaque,  yellowish  spots  with  a  halo  of  haemor- 
rhage, and  heal  with  the  formation  of  small  scars. 

In  the  bone-marrow  very  similar  lesions  are  found  with  central  necrosis 
involving  the  blood-forming  cells  and  marginal  infiltration  of  mononuclear 
elements.  The  formation  of  polynuclear  leucocytes  is  seen  to  be  in  abey- 
ance in  the  bone-marrow  and.  many  degenerated  forms  are  found.  In  the 
later  stages  of  the  disease  the  mononuclear  types  hold  a  predominant  place 
among  the  emigrating  cells  on  this  account.  Chiari  has  described  this 
lesion  as  osteomyelitis  variolosa,  but  it  obviously  does  not  resemble  other 
forms  of  osteomyelitis. 

In  the  liver  there  is  intense  cloudy  swelling,  and  focal  necroses  are  oc- 
casionally found.  The  organ  is  ordinarily  much  enlarged.  In  the  kidneys 
there  is  no  characteristic  lesion,  but  degenerative  changes  appear  in  the 
epithelium  of  the  tubules  and  occasionally  there  is  acute  glomerulonephritis. 
Interstitial  accumulations  of  mononuclear  cells  are  relatively  common. 
Similar  non-specific  changes  may  be  found  in  other  organs,  but  it  remains 
a  question  as  to  whether  they  are  not  produced  by  the  streptococci.  This 
is  true  also  of  the  degenerative  changes  in  the  heart-muscle,  which  are  like 
those  seen  in  other  acute  infections,  and  perhaps  also  of  the  swelling  of  the 
lymph-nodes  and  spleen.  In  the  lymph-nodes,  the  changes  in  the  lymph 
sinuses  include  the  appearance  of  many  large  phagocytic  cells,  together 
with  abundant  smaller  mononuclear  cells. 

In  most  cases  there  is  an  acute  bronchitis  and  in  many  there  occurs  a 
rather  severe  lobular  pneumonia  which  may  be  confluent  in  character. 
This  is  often  the  actual  cause  of  death  and  is  probably  to  be  ascribed  to  the 
bacterial  infection. 

LITERATURE 

Weigert:  Anat.  Beitr.  zur  Lehre  von  den  Pocken,  Breslau,  i,  1874;  ii,  1875. 
Councilman  and  others:  Jour.  Med.  Research,  1904,  xi,  1-360,. Lit. 
Calkins:  Ibid.,  136. 

Councilman  and  Beardsley:  Osier  and  McCrae,  Modern  Medicine,  1913,  i,  783. 
Steinhardt  and  Lambert:  Jour,  of  Infect.  Dis.,  1914,  xiv,  87. 
Noguchi:  Jour.  Exp.  Med.,  1915,  xxi,  539. 


CHAPTER  XXXVIII 
TYPES  OF  INJURY.— DISEASES  DUE  TO  ANIMAL  PARASITES 

Introduction.  General  relation  of  parasites  to  host.  Table  of  main  zoological  divisions. 
Amoebic  infections:  Types  of  parasites  and  life-history;  intestinal  infection;  liver  abscesses; 
abscess  of  lung.  Pyorrhoea  alveolaris.  Malaria:  Types  and  life-history  of  parasites; 
symptoms  and  pathological  anatomy;  Blackwater  fever.  Trypanosome  infections:  biology; 


IT  has  been  seen  that,  through  the  invasion  of  the  lowliest  forms  of  plant 
life  and  their  adaptation  to  a  parasitic  existence  in  the  animal  body,  many 
diseases  arise.  This  is  not  less  true  of  members  of  several  of  the  great 
groups  of  the  animal  kingdom  which  have  undergone  biological  alterations 
in  the  course  of  a  parasitic  mode  of  existence,  involving  in  many  cases 
anatomical  changes  which  separate  them  from  their  closest  relatives.  The 
animals  which  have  thus  come  to  live  as  parasites  belong  to  the  protozoa, 
the  worms,  and  to  a  less  extent  to  the  arthropods.  The  student  must  be 
referred  for  a  discussion  of  their  anatomy  and  their  systematic  relations  to 
one  another  and  to  the  related  free  living  forms,  to  works  on  zoology  and 
parasitology,  perhaps  particularly  to  the  volumes  of  Brumpt  and  Braun. 
Only  a  few  types  can  be  mentioned  here  in  their  relation  to  common  para- 
sitic diseases  of  man. 

General  Relation  of  Parasite  to  Host. — Those  parasites  which  live  on  the 
body  surface  are  more  nearly  capable  of  maintaining  their  existence  apart 
from  their  host  than  the  obligate  parasites  which  spend  their  lives 
in  the  interior  of  the  body.  The  latter  may  go  through  their  whole 
life-history  in  the  body  of  one  animal,  or  may  pass  a  stage  of  it  as  free  living 
creatures  in  the  outer  world;  but  most  of  them  with  or  without  such  a 
period  of  freedom  are  compelled  to  pass  through  an  important  epoch  of 
their  development  as  parasites  in  a  totally  different  animal.  This  alterna- 
tion of  generations  is  a  most  wide-spread  phenomenon  and  leads  to  great 
complexities  in  the  life-history  of  such  parasites.  So  difficult  to  unravel 
are  these  metamorphoses  and  changes  of  host  that  the  whole  story  of  great 
numbers  of  parasites  is  still  unknown,  and  that  of  even  the  most  familiar  has 
been  revealed  only  recently.  Thus  the  common  tapeworm  lives  as  a  ma- 
ture worm  in  man,  while  its  larval  form  is  found  in  the  ox;  the  Bothrio- 
cephalus  of  man  passes  its  larval  stage  in  various  fish;  the  filaria  which 

764 


GENERAL  RELATION  OF  PARASITE  TO  HOST         765 

invades  the  blood  and  lymphatics  of  man  is  larval  in  a  mosquito,  and  so  on. 
Naturally,  in  order  that  the  transfer  from  one  animal  to  the  other  should  be 
made  at  the  proper  time,  extraordinary  adaptations  have  come  about. 
In  blood-sucking  insects  which  act  as  intermediate  host,  the  larvae,  or 
spores,  as  though  by  an  intelligent  decision,  lodge  themselves  in  the  salivary 
glands,  and  nowhere  else  in  the  body,  and  are  consequently  inoculated  into 
the  blood  of  the  next  host.  The  effect  of  the  specific  adaptation  is  further 
seen  in  the  complete  dependence  of  the  parasite  upon  one  particular  kind 
of  intermediate  host,  as  well  as  its  particular  kind  of  main  host.  Malarial 
organisms  sucked  into  the  stomach  of  a  culex  mosquito  must  die  there  al- 
though they  develop  in  an  anopheles,  and  after  they  have  made  the  an- 
opheles infective  for  man  they  perish  if  by  mistake  it  bites  a  cow,  and  in- 
jects them  into  the  cow's  blood.  Many  nematodes,  or  round  worms,  bring 
forth  active  larva?  instead  of  eggs,  and  sometimes  these  are  left  to  fend  for 
themselves  and  attack  their  new  host  by  their  own  activities.  In  this, 
some  pursue  a  most  devious  course,  as  when  the  ankylostoma,  necator,  and 
strongyloides  larva?  penetrate  into  the  skin  of  man  and  are  swept  by  the 
blood  into  the  lungs  and  bronchi  whence  they  reach  the  intestine.  Others, 
like  ascaris,  oxyuris,  and  trichocephalus,  round-worm  parasites  of  the  in- 
testines, lead  a  simpler  life,  their  eggs  being  transferred  with  water  or 
vegetables  to  another  person's  alimentary  tract,  or  more  directly  to  that  of 
the  patient  himself,  producing  an  intense  infection.  Of  their  life  in  these 
hosts,  and  the  duration  of  their  stay,  some  idea  may  be  derived  from  the 
examples  given. 

Parasites  act  mechanically  in  several  ways  to  injure  the  host.  In  the  case 
of  many  of  the  worms  which  pass  their  larval  stage  in  man  (Ta?nia  echinococ- 
cus,  etc.),  the  great  bulk  of  the  cystic  larva  may  occasion  mechanical 
injury,  especially  in  the  brain,  which  lies  in  a  confined  space.  The  ordinary 
round  worms  (ascaris)  produce  many  symptoms  by  mechanical  irritation  of 
the  intestine  and  by  wandering  into  such  channels  as  the  bile-ducts  or  the 
Eustachiantube  or  the  appendix,  where  they  cause  obstruction.  Strongyles, 
and  the  trematode,  schistosomum,  which  live  in  the  blood-vessels,  may 
cause  serious  obstruction,  disturbing  the  nutrition  of  the  tissues.  Toxic 
action  is  clearly  associated  with  the  uncinaria  and  bothriocephalus  which 
produce  profound  anemia,  and  Schaumann  and  Tallquist  have  isolated  a 
haemolytic  substance  from  the  bothriocephalus.  In  other  cases,  as  with 
malaria,  the  anaemia  is  produced  in  a  more  mechanical  way  by  the  destruc- 
tion of  the  corpuscles  in  which  the  parasites  live.  The  trichocephalus  and 
the  uncinaria  actually  suck  the  blood  from  the  intestinal  wall.  Inflamma- 
tory reaction  following  upon  tissue  destruction  is  characteristic  of  infection 
with  the  trichina,  amcebse,  and  other  organisms,  and  those  which  lodge  in 
the  tissues  and  remain  there,  commonly  set  up  the  new  formation  of  much 
fibrous  tissue  in  their  neighborhood. 

The  following  table  will  serve  to  indicate  briefly  the  relations  of  these 
organisms. 


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SPOROZOA : 


INFUSORIA  : 


WORMS: 


PROTOZOA: 

SARCODINA  : 

Rhizopoda:  Amoeba,  etc. 
MASTIGOPHORA  : 

Flagellata: 

Trypanosoma  (Sleeping  sickness). 
Leishmania  (Kala  azar). 
Giardia  (Lamblia)  intestinalis. 
Trichomonas,  etc. 
Spirocha?tae. 

Telosporidia: 

Gregarinida. 

Coccidiidea. 

Hsemosporidia  (Malarial  parasites). 
Neosporidia: 

Myxosporidia  (Parasites  of  fishes). 

Microsporidia. 

Sarcosporidia  (Occasional  parasites  of  man). 

Ciliata: 

Balantidium,  etc. 

Cestoda  (Tapeworms): 

Tsenia. 

Bothriocephalus. 
Trematoda  (Fluke  worms) : 

Distoma. 

Opisthorchis. 

Schistosomum,  etc. 
Nematoda  (Round  worms) : 

Filaria. 

Trichocephalus. 

Trichinella. 

Ankylostomum  (Hook  worm). 

Ascaris. 

Oxyuris,  etc. 

Arachnoidea: 

Acarina:  Ixodes  (Tick). 

Sarcoptes  (Itch  mite,  etc.). 
Insecta: 

Rhyncota:  Pediculi  (Lice). 

Cimex  (Bedbug). 
Diptera:  Pulex  (Flea). 
Musca  (Fly). 

Anopheles  }  Mosquitos. 

AM(EBIC  INFECTIONS 

There  are  known  to  zoologists  great  numbers  of  amcebse,  most  of 
which  are  free  living;  a  few  are  parasitic  in  various  animals,  and  among 
these  are  certain  forms  which  infect  man.  Craig,  in  his  recent  paper, 
enumerates  all  the  genera  and  species  and  points  out  that,  although  forms 
of  Vahlkampfia  and  Trimastigamceba  may  be  of  interest  as  occurring  in 
such  a  way  as  to  be  confused  with  the  parasitic  forms,  it  is  only  in  the  genera 
Craigia  and  Entamceba  that  true  parasites  of  man  are  found.  Chief  in- 
terest is  attached  to  the  genus  Entamceba,  which,  together  with  about  40 
other  species,  contains  the  forms  Entamceba  coli  and  E.  histolytica.  Briefly, 
it  may  be  said  that  E.  coli  is  a  harmless  commensal  in  the  intestine  of  man. 
It  is  found  in  a  great  proportion  of  healthy  people  who  have  never  had 


ARTHROPODS: 


AMCEBIC    INFECTIONS 


767 


dysentery,  and  is  distinguished  from  E.  histolytica  as  follows.  It  averages 
30  microns  in  diameter,  is  grayish  and  dull-looking,  without  clearly  defined 
ectoplasm,  and  possesses  a  large  nucleus.  Its  movements  are  sluggish, 
and  when  it  becomes  encapsulated  it  divides  into  eight  young  entamcebse. 
The  Entamceba  histolytica  is  a  distinct  parasite  in  the  intestine  of  man,  and 
produces  there  and  in  other  organs  most  intense  destructive  changes.  It 
is  recognizable  by  its  larger  size  (20-60  microns)  and  by  the  striking  con- 
trast between  its  granular  cytoplasm 
and  its  glassy,  refractive,  colorless 
ectoplasm.  This  latter  is  usually  in 
active  motion,  throwing  out  and  re- 
tracting pseudopods  into  which  the 
remainder  of  the  body  streams.  It 
multiplies  also  by  fission,  and  w^hen  it 
undergoes  encapsulation  divides  into 
four  new  amoebae.  The  Entamceba 
tetragena  is  identical  with  this. 

The  pathogenic  amcebse  are  possibly 
introduced  into  the  digestive  sys- 
tem with  uncooked  vegetables  or  con- 
taminated water,  although,  as  Walker 
and  Sellards  have  shown,  it  must  be 
remembered  that  the  amoeboid,  or 
vegetative  form,  is  very  little  resist- 
ant to  exposure  to  external  conditions. 
The  more  resistant  encysted  form  is, 
however,  found  in  the  stools  of  many 
apparently  healthy  carriers,  and  trans- 
mission is  probably  more  easily  ex- 
plained as  the  result  of  contamina- 
tion of  food  by  these  people.  It  has 
been  shown  by  experiment  that  they 
are  pathogenic  for  cats  also.  They 
have  probably  not  been  cultivated 
outside  the  body. 

Intestinal  Infection. — In  the  intes- 
tine the  amcebse  find  their  way  into       Fig.    377. — Amoebic   colitis.    There 
the  crypts  of  the  mucosa  of  the  colon    are  numerous  confluent  and  discrete 
and  there  produce  small  areas  of  necro- 
sis from  which  further  invasion  into 
the  submucosa  occurs.     In  most  cases 

the  mucosa  of  the  colon  is  the  only  area  affected,  the  invasion  taking 
place  especially  in  the  upper  part  of  the  large  intestine.  It  is  rare  to  find 
any  lesions  in  the  lowermost  part  of  the  ileum  or  in  the  appendix. 

The  earliest  changes  appear  as  elevations  in  the  mucosa,  with  hypersemia 
or  hsemorrhagic  halo  and  a  central  plug  of  yellowish,  necrotic  material. 


elevated   necrotic  patches   and   many 
small  ragged  ulcerations. 


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Sometimes  these  elevations  become  quite  large  before  the  necrotic  tissue  is 
discharged,  and  I  have  seen  cases  in  which  the  whole  mucosa  was  covered 
with  such  patches  without  definite  ulceration  (Fig.  377).  Usually,  how- 
ever, the  softened  substance  falls  away  and  reveals  ulcers  which  show  a 
great  tendency  to  undermine  the  mucosa  and  to  coalesce  with  one  another, 
leaving  bridges  of  mucosa  between  them.  This  is  not  always  the  case: 
numerous  large  or  small  discrete  ragged  ulcers  may  be  formed  instead; 
but  when  it  occurs  extensively,  as  it  does  in  some  cases,  the  undermined 
mucosa  dies  and  is  found  hanging  in  long  shreds  or  sheets  from  the  wall 
(Fig.  378).  In  one  case  observed  recently  at  autopsy  nearly  the  whole 
mucosa  was  thus  destroyed,  and  great  blackened,  ragged  films  of  mucosa 
were  found  hanging  in  the  lumen.  As  a  rule,  the  process  is  rather  slow, 
and  attempts  at  healing  take  place,  so  that  the  intestine  tends  to  become 
greatly  thickened  by  the  formation  of  granulation  tissue  rather  than  to  be 
perforated.  Nevertheless,  perforation  does  sometimes  occur  and  is  usually 
met  by  adhesions,  so  that  only  local  abscesses  are  produced.  Narrowing  of 
the  gut  may  follow  such  ulceration  and  healing. 

Microscopically  one  may  find  in  the  earliest  stages  minute  ulcers  involv- 
ing the  mucosa  alone,  with  amoebae  in  the  margins  of  the  tissue  (Fig.  379), 
but  more  commonly  the  ulcer  is  found  to  extend  in  the  submucosa  and  to 


Fig.  378. — Amoebic  colitis.    Two  large  ulcerated  areas  over  which  the  mucosa  has  been 
undermined  and  hangs  in  necrotic  shreds. 

be  partly  filled  with  disintegrated  tissue  with  fragmented  nuclei.  On 
account  of  the  exposure  to  the  intestinal  contents  many  bacteria  are  present 
and  there  is  some  inflammatory  reaction,  but  this  is  by  no  means  so  promi- 
nent as  in  the  case  of  the  bacterial  forms  of  dysenteric  ulceration.  In  the 
edges  of  the  necrotic  tissue  the  amoebae  are  found  lying  in  the  crevices. 
Often  they  can  be  traced  far  into  the  submucosa  or  down  into  the  interstices 
of  the  muscle  or  even  into  the  subserous  tissues,  and  when  they  are  found, 
those  in  advance  are  usually  not  surrounded  by  any  reaction  nor  by  any 


AMCEBIC   INFECTIONS  769 

evident  changes  in  the  tissues.  At  times  they  are  observed  underneath 
the  endothelium  of  the  branches  of  the  portal  vein,  and  in  many  cases  I 
have  found  them  lying  free  in  the  lumen  of  such  venules  together  with  the 
blood-cells.  This  is  important,  since  it  explains  readily  their  transportation 
to  the  liver.  The  reparative  changes  are  quite  like  those  seen  in  any  other 
ulcer,  but  it  is  evident  that  they  are  frustrated  by  new  necrosis  of  the  tissue 
and  must  be  repeated  constantly. 

There  is  practically  no  difficulty  in  recognizing  the  amoebae  which  are 
found  invading  the  tissue  as  the  cause  of  the  disease,  although  the  clinician 
may  run  the  risk,  in  the  examination  of  the  faeces,  of  mistaking  the  harmless' 
and  common  E.  coli  for  the  pathogenic  form. 

Such  ulcerative  dysentery  causes  diarrhoea,  with  much  tenesmus  or  pain- 
ful straining,  and  the  stools  are  made  up  of  small  amounts  of  mucus  flecked 
with  blood.  The  mucus  may  contain  the  amoebae,  but  they  are  found  more 
abundantly  after  a  saline  cathartic  is  given.  The  infection  is  extremely 
persistent  and  often  drags  on  for  months  or  even  years. 


&     •  '    ;•*  I  •     •  >  V*     f,  '      ~»  2*      ...      «       »„ "    ' 

»M&    ili  J?3HM; 


«,       .  A  &        *- •»•"-«. 

/'-' 


Fig.  379. — Beginning  amoebic  ulceration  of  the  mucosa  of  the  colon.  Amoebae  (a)  are 
seen  in  the  crypts,  in  the  stroma  of  the  mucosa  and  submucosa,  and  in  one  case  beneath 
the  endothelium  of  a  vein. 

Liver  Abscesses. — Of  the  sequelae  of  amoebic  dysentery,  the  commonest 
is  the  development  of  abscess  of  the  liver.  It  is  known  that  amoebae  enter 
the  branches  of  the  portal  veins  in  the  intestine,  and  are  swept  into  the  liver, 
where  they  lodge  in  the  capillaries  and  produce  effects  similar  in  principle 
to  those  set  up  in  the  intestine.  The  amoebae  in  the  intestine  take  into  their 
cytoplasm  red  corpuscles  and  bacteria  as  well  as  the  debris  of  tissue-cells, 
and  it  is  not  surprising,  therefore,  that  there  are  sometimes  evidences  of 
bacterial  infection  in  the  liver  also.  But  usually  it  seems  that  these  bac- 
teria are  digested,  for  the  abscesses  are  likely  to  be  sterile  except  for  the 

presence  of  the  amoebae  themselves.     Although  the  lesions  are  commonly 
50 


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TEXT-BOOK   OF   PATHOLOGY 


called  abscesses,  they  are  really  not  quite  like  the  abscesses  produced  by 
pyogenic  bacteria,  inasmuch  as  the  amoebae  cause  the  necrosis  and  liquefac- 
tion of  tissue  without  any  very  pronounced  inflammatory  reaction.  The 
contents  of  such  abscesses,  therefore,  consist  chiefly  of  the  debris  of  liver 
tissue,  with  relatively  slight  admixture  of  leucocytes.  Ordinarily  only  one 
such  abscess  is  found,  but  in  about  one-third  of  the  cases  the  abscesses  are 
multiple,  two  or  three  rather  large  cavities  being  found  in  different  parts 
'of  the  organ  (Fig.  380).  Rarely  there  are  hundreds  of  small  foci.  The 
drawing  shows  well  the  appearance  of  the  rapidly  forming  fresh  abscesses, 
of  which  there  were  several  in  this  case,  together  with  numerous  very  small 
ones.  A  description  of  the  case  may  serve  to  present  the  fresher  stages. 
The  small  abscesses  (from  which  the  contents  can  be  squeezed  out  like 
paint)  appear  as  opaque,  yellowish-white  areas  occupying  the  space  of  one 
or  two  lobules.  The  large  ones  have  a  definite  cavity  lined  with  yellowish- 


Fig.  380. — Multiple  amoebic  abscesses  of  liver   (Mense' 

heiten). 


Handb.    d.   Tropenkrank- 


white  necrotic  material  resembling  badly  made  custard.  In  the  cavity  one 
may  find  a  similar  substance  or  a  turbid  fluid  with  shreds  of  necrotic  tissue 
hanging  from  the  wall.  In  one  abscess  in  this  case  there  was  a  clear,  straw- 
yellow  fluid.  The  surrounding  tissue  ends  abruptly  in  the  necrotic  lining 
of  the  abscess,  but  from  the  rapid  extension  of  the  cavity  and  the  accumula- 
tion of  fluid  it  becomes  much  compressed.  The  effect  of  this  pressure  is  to 
stop  the  outflow  of  blood  from  regions  drained  by  branches  of  the  hepatic 
vein  which  pass  by  the  abscess,  and  thus  to  produce  local  areas  of  passive 
congestion.  The  same  thing  is  to  be  observed  in  the  neighborhood  of 


AMOEBIC    INFECTIONS 


771 


metastatic  tumor  nodules  in  the  liver.    Other  areas  become  anaemic  from 
the  compression  of  branches  of  the  portal  vein. 

Far  more  commonly  one  finds  the  abscesses  in  a  more  advanced  state  in 
which  it  is  no  longer  possible  to  recognize  necrotic  curdled  liver  tissue  in  the 
contents.  Then  they  are  filled  with  thick,  creamy,  gelatinous,  purulent 
fluid  or  with  a  more  pasty  tenacious  opaque  material,  which  is  often  stained 
greenish  from  the  admixture  of  bile  from  some  duct  which  has  been  invaded. 
In  these  abscesses  efforts  at  healing  have  been  made  in  the  adjacent  liver 
tissue  which  result  in  the  formation  of  a  thick  wall  of  granulation  tissue. 
After  that,  the  advance  of  the  abscess  through  the  liver  tissue  is  far  slower. 
Even  when  a  distinct  wall  is  formed,  shreds  and  long  strands  of  necrotic 
liver  tissue  may  be  found  hanging  in  the  cavity.  Later  still,  the  amcebse 
may  die  out,  most  of  the  fluid  be  absorbed  from  the  pus,  and  the  wall 


v%!vv'-r''*-'Vi  £;,?'  •'•-  "i\y  '<<^""-*'l-; ,' "'  v?  'V *^Xi0%*i;^?^?r* V**«  ¥$**&** 


Fig.  381. — Subacute  amoebic  abscess  of  the  liver.     The  amoebae  are  seen  in  the  crevices 
of  the  loose  connective  tissue  which  is  forming  round  the  abscess. 

contract  down  around  the  mortar-like  material  which  remains.  Usually 
this  becomes  pigmented  with  an  orange-yellow  pigment  derived  from  ex- 
travasated  blood.  Finally  the  whole  may  be  replaced  by  a  pigmented  scar. 
But  although  one  occasionally  sees  this  spontaneous  healing,  it  occurs  in 
my  experience  usually  in  those  cases  in  which  another  abscess  has  formed 
elsewhere  in  the  liver  or  in  the  lung,  or  in  which  rupture  of  the  abscess  has 
taken  place  either  spontaneously  or  through  surgical  intervention. 

The  affection  is  a  very  serious  one,  and  the  mortality  is  high  even  with 
modern  treatment.  The  growth  and  extension  of  the  abscesses  often  bring 
them  to  the  surface  of  the  liver,  so  that  other  tissues  are  invaded  and  rupture 


772  TEXT-BOOK    OF    PATHOLOGY 

occurs  in  one  or  other  direction.  The  commonest  site  is  in  the  dome  of  the 
right  lobe,  whence  extension  can  occur  through  the  diaphragm  into  the 
substance  of  the  adherent  lung,  with  rupture  and  discharge  of  the  pus 
(now  stained  brownish-red,  " anchovy  sauce  appearance")  through  the 
bronchus,  so  that  it  is  coughed  up  and  expectorated.  This  is  the  most 
frequent  and  favorable  outcome.  But  extension  and  rupture  may  also 
occur  into  the  free  pleural  cavity  or  the  pericardium,  into  the  peritoneal 
cavity  or  adherent  colon  or  stomach  or  duodenum,  or  even  through  the 
outer  skin.  More  rarely  the  portal  vein  or  vena  cava  receives  the  con- 
tents of  the  abscess. 

Histologically  the  appearances  vary  with  the  age  of  the  abscess.  In 
the  very  fresh  ones  the  form  of  many  liver-cells  can  still  be  seen,  there  is 
oedema  of  the  surrounding  tissue,  the  amoeba?  are  found  in  the  edge  of  the 
living  tissue,  and  there  are  a  few  mononuclear  wandering  cells  whose  nuclei 
are  mingled  with  the  fragmented  nuclei  of  the  tissue.  Later  the  necrotic 
lining  of  the  cavity  loses  its  recognizable  constituents  and  shows  only  a 
mass  of  nuclear  fragments  with  a  few  leucocytes  (Fig.  381).  The  amoebae 
are  still  found  only  in  the  margin  of  the  living  tissue  unless  the  abscess  has 
been  opened  to  the  air.  This  is  because  of  their  need  of  oxygen,  and  it  is 
observed  by  surgeons  that  when  an  amoebic  abscess  is  opened,  no  amoeba? 
are  to  be  found  in  the  pus  which  escapes,  but  only  in  scrapings  of  the  wall. 
Next  day,  however,  after  the  cavity  has  been  exposed  to  the  air,  the  pus 
which  escapes  is  full  of  active  amoebae.  When  the  dense  connective  tissue 
with  its  lining  of  partly  necrotic  granulation  tissue  is  formed  the  amoebae 
wander  in  the  crevices  of  that  tissue. 

These  abscesses  may  reach  a  great  size  before  rupture  or  evacuation  takes 
place  and  may  contain  several  litres  of  pus.  They  consequently  destroy 
much  of  the  liver  tissue  and  occasionally  one  may  find  efforts  at  its  re- 
generation. 

Abscesses  of  the  lung  of  quite  the  same  character  are  produced  by 
transportation  of  the  amoebae  from  the  liver,  apparently  by  way  of  the  he- 
patic veins  rather  than  by  direct  extension.  Indeed,  Bunting  was  able  to 
trace  in  one  of  our  cases  emboli  containing  amoebae  from  a  thrombus  in  the 
hepatic  vein  which  also  contained  them,  and  to  show  that  this  embolism 
of  the  pulmonary  arteries  had  produced  an  amoebic  abscess  in  the  lung. 
By  this  time  the  original  amoebic  ulcers  in  the  intestine  were  healed. 

In  the  so-called  Rigg's  disease,  or  pyorrhoea  alveolaris,  the  Entamceba 
buccalis  has  been  thought  to  be  the  aetiological  factor  and  is  found  in  great 
numbers  in  the  pus  which  forms  in  the  cavities  between  the  loosened  gums 
and  the  roots  of  the  teeth.  Such  cavities  extend  down  into  the  alveolar 
process  of  the  jaw,  which  is  eroded  away.  The  good  effects  of  emetine  in 
curing  the  disease  seemed  to  show  that  the  amoebae  are  responsible  for  its 
existence,  but  doubt  has  been  cast  upon  this  recently. 

LITERATURE 

Craig:  American  Medicine,  1905,  ix,  854.     Arch.  Int.  Med.,  1914,  xiii,  737. 
Schaudinn:  Arb.  a.  d.  Kais.  Gesundheitsamte,  1903,  xix,  547. 


MALARIA  773 

Councilman  and  Lafleur:  Johns  Hopkins  Hosp.  Rep.,  1891,  ii,  395. 

Musgrave  and  Clegg:  Bull.  Gov.  Laboratories,  Manila,  1904,  xviii. 

Sachs:  Arch.  f.  kl.  Chir.,  1876,  xix,  235. 

Kruse  and  Pasquale:  Zeitsch.  f.  Hyg.  u.  Infektionskr.,  1894,  xvi,  1. 

MacCallum:  Handb.  d.  Tropenkrankheiten,  Mense,  1906,  iii,  22. 

Bunting:  Arch.  f.  Schiffs-  u.  Tropenhygiene,  1906,  x,  73. 

Woolley  and  Musgrave:  Bureau  of  Gov.  Laboratories,  Manila,  1905,  xxxii,  31. 

Futcher:  Jour.  Amer.  Med.  Assoc.,  1903,  xli,  480. 

Bass  and  Johns:  Jour.  Amer.  Med.  Assoc.,  1915,  Ixiv,  553. 

Walker  and  Sellards:  Philippine  Jour,  of  Sci.,  B,  1913,  viii,  253. 

James,  W.  M.:  Ann.  Tropical  Med.  and  Parasitology,  1914,  viii,  133. 

MALARIA 

Since  the  discovery  by  Laveran  in  1880  of  the  protozoan  parasites  which 
cause  this  disease,  it  has  been  possible  to  give  a  precise  reason  for  the  ex- 
istence of  three  different  types  of  malarial  fever  in  man,  since  it  is  found 
that  there  are  three  different  species  of  parasite.  These  can  be  recognized 
through  differences  in  their  morphology  and  by  the  differences  in  the  time 
required  for  them  to  become  mature,  which  decides  the  type  of  fever. 
Tertian  malaria  is  that  in  which  there  is  a  chill  every  other  day.  In 
quartan  malaria  the  chill  comes  on  every  third  day,  while  in  the  aestivo- 
autumnal  forms  chills  and  the  associated  fever  appear  at  irregular  intervals. 

The  tertian  parasite  (Plasmodium  vivax)  is  found  in  the  red  blood-cor- 
puscles in  the  form  of  a  pale,  amoeboid  body  growing  rapidly  to  a  rather 
large  size  and  accumulating  yellowish-brown  pigment  in  fine  granules  which 
dance  actively.  It  causes  swelling  and  pallor  of  the  red  corpuscle  which 
contains  it,  and  on  reaching  maturity  divides  into  18  to  20  segments  leaving 
the  pigment  in  the  centre  of  the  rosette.  Flagellated  forms  are  seen.  It 
requires  forty-eight  hours  to  develop  from  the  earliest  small  hyaline  form 
without  pigment  to  the  point  of  segmentation. 

The  quartan  parasite  (Plasmodium  malarise)  appears  also  as  a  small  hya- 
line body  in  the  red  corpuscles;  it  grows  more  slowly,  requiring  seventy- 
two  hours  to  complete  its  development  up  to  the  point  of  segmentation, 
and  is  throughout  smaller  and  more  dense  and  refractive  than  the  tertian 
form.  It  produces  blackish  pigment  in  coarser  granules  and  is  more  quies- 
cent than  the  tertian  form.  Finally  it  breaks  up  into  a  small  rosette  of  6 
to  12  segments,  having  at  no  time  caused  the  corpuscle  to  swell  or  become 
pale,  but  leaving  it  rather  shrunken  and  deeply  colored. 

The  cestivo-autumnat  parasite  (Plasmodium  falciparum)  is  often  at  first 
ring-formed,  but  later  becomes  an  amoeboid  body  with  brownish  pigment. 
It  develops  in  twenty-four  to  forty-eight  hours  and  forms  8  to  10  seg- 
ments, but  these  are  rarely  seen  in  the  circulating  blood,  although  they 
are  to  be  found  in  the  spleen  and  perhaps  other  internal  organs.  In  its 
more  mature  form  the  organism  is  often  found  in  the  circulating  blood  in 
the  shape  of  a  rounded  crescent,  across  the  concavity  of  which  the  re- 
mainder of  the  corpuscle  is  seen  to  stretch.  Such  crescents  may  or  may 
not  give  rise  to  the  flagellated  forms. 


774  TEXT-BOOK    OF    PATHOLOGY 

In  studying  the  related  forms,  Proteosoma  and  Halteridium,  in  birds,  I 
was  able  to  show  that  when  these  parasites  were  removed  from  the  circu- 
lation the  maturer  forms,  which  were  inconspicuous  before,  proceeded  to 
enter  upon  a  sexual  cycle.  During  the  existence  of  any  of  the  types  as 
parasites  in  the  blood-corpuscles  of  the  circulating  blood,  they  merely  con- 
tinue the  asexual  cycle,  wherein  they  grow  in  the  corpuscle  for  a  certain 
time,  after  which  they  divide  by  fission  into  many  small  segments  which 
burst  out  of  the  corpuscle  and  enter  others,  starting  the  cycle  afresh. 

The  sexual  cycle  has  a  different  purpose.  Under  the  microscope  the 
mature  forms  are  seen  to  break  out  of  the  blood-corpuscles  into  the  plasma. 
Some  remain  quiescent;  others,  after  violent  convulsions  of  the  proto- 
plasm, throw  out  long,  active  flagella  which  beat  about  and  soon  become 
separate  free-swimming  threads,  like  spermatozoa.  These  make  their  way 
to  the  quiescent  forms,  and  of  the  little  swarm  which  hovers  about  each  of 
these  female  forms,  or  macrogametes,  it  is  seen  that  one  and  only  one  buries 
itself  in  the  protoplasm,  while  the  rest  perish.  The  flagella,  or  microga- 
metes,  are  really  analogous  to  spermatozoa.  A  short  time  after  the  fertili- 
zation the  zygote,  or  fertilized  form,  becomes  very  active  and  wanders  about. 
At  this  point  Ross,  in  India,  discovered  that  there  appeared  pigmented  cysts 
in  the  walls  of  the  stomach  of  those  mosquitoes  which  have  bitten  persons 
ill  with  malaria,  and  formed  the  idea  that  the  process  of  fertilization  and 
formation  of  a  motile  zygote  described  above  must  occur  in  the  mosquito's 
stomach,  and  that  the  development  of  cysts  in  the  walls  of  that  organ  must 
be  due  to  the  fact  that  this  new  active  zygote  could  push  its  way  into  that 
situation  and  there  become  encapsulated.  After  that,  Ross  found  that 
minute  transparent  spores  were  produced  in  great  numbers  in  such  cysts 
and  liberated  into  the  body  cavity  of  the  mosquito.  Thence  they  wandered 
into  the  epithelial  cells  of  the  salivary  gland  of  the  mosquito,  and  were  in- 
jected into  the  blood  of  the  next  person  bitten,  together  with  the  salivary 
secretion.  There  the  spores  or  sporozoites  entered  the  red  corpuscles 
exactly  as  did  the  hyaline  segments  from  the  rosette  of  the  asexual  stage. 
Hence,  since  an  important  part  of  the  development  occurs  in  the  body  of  the 
mosquito,  which  is  thus  a  host  of  the  parasite,  it  seems  certain  that  trans- 
mission to  human  beings  must  always  occur  in  this  way.  Further,  it  is 
learned  that  while  a  form  of  culex  transmits  the  proteosoma  to  birds,  it  is 
incapable  of  transmitting  any  human  form  of  the  parasite.  For  these 
another  mosquito  (anopheles)  is  the  specific  host  and  transmitting  agent. 

To  recapitulate  briefly,  the  malarial  parasite  passes  part  of  its  existence 
in  the  blood-corpuscles  of  man,  where  it  goes  through  a  round  of  develop- 
ment ending  in  segmentation  and  the  infection  of  other  corpuscles  by  the 
segments  which  are  set  free.  The  other  part  of  its  existence  is  passed  in 
the  body  of  the  mosquito.  In  the  mosquito's  stomach  the  elaboration  of 
the  sexual  forms,  conjugation,  and  the  development  of  the  actively  motile 
zygote  take  place.  There  follows  penetration  of  the  stomach  wall  by  the 
zygote,  its  encapsulation  and  the  formation  of  tiny  spores  or  sporozoites, 
which,  wandering  through  the  body  cavity  into  the  salivary  glands,  are 


MALARIA 


775 


injected  by  the  bite  of  the  mosquito  into  the  human  body,  infect  the  cor- 
puscles, and  start  again  the  asexual  cycle. 

Symptoms. — The  evil  effects  of  infection  in  the  human  being  are  there- 
fore dependent  upon  the  asexual  cycle  alone.  The  liberation  of  the  seg- 
ments involves  the  bursting  and  destruction  of  the  red  corpuscle,  the  spill- 
ing of  the  remaining  haemoglobin  and  of  the  malarial  pigment  into  the 
plasma,  and  the  wandering  of  the  motile  segments  to  new  corpuscles. 
This  is  accompanied  by  a  sudden  and  extreme  rise  in  temperature  with  a 
chill.  According  to  the  length  of  the  cycle  of  development  the  chills  are 
spaced  twenty-four,  forty-eight,  or  seventy- two  hours  apart.  But  this  is 


Fig.  382. — Malaria.     Capillary  in  the  brain  filled  with  parasites  of  the  sestivo-autumnal 

type. 

only  because  large  groups  of  parasites  reach  maturity  at  those  moments. 
If,  for  example,  in  the  tertian  infection  the  parasites  are  not  all  of  the 
same  age,  but  fall  into  two  groups  which  mature  at  different  times,  there 
may  be  a  chill  every  day.  The  liberation  of  haemoglobin  and  of  malarial 
pigment,  which  is  a  kind  of  melanin,  results  in  the  pigmentation  of  the  or- 
gans with  hsemosiderin  and  melanin,  and  the  associated  destruction  of  red 
corpuscles  produces  an  anaemia  which  may  reach  a  profound  degree.  There 
is,  as  a  rule,  a  marked  diminution  in  the  number  of  leukocytes,  although 
there  may  at  times  be  a  leucocytosis  during  the  chills.  The  relative  num- 
ber of  lymphocytes  is  increased. 

The  severer  symptoms  of  the  disease,  aside  from  the  anaemia  and  general 


776 


TEXT-BOOK   OF   PATHOLOGY 


evidences  of  poisoning  which  may  constitute  what  is  commonly  spoken  of 
as  cachexia,  are  dependent  upon  the  great  accumulation  of  the  parasites 
in  the  brain  or  in  the  gastro-intestinal  mucosa.  There  are,  of  course,  other 
phenomena  due  to  injuries  to  the  liver  and  kidneys,  but  the  symptoms  of 
general  intoxication  are  sometimes  combined  with  coma  when  the  brain  is 
especially  affected,  or  with  choleriform  diarrhoea  when  the  intestinal  capil- 
laries are  loaded  with  parasites.  In  all  cases  the  spleen  becomes  enlarged, 
and  when  the  infection  has  lasted  a  long  time,  it  may  be  enormous  and 
very  hard. 


-        <£ 

, 


8   >  *&• ®  •      ;?*^ftX**    <-•••      Q 


Fig.  383. — Malaria.     Liver  from  a  case  of  malaria  of  long  standing.     Endothelial  cells 
and  wandering  cells  in  the  capillaries  are  loaded  with  clumps  of  pigment.. 

Pathological  Anatomy. — At  autopsy  there  is  a  distinct  slaty  or  blackish 
pigmentation  affecting  especially  the  spleen,  the  liver,  the  brain,  and  some- 
times the  intestinal  mucosa.  It  is  due  not  only  to  the  parasites  themselves, 
with  their  grains  of  pigment,  but  more  especially  to  the  quantities  of  pig- 
ment set  free  from  other  parasites  and  now  held  in  innumerable  phagocytic 
cells,  both  of  the  type  of  wandering  macrophages  and  of  the  endothelial 
cells  of  the  capillaries.  This  pigmentation  is  the  most  characteristic  feature 
in  the  autopsies  performed  upon  cases  which  have  died  after  protracted 
infections. 


MALARIA  777 

In  the  brain,  the  endothelial  cells  of  the  capillaries  in  the  brain  substance 
may  show  such  pigment,  but  in  intense  infections  one  often  finds  that  the 
capillaries  are  actually  plugged  with  masses  of  corpuscles  bearing  parasites, 
together  with  phagocytic  cells  and  occasional  free  parasites  (Fig.  382). 

In  the  intestine  the  same  condition  may  prevail,  the  capillaries  of  the 
mucosa  being  rendered  impermeable  by  the  mass  of  these  cells. 

In  the  liver  Barker  has  described  focal  necroses.  I  have  not  found  these 
in  other  cases,  but  there  are  always  parasites  in  the  capillaries  and  much 
pigment  is  present,  especially  in  the  stellate  cells  of  Kupfer  and  in  the  en- 
dothelial cells  in  general  (Fig.  383). 


' 


**_ 


Fig.  "384. — Malaria.     Splenic  pulp  in  sestivo-autumnal  infection  showing  many  pig- 
mented  parasites  either  free  or  enclosed  in  large  phagocytic  cells. 

The  spleen  is  particularly  rich  in  the  parasites  and,  indeed,  in  the  case 
of  the  sestivo-autumnal  form,  the  segmenting  forms  are  to  be  found  only 
there.  The  endothelial  cells  of  the  splenic  sinuses  are  loaded  with  pigment 
and  with  fragments  of  cells  and  parasites  (Fig.  384).  These  cells  become  so 
enlarged  and  so  distended  with  this  material  that  they  finally  burst,  the 
debris  being  taken  up  by  other  phagocytic  cells  which  are  less  engorged. 
Mononuclear  wandering  cells  of  other  types  take  part  in  this  process  as 
well.  Here,  as  in  the  liver,  much  of  the  pigment  is  the  iron-containing 


778  TEXT-BOOK    OF    PATHOLOGY 

hsemosiderin  derived  from  the  haemoglobin  set  free  in  the  destruction  of  the 
red  corpuscles.  In  later  stages  there  is  found  a  great  increase  in  the  amount 
of  connective  tissue  throughout  the  organ,  doubtless  caused  to  grow  by  the 
presence  of  so  much  pigment  and  the  long-continued  infection. 

The  bone-marrow  is  likewise  pigmented,  and  while  showing  little  new 
formation  of  polynuclear  leucocytes,  is  rich  in  large  phagocytic  endothelial 
and  reticular  cells  which  have  acted  as  macrophages. 

Many  other  changes  in  the  organs,  such  as  cirrhosis  of  the  liver,  chronic 
nephritis,  etc.,  have  been  ascribed  to  the  action  of  the  malarial  parasite, 
but  it  seems  that  the  evidence  in  these  cases  is  not  quite  decisive. 

LITERATURE 
Thayer  and  Hewetson:  Malarial  Fevers  of  Baltimore,  Johns  Hopkins  Hosp.  Rep.,  1895, 

vol.  v,  3  (Early  literature). 

Thayer:   Lectures  on  the  Malarial  Fevers,  New  York,  1897. 
Barker:   Johns  Hopkins  Hosp.  Rep.,  1895,  vol.  v,  219. 
Laveran:  Bull,  de  1'Acad.  de  med.  de  Paris,  1880,  ix,  1268.    Compt.  Rend,  de  1'Acad. 

des  Sc.,  1881,  xlii,  627. 

Ross:   Malaria,  Nobel  Lecture  for  1902,  Stockholm,  1904. 
MacCallum:  Jour.  Exp.  Med.,  1898,  iii,  103.     Lancet,  1897,  ii,  1240. 
Elting:    (Inoculation)  Zeitschr.  f.  kl.  Med.,  1899,  xxxvi,  491. 
Daniels:  Proc.  Roy.  Soc.,  1899,  Ixiv,  443. 
Bastianelli  and  Bignami;    Grassi;    Celli:    Ann.  d'Igiene  Sperimentale,  1899,  ix,  245. 

(Beautiful  plates.) 

Nuttall:  Centbl.  f.  Bakt.  u.  Paras.,  I.  Abth.,  1899  and  1900,  xxv-xxvii. 
Schaudinn:  Arb.  a.  d.  Kaiserl.  Gesundheitsamt,  1904,  xx,  Heft  3. 
Ewing:   Jour.  Exp.  Med.,  1900,  v,  419. 

ILEMOGLOBINURIC  OR  BLACKWATER  FEVER 

In  persons  who  have  had  malaria  or  who  are  still  infected  with  the  parasites  there  may 
occur  a  violent  and  rapidly  fatal  disease  in  which  the  most  striking  symptom  is  the 
passage  of  red  or  almost  black  urine,  the  color  being  due  to  the  presence  of  haemoglobin. 
Diminution  of  the  urine  to  complete  anuria  may  follow.  There  are  general  evidences  of 
intoxication,  with  the  most  rapid  and  extreme  blood  destruction,  which  quickly  leads  to 
profound  anaemia.  The  spleen  is  greatly  swollen  and  tender,  there  is  vomiting  and 
intense  icterus  and  fever.  Recovery  may  occur  without  conferring  any  immunity,  but 
rather  predisposing  to  another  attack,  or  the  patient  may  die  from  suppression  of  urine 
or  from  exhaustion. 

The  condition  has  every  appearance  of  being  due  to  the  action  of  some  intense  poison 
which  produces  haemolysis,  but  no  such  poison  has  been  demonstrated.  In  some  patients 
the  administration  of  quinine  will  bring  on  an  attack,  but  there  are  many  cases  in  which 
it  occurs  although  no  quinine  has  been  given.  There  are  several  hypotheses  as  to  its 
nature:  That  it  is  an  especially  intense  manifestation  of  malaria;  that  it  is  due  to 
quinine  and,  lastly,  that  it  is  caused  by  some  specific  infectious  agent  as  yet  undiscovered. 
Most  writers,  failing  to  prove  any  of  these  theories,  conclude  that  malaria  produces  a 
condition  which  predisposes  to  blackwater  fever,  which  may  at  times  be  induced  under 
the  circumstances  by  quinine.  In  spite  of  the  earnest  endeavors  of  many  investigators, 
the  matter  is  no  more  cleared  up  than  this.  The  advocates  of  the  theory  that  there  is  a 
specific  infective  agent  have  not  proven  their  point. 

At  autopsy  the  spleen  is  found  to  be  greatly  swollen  with  many  phagocytes  and  with 
extensive  necroses.  It  is,  bright  red  and  velvety  on  section,  in  contrast  to  the  slaty  or 


TRYPANOSOME    INFECTION  779 

blackish  spleen  of  chronic  malaria.  Necroses  occur  also  in  the  lymphatic  glands  and  in 
the  liver.  The  kidneys  are  somewhat  enlarged  and  necked  with  red  and  black  dots  which 
are  due  to  the  haemoglobin  in  the  tubules.  The  glomeruli  are'usually  normal,  the  tubules 
filled  with  irregular  clumps  of  haemoglobin,  their  epithelial  cells  slightly  degenerated. 
Acute  nephritis  supervenes  in  some  cases. 

LITERATURE 

Deaderick:   Memphis  Med.  Monthly,  1907,  xxvii,  637,  et  seq. 
Whipple:  Malaria,  1909,  i,  215. 

Decks  and  James:    Report  on  Hasmoglobinuric  Fevers  in  the  Canal  Zone:    Isthmian 
Canal  Commission,  1911. 

TRYPANOSOME  INFECTION 

Various  diseases  of  animals  and  at  least  one  disease  of  man  are  caused  by 
the  invasion  of  the  trypanosomes,  which  are  large  flagellated  organisms  of 
elongated  form  with  an  undulant  membrane  rising  from  the  blepharoplast 
at  the  posterior  end  and  terminating  in  the  long  flagellum  at  the  anterior 
end.  These  multiply  by  fission  in  the  circulating  blood  and  invade  all  the 
tissues,  being  found  especially  in  the  lymph-glands  and  spleen  and  in  the 
central  nervous  system  and  meninges.  The  intermediate  host  is  some  form 
of  biting  insect — in  the  case  of  Trypanosoma  lewisi  of  the  rat  it  is  a  louse, 
in  the  tsetse-fly  disease  of  cattle  (nagana)  caused  by  T.  brucei  it  is  a  fly 
(Glossina).  In  the  sleeping  sickness  of  human  beings,  caused  by  T.  gam- 
biense  and  T.  rhodesiense,  it  is  also  a  Glossina,  the  G.  palpalis  being  con- 
cerned in  the  first  and  G.  morsitans  in  the  second  case. 

The  organisms  conjugate  in  the  intestine  of  the  fly,  and  smaller  flagellated 
forms  are  produced  in  great  numbers  which  enter  the  salivary  glands  and 
are  inoculated  into  the  new  host  by  the  next  bite. 

The  infection  is  extremely  persistent  and  produces  in  man  a  disease 
which  is  fatal  after  a  prolonged  illness,  or,  at  least,  in  spite  of  every  effort 
at  cure,  drags  on  for  a  very  long  time.  The  sleeping  sickness,  a  disease 
essentially  of  Africa,  is  characterized  by  swelling  of  the  glands  and  fever, 
later  followed  by  disinclination  to  work,  rapid  fatigue,  and  a  soporous  con- 
dition which  may  pass  into  almost  continuous  sleep.  Occasionally  there 
is  agitation  and  delirium.  The  victims  become  greatly  emaciated  and  lie 
helpless  until  they  die,  with  or  without  the  help  of  intercurrent  infections. 

The  organisms  are  found  widely  scattered  in  the  tissues,  and  in  the  brain 
produce  hypersemia  and  infiltration  of  the  meninges  and  perivascular  tis- 
sues, somewhat  resembling  that  in  dementia  paralytica. 

LITERATURE 

Laveran  and  Mesnil:   Trypanosomes  (Tr.  by  Nabarro,  Chicago,  1907). 
Ltihe:   Mense's  Handb.  d.  Tropenkrankheiten,  1906,  iii,  69. 
Mense:  Ibid.,  617. 

Kinghorn,  Yorke,  Lloyd:  Annals  of  Trop.  Med.  and  Paras.,  1913,  vii,  183  (Rep.  Sleep- 
ing Sickness  Commission). 

Wolbach  and  Binger:   Jour.  Med.  Research,  1912,  xxvii,  83. 
Novy  and  McNeal:  Jour.  Infect.  Dis.,  1904,  i,  p.  1. 


CHAPTER  XXXIX 

TYPES   OF  INJURY.— DISEASES   DUE   TO   ANIMAL   PARASITES 

(Continued) 

Cestode  Infections:  Tcenia  and  bothriocephalus;  T.  echinococcus;  echinococcus  cysts  in 
man.  Trematode  infections:  Bilharziosis;  Paragonimus  and  Clnnorchis  Trichiniasis: 
Biology  of  the  parasite,  symptomatology,  pathological  anatomy.  Uncinariasis:  Symptoma- 
tology; life-history  of  parasite;  pathological  anatomy.  Infections  with  ascaris,  oxyuris, 
trichocephalus,  and  filaria.  Elephantiasis. 

CESTODE  INFECTIONS 

FOUR  principal  types  of  cestode  worms  are  concerned  in  the  infection  of 
human  beings,  as  follows: 

Tcenia  saginata,  or  mediocanellata 
Toenia  solium 
Bothriocephalus  lotus 
Tcenia  echinococcus 

Each  of  these  worms  requires  an  intermediate  host  for  the  development  of 
its  larval  form,  after  which  the  ingestion  of  the  tissues  of  that  host  allows 
the  formation  of  the  mature  worm  in  the  definite  host. 

Tsenia  saginata  is  found  in  its  mature  form  in  the  small  intestine  of  man, 
whence  ripe  segments,  loaded  with  eggs,  are  discharged.  The  eggs  pass  into 
the  digestive  tract  of  the  ox,  and  the  embryo  penetrates  through  the  in- 
testinal wall  by  the  aid  of  six  booklets  at  its  anterior  end.  It  is  then  swept 
everywhere  by  the  blood-stream,  and  lodging  in  muscles  develops  into  the 
cystic  larval  form  which,  if  the  beef  be  eaten  uncooked,  becomes  the  mature 
form  once  more  in  the  human  intestine.  The  mature  tapeworm  has  a 
head  with  four  suckers  but  no  hooks.  Its  segments  are  characterized  by 
having  a  great  many  lateral  uterine  diverticula  filled  with  eggs. 

Taenia  Solium. — The  mature  worm,  which  is  provided  with  a  circle  of 
hooks  as  well  as  four  suckers  on  its  head,  is  rare  in  the  human  intestine  in 
this  country.  It  has  segments  which  differ  from  those  of  T.  saginata  in 
showing  relatively  few  lateral  uterine  pouches.  The  eggs  get  into  the 
intestine  of  the  pig,  and  exactly  as  in  the  case  of  the  T.  saginata,  pass  into 
the  muscle  and  organs  to  produce  cystic  larroe  (Cysticercus  cellulosse). 
Occasionally  by  self-infection  the  eggs  can  reach  the  intestine  of  man,  who 
then  becomes  also  the  intermediate  host,  allowing  the  development  of  the 
Cysticercus  cellulosae  in  his  organs.  There  is  a  specimen  in  the  Baltimore 
museum  which  shows  a  human  brain  studded  everywhere  with  cystic 
larval  forms  of  the  T.  solium. 

780 


CESTODE    INFECTIONS 


781 


Bothriocephalus  Latus.— The  larval  form  of  this  worm  is  found  in  the 
muscles  of  several  fish,  including  the  salmon,  trout,  perch,  ling,  etc.,  upon 
the  ingestion  of  which  the  mature  worm  develops  in  the  human  intestine. 
It  is  a  large,  broad  worm  with  elongated  lateral  suckers  and  with  a  different 
arrangement  of  the  geni- 
talia,  the  genital  opening 
being  on  the  face  of  each 
segment  instead  of  at  the 
edges,  as  in  the  tsenia.  Its 
presence  in  the  intestine 
causes  an  intense  anaemia 
which  has  already  been 
mentioned. 

Tsenia  Echinococcus. — In 
the  case  of  this  worm,  of 
which  there  are  two  varie- 
ties, man  is  the  interme- 
diate host,  while  the  mature 
form  is  a  parasite  of  the  in- 
testine of  the  dog.  It  is 
a  very  small  worm,  only  3 
to  6  mm.  in  length,  in  con- 
trast to  those  tsenise  just 
described,  which  may  reach 
the  length  of  30  to  40  feet. 
Many  other  animals  can 
also  act  as  the  intermediate 
hosts.  The  adult  is  a  worm 
with  four  suckers  and  two 
rows  of  hooks,  which  forms 
only  three  or  four  segments 
instead  of  many  hundreds. 
From  dogs,  especially  in 
such  countries  as  Iceland, 
where  men  and  dogs  live  in 
the  same  rooms,  the  eggs 
are  transmitted  to  the  hu- 
man digestive  tract.  The 
wandering  of  the  embryos 
can  take  them  to  any  organ 
of  the  body,  and  the  devel- 
opment of  the  huge  cystic  larva  is  reported  for  every  possible  situa- 
tion. In  the  case  of  T.  echinococcus,  single  cysts  form,  but  in  infection 
with  the  allied  form,  T.  multilocularis,  the  larval  cysts  are  like  a  ramifying 
spongy  tissue  full  of  small  cavities.  The  parasite  produces  injury  by  the 


Fig.  385. — Fresh  echinococcus  cyst  in  the  liver. 
The  lining  of  the  cyst  is  partly  dislocated  from  the 
chitinous  and  fibrous  wall. 


782 


TEXT-BOOK   OF   PATHOLOGY 


space  it  occupies  (as  in  the  brain),  or  by  the  toxic  products  or  by  the  devel- 
opment of  great  numbers  of  secondary  cysts  through  the  rupture  of  the 
first  and  the  liberation  of  the  larvae. 

When  the  eggs  hatch  in  the  human  intestine,  the  embryo  bores  through 
the  intestinal  wall  and  is  transported  by  the  blood-stream  to  its  lodging 
place.  There  it  grows  and  surrounds  itself  with  a  thin,  chitinous  membrane 
of  pearly  translucence  which  in  turn  is  densely  enclosed  in  a  capsule  pro- 
duced by  the  reaction  of  the  surrounding  tissue.  Inside  the  chitinous  mem- 
brane the  embryonic  tissue  grows  and  separates  in  its  central  part  to  allow 


Fig.  386.— Chitinous  wall  of  echinococcus  cyst  with  lining  membrane  of  the  parenchyma 
of  the  worm  and  several  daughter  cysts  with  scolices. 

of  the  accumulation  there  of  a  clear  fluid  rich  in  salt  and  albumin.     It 

thus  becomes  a  lining  of  a  cyst  (Fig.  385).     From  this  lining  there  spring 

up  buds  which  may  be  extremely  numerous  as  the  cyst  grows  larger,  and 

are  finally  recognizable  as  the  heads  of  new  worms.     Some  of  the  buds 

lay    however,  enlarge   and  themselves   become   hollow   and  constitute 

aughter  cysts  in  whose  lining  once  more  there  may  spring  up  little  buds 

which  give  rise  to  new  heads  (Fig.  386).     Such  buds  in  the  main  cyst  or  in 

'  daughter  cyst  elevate  themselves  in  bunches  on  little  stalks  and  are  now 

wol  is  nnrrgi^ated^SO  that  What  is  to  become  the  he*d  of  the  adult 
rorm  i,  now  turned  inside  out,  so  that  in  the  dell  at  the  tip  of  the  bud  one 

the  crown  of  booklets  and  four  suckers  facing  inward  (Fig    387) 


CESTODE    INFECTIONS 


783 


Fig.  387. — Single  scolex  or  head  from  echinococcus  cyst  cut  in  median  line,  showing  in- 
verted suckers  and  rostellum  of  hooks.     Two  of  the  hooks  are  drawn  separately. 


Fig.  388. — Old  echinococcus  cyst  of  liver  with  mortar-like  contents.     The  chitinous 
lining  is  loosened  and  thrown  up  in  folds. 


784  TEXT-BOOK   OF   PATHOLOGY 

With  the  liberation  of  such  buds  or  scolices  by  the  ingestion  of  the  cyst 
material  by  a  dog  or  other  suitable  host,  the  heads  are  quickly  evaginated 
so  that  suckers  and  hooks  present  themselves  in  proper  relations  and  fix 
themselves  in  the  mucosa  of  the  intestine,  after  which  the  worm  proceeds 
to  assume  its  mature  form. 

Such  cysts  are  quite  common  in  the  liver  of  the  pig,  where  they  are  mul- 
tiple and  cause  huge  enlargement  of  the  organ.  Later,  in  any  organ  which 
harbors  such  a  cyst,  if  the  opportunity  for  its  ingestion  by  the  definite  host 
is  postponed,  the  embryos  may  die  and  the  fluid  be  absorbed.  There 
remains  what  is  easily  recognizable  as  an  obsolete  echinococcus  cyst,  a 
rounded  mass  of  mortar-like  whitish  material  densely  encapsulated  with 
fibrous  tissue,  underneath  which  can  still  be  discerned  the  wavy,  lami- 
nated, translucent  chitinous  membrane  which  is  in  itself  so  peculiar  as  to 
be  of  diagnostic  importance  (Fig.  388).  In  the  crumbly  mass  left  after 
absorption  of  the  fluid  loose  booklets  can  be  found  scattered  about,  de- 
rived of  course  from  the  armament  of  the  dead  scolices. 

The  dissemination  of  some  toxic  material  often  gives  rise  to  repeated 
attacks  of  urticaria  and  also  to  an  alteration  of  the  blood  plasma,  such  that 
the  presence  of  the  echinococcus  cyst  can  be  recognized  by  complement 
deviation  reactions. 

LITERATURE 

Stiles:  Hygienic  Laboratory,  Marine  Hosp.  Service,  Bulletins  25  and  28  (Cestode  para- 
sites of  man). 

Stiles  and  Hassal:  Index  catalogue  of  Medical  and  Veterinary  Zoology,  Washington, 
1908. 

Braun:  Thierische  Parasiten  des  Menschen,  Wurzburg,  1903  (Transl.  1906,  New  York). 

Brumpt:   Precis  de  Parasitologie,  Paris,  1910. 

Marchand:  Handb.  d.  allg.  Pathologic,  1908,  i,  340. 

Melnikow  Raswedenkow:  Echinococcus  multilocularis,  Ziegler's  Beitr.,  1901,  iv, 
Suppl.-Heft,  5. 

TREMATODE  INFECTIONS 

Fluke  worms  rarely  cause  disease  in  man  in  this  country,  but  there  are 
several  wide-spread  types  of  human  disease  due  to  their  invasion  in 
Africa  and  Asiatic  countries. 

Of  these,  the  most  important  is  the  bilharziosis,  caused  by  the  various 
forms  of  Schistosomum.  These  are  trematode  worms  in  which  the  sexes  are 
separate,  the  male  being  provided  with  a  gynaBcophoric  canal  in  which  the 
female  is  carried  during  conjugation.  There  are  three  known  forms: 
S.  hsematobium,  which  is  the  common  African  form,  producing  eggs  with 
a  terminal  spine;  S.  mansoni,  found  in  the  West  Indies  and  South  Amer- 
ica and  probably  also  found  in  Africa,  with  eggs  with  a  lateral  spine, 
and  S.  japonicum,  the  Asiatic  form,  whose  eggs  are  elliptical  and  with- 
out any  spine.  It  has  been  shown  by  Leiper  that  the  eggs  set  free  in  the 
water  motile  miracidia,  which  invade  various  snails,  Bullinus,  Planorbis, 
Blanfordia,  Physopsis,  Limnseus,  etc.,  in  which  they  develop  into  active 


TREMATODE    INFECTIONS  785 

cercarise,  which  escape  into  the  water  and  can  penetrate  the  skin  of  per- 
sons bathing.  The  cercarise  wander  in  the  body  and  become  mature  in 
the  veins.  The  eggs  are  carried  into  various  tissues  and  cause  destruction 
and  scarring.  S.  hsematobium  produces  especially  hsematuria  because  of 
infection  of  the  urinary  tract  with  formation  of  polypoid  granulation 
tissue  in  the  bladder.  There  is  prostatitis  and  intense  cystitis,  often  with 
fistulous  communications  with  surrounding  tissues,  renal  infection,  etc. 
Vesical  calculi  are  frequently  formed.  S.  mansoni  causes  chronic  dysen- 
tery with  tenesmus  and  the  passage  of  blood.  There  is  great  thickening 
of  the  mucosa  of  the  colon  with  the  formation  of  polyps  loaded  with 
eggs.  S.  japonicum  also  produces  dysentery,  but  no  infection  of  the  urinary 
tract.  Later  it  gives  rise  to  cirrhosis  of  the  liver  through  the  irritating 
deposit  of  its  eggs  in  the  tissues  of  that  organ.  In  an  autopsy  which  I 
saw  recently  the  liver  was  hard  and  nodular,  and  in  the  depressions  be- 
tween the  nodules  there  were  ochre-yellow  patches  which  proved,  when 
portions  of  the  capsule  were  torn  off  and  examined  with  the  microscope, 
to  be  full  of  eggs  which  gave  the  yellow  color.  On  section,  the  same  yellow 
discoloration  was  to  be  seen  through  many  of  the  scarred  areas.  Similar 
patches  of  dull  yellow  were  found  in  the  mucosa  of  the  colon,  and  in  these, 
too,  there  were  found  thousands  of  eggs. 

Paragonimus  westermanii  is  another  trematode  which  causes  in  For- 
mosa, Japan,  and  Korea  frequent  infection  of  human  beings.  It  gives 
rise  to  cough  with  haemoptysis  and  later  to  emaciation  and  anaemia.  In 
some  chronic  cases  epileptic  seizures  of  Jacksonian  type  form  the  final 
symptoms.  The  worm  is  found  in  its  mature  form  encapsulated  in  the 
lungs,  where  it  sets  up  an  inflammatory  reaction.  The  capsules  are  always 
connected  by  channels  with  the  bronchi,  and  often  with  one  another. 
Indeed,  the  worms  may  lodge  and  form  their  capsule  within  the  lumen 
of  the  bronchus.  In  any  case  the  eggs  are  abundantly  discharged  in  the 
sputum.  Occasionally,  however,  they  are  carried  in  the  blood-stream  to 
the  brain,  and  there  they,  or  even  mature  worms  which  can  pass  into  the 
brain  in  the  same  way,  give  rise  to  the  injury  and  irritation  which  produces 
the  epileptic  attacks.  Other  organs  may  also  become  the  lodging  place 
for  the  worms  and  their  eggs. 

The  development  has  been  worked  out  by  Nakagawa  and  is  essentially 
as  follows :  The  eggs  develop  in  water  into  free  swimming  miracidia,  which 
penetrate  into  the  body  of  snails,  Melania,  where  they  develop  into 
cercarise  and  escape.  The  cercarise  enter  the  tissues  of  freshwater  crabs 
(Potamon,  Eriocheir,  etc.).  These  crabs  when  eaten  raw  or  insufficiently 
cooked  transmit  the  infection  to  man,  in  whom  the  encysted  cercariae  are 
set  free  when  the  cysts  reach  the  intestine.  They  bore  through  the  in- 
testinal wall,  pierce  the  diaphragm,  and  enter  the  lungs  through  the  pleura. 
There  they  form  capsules  and  develop  into  adult  forms. 

In  the  Chinese  and  sometimes  in  the  Japanese  there  is  another  trematode, 
which  in  its  mature  form  infests  the  gall-ducts  and  gall-bladder.  This  is 


786  TEXT-BOOK    OF    PATHOLOGY 

the  Clonorchis  (Opisthorchis)  sinensis.  The  worms  do  not  necessarily 
produce  much  change  in  the  liver,  but  in  a  case  recently  seen  at  autopsy 
in  Panama  the  liver  showed  many  areas  of  atrophy  and  scarring  of  the 
tissue  with  inflammatory  reaction  about  the  bile-ducts.  Kobayashi  has 
shown  that  several  cyprinoid  fishes  act  as  the  intermediate  host,  including 
Pseudorasbora,  Leucogobus,  and  Carassius,  some  of  which  are  eaten  raw, 
and  thus  readily  transmit  the  infection. 

For  descriptions  of  other  trematodes  which  infect  human  beings,  Fas- 
ciolopsis,  Heterophyes,  etc.,  works  on  parasitic  diseases  must  be  consulted. 

LITERATURE 
Schistosomum: 

Looss:  Mense's  Handb.  d.  Tropenkrankheiten,  2  Aufl.,  1913. 
Reed:  Amer.  Jour.  Trop.  Dis.,  1915-16,  iii,  250. 

Leiper:  Jour.  Royal  Army,  M.  C.,  1915,  xxv,  2,  148,  253;  1918,  xxx,  235. 
Diamantis:  Jour.  d.  Urol.  med.  et  chir.,  1917,  vii,  9. 

Paragonimus: 

Nakagawa:  Jour.  Exp.  Med.,  1917,  xxvi,  297. 

Yoshida:  Jour.  Parasitol.,  1916,  ii,  111. 

Clonorchis: 

Kobayashi:    Mitth.  a.  d.  Med.  Fachschule,  Keijo,   1917,  251.     Reviewed,  Japanese 

Med.  Literature,  1917,  ii,  34. 
Refer  also  in  general  to — 

Fantham,  Stephens,  and  Theobald:  Animal  Parasites  of  Man,  N.  Y.,  1916. 
Brumpt:  Precis  de  Parasitologie,  Paris,  1910. 

TRICHINIASIS 

The  trichina,  or,  as  it  is  now  called,  Trichinella  spiralis,  was  discovered  by 
Owen  in  1835  and  has  since  been  studied  by  Virchow,  Zenker,  Leuckart, 
and  a  host  of  others,  the  most  compendious  publication  being  that  of 
Staubli.  It  is  a  nematode,  or  round  worm,  the  anatomical  structure  of 
which  will  be  found  in  any  book  on  animal  parasites.  It  carries  out  its 
whole  life  cycle  in  one  animal,  but  it  must  then  pass  into  the  digestive 
tract  of  another  animal  to  begin  another  cycle.  The  reason  for  this  will 
be  found  in  the  following  brief  summary  of  its  life-history.  The  worm  is 
essentially  a  parasite  of  swine,  but  can  live  in  rats,  mice,  guinea-pigs, 
rabbits,  dogs,  cats,  and  many  other  animals  as  well  as  man.  It  is  from 
eating  insufficiently  cooked  pork  that  man  is  infected,  but  the  pigs  them- 
selves are  often  infected  through  eating  dead  rats.  The  embryos,  both 
male  and  female,  are  found  in  the  muscle  substance  of  the  pig,  and  on 
being  eaten  by  man  quickly  develop  into  mature  forms  when  they  reach 
the  intestine.  There  the  females  penetrate  into  the  substance  of  the  villi 
and  often  actually  enter  the  central  lymphatic;  the  eggs  hatch  in  the 
uterus  of  the  worm,  and  the  active  embryos  are  set  free  from  the  genital 
opening,  after  which  they  bore  their  way  into  the  lymphatics,  if  they  are 
not  actually  deposited  there  by  the  mother.  Thence  they  are  swept  in 
great  numbers  through  the  mesenteric  lymph-glands  and  the  thoracic 
duct  into  the  blood,  and  are  to  be  found  there  by  centrifugalizing,  after 


TRICHINIASIS 


787 


treating  the  blood  with  3  per  cent,  acetic  acid,  which  dissolves  away  the 
red  corpuscles.  They  are  thus  carried  through  the  whole  body  but  choose 
the  voluntary  muscles  for  their  permanent  abode.  Doubtless  they  have 
to  penetrate  into  them  from  the  capillary  by  their  own  activity.  They 
lodge  in  every  other  tissue,  but  appear  to  find  conditions  unsuitable  and 
never  develop  there;  indeed,  they  are  rarely  found  anywhere  else  than  in 
the  skeletal  muscles.  They  are  not  found  in  the  heart  muscle,  but  are 
occasionally  seen  in  the  mesenteric  lymph-glands  and  for  a  time  are  abun- 
dant in  the  peritoneal  cavity. 


Fig.  389. — Pectoral  muscle  with  encapsulated  and  calcined  trichinae. 

Having  entered  the  muscle,  each  one  penetrates  into  a  muscle-fibre 
where  it  lies  as  a  small,  rod-like  structure  in  the  middle  of  the  fibre.  As  the 
embryo  grows  the  fibre  loses  its  striations  and  becomes  granular  and 
swollen.  The  sarcolemma  nuclei  sink  into  the  more  or  less  homogeneous 
mass  and  surround  the  little  worm.  A  little  later  the  parasite,  having 
developed  until  it  shows  the  alimentary  tract  and  a  rudiment  of  the  re- 
productive glands,  coils  itself  up  and  becomes  surrounded  by  a  rather 
thick  hyaline  capsule  which  is  usually  elliptical  (Fig.  389).  There  is  a 


788 


TEXT-BOOK   OF   PATHOLOGY 


dispute  as  to  the  origin  of  this  capsule,  but  it  seems  most  probable  that  it 
is  formed  by  the  worm,  as  Leuckart  thought,  although  there  are  many 
who  think  it  produced  by  the  host.  But  the  host  does  not  produce  such 
a  peculiar  capsule  for  any  other  foreign  body,  and  it  seems  specifically  a 
part  of  this  parasite.  Fat  may  collect  at  its  poles  outside,  and  within  it 
there  are  usually  found  a  few  cells  at  each  pole.  These  may  be  included 
parts  of  the  group  of  sarcolemma  nuclei.  Later,  the  capsule  becomes 


Fig.  390.— Larva  of  trichinae  encapsulated  in  muscle.  There  is  abundant  infiltra- 
tion of  leucocytes,  most  of  which  are  eosinophiles,  and  many  muscle-fibres  are  reduced 
to  hyaline  masses. 

partly  or  completely  calcified,  and  then  the  worm  is  likely  to  die  or  has 
already  died.  Nevertheless,  they  live  for  years  in  the  muscle,  awaiting 
a  chance  to  go  through  the  development  to  maturity,  in  their  turn,  in  the 
body  of  another  animal. 

The  disease  trichiniasis  is  a  serious  one,  and  often  ends  fatally  when 
much  of  the  infected  meat  is  eaten.  Death  is  probably  due  to  the  in- 
tense injury  produced  by  the  penetration  of  the  intestinal  wall,  although 


UNCINARIASIS  789 

more  rarely  it  may  occur  after  the  embryo  has  entered  the  muscle.  Much 
care  is  taken  by  the  German  government  to  prevent  the  sale  of  infected 
pork,  and  Staubli's  book  is  one  long  outcry  against  American  pork.  The 
frequency  with  which  epidemics  of  trichiniasis  occur  in  Germany  is,  how- 
ever, probably  the  outcome  of  the  German  habit  of  eating  raw  pork  and 
blood  sausages  and  makes  the  meat  inspection  futile. 

The  disease  may  simulate  typhoid  fever.  There  is  fever  and  malaise, 
often  with  diarrhoea  when  the  infection  is  intense,  with  oedema  of  the 
tissue  below  the  eyes  and  sometimes  of  other  parts  of  the  body  and  often 
with  profuse  sweats.  There  is  no  Widal  reaction,  and  there  is  a  marked 
leucocytosis  with  an  extraordinary  increase  in  the  eosinophile  cells  (Brown) . 
Later  the  muscles  become  stiff  and  painful,  and  in  the  effort  to  relieve 
them  there  is  dyspnoea,  aphonia,  and  general  immobility.  With  the  estab- 
lishment of  the  worms  in  the  muscle  and  their  encapsulation,  the  symptoms 
gradually  disappear. 

If-  a  person  thus  infected  dies,  the  appearance  of  the  organs  varies  with 
the  stage  of  the  disease.  In  the  fresher  stages  the  intestinal  mucosa  is 
said  to  be  swollen  and  reddened  but  without  definite  haemorrhages.  The 
lymph-glands  are  swollen  in  the  mesentery  and  there  is  bronchitis,  but 
there  is  usually  no  other  organic  change  dependent  upon  the  infection 
except,  of  course,  the  change  in  the  skeletal  muscles.  The  bone-marrow 
is  hyperplastic  and  rich  in  eosinophile  myelocytes. 

The  muscle  parasites  are  not  visible  to  the  naked  eye  and  there  may  be 
no  sign  of  any  change.  It  is  only  much  later  when,  after  years,  they  become 
calcified  that  they  are  visible  (Fig.  390) .  Then  they  look  like  tiny  opaque 
yellowish-white  flecks  in  the  muscle.  Their  distribution  has  guided  the 
meat  inspection  in  Germany  and  the  diaphragm  or  neck  muscles  are 
chosen  for  study,  since  those  places  seem  especially  favorable  for  their 
growth. 

LITERATURE 

Staubli:    Trichinosis,  Wiesbaden,  1909. 
Askanazy:    Virch.  Arch.,  1895,  cxli,  42. 
Brown:    Jour.  Exp.  Med.,  1898,  iii,  315. 
Herrick  and  Janeway:    Arch.  Int.  Med.,  1909,  iii,  263. 

UNCINARIASIS 

Through  the  work  of  Stiles  in  this  country  and  Ashford  in  Porto  Rico 
the  enormous  importance  of  this  infection  has  been  made  clear  and  Stiles 
has  shown  that,  in  addition  to  the  Anchylostomum  duodenale  or  Uncinaria 
duodenalis,  there  is  another  form,  called  by  him  Necator  americanus,  which 
is  the  parasite  especially  concerned  in  America  and  the  West  Indies. 

All  through  the  southern  states  and  in  tropical  and  sub-tropical  countries 
around  the  world,  the  so-called  " hookworm  disease"  is  more  or  less  pre- 
valent. Ashford's  description  of  it  as  it  occurs  in  the  "jibaro"  or  laborer 
in  Porto  Rico  is  most  vivid  and  gives  a  better  idea  of  the  ravages  it  causes 


790  TEXT-BOOK   OF   PATHOLOGY 

than  any  other  I  have  read.  The  people  who  work  in  damp  coffee  planta- 
tions are  especially  affected  there.  Elsewhere,  those  who  work  in  the  soil 
are  the  ones  to  suffer,  chiefly  when  they  get  into  mud,  although  Stiles 
suspected  especially  the  influence  of  sandy  soils.  After  having  walked 
barefoot  in  the  mud,  they  have  a  peculiar  eruption  on  the  skin  which 
burns  and  itches.  Some  time  after  that  such  people  find  themselves  weak 
and  easily  tired  and  unable  to  work.  They  grow  pale  and  the  skin  assumes 
a  yellowish  clay  color.  The  digestion  is  disordered,  there  is  constipation 
or  diarrhoea  with  occasional  periods  of  abdominal  pain.  The  nervous 
system  is  often  much  affected,  and  in  some  cases  actual  maniacal  attacks 
interrupt  the  usual  stupid  condition.  The  extreme  anaemia,  often  with 
eosinophilia,  becomes  more  profound  and  there  is  often  associated  with  it 
oedema  of  the  face  or  of  the  whole  body.  The  patient  becomes  unable 
to  walk  or  to  help  himself  in  any  way  and  may  die.  The  faeces  contain 
numbers  of  the  elliptical  ova  of  the  worm,  but  in  Ashford's  experience  no 
blood.  The  whole  affection  can  be  cured  with  thymol. 

Most  interesting  is  the  pathogenesis  of  this  disease  which  has  been 
worked  out  by  Looss  in  Egypt.  The  eggs  passed  with  faeces  develop,  if 
they  find  themselves  in  a  moist  place,  into  small  active  embryos.  Whole 
areas  of  moist  ground  can  be  thus  infected.  Ashford  mentions  the  damp 
ground  in  the  shade  of  coffee  bushes,  Looss  the  mud  in  which  the  fellaheen 
work  after  the  Nile  recedes.  Looss'  beautiful  experiments  showed  that  if 
water  or  mud  containing  larvae  at  this  stage  were  applied  to  the  skin  there 
arose  almost  at  once  a  burning  and  itching  sensation,  and  by  the  time  the 
water  had  dried  all  the  larvae  had  bored  their  way  into  the  skin,  leaving 
their  shed  skins  as  empty  shells  on  the  outside.  He  repeated  this  with  a 
leg  about  to  be  amputated  and  was  able  to  trace  the  larvae  into  the  hair 
follicle  and  thus  through  the  skin.  They  do  not  enter  sweat-glands  or 
sebaceous  glands,  but  Schuffner  found  that  they  could  pierce  the  skin 
anywhere.  Further  experiments  with  dogs  showed  that  they  wander  into 
the  blood-vessels  and  are  carried  to  the  lungs,  where  they  are  too  large  to 
pass  through  the  capillaries,  but  emerge  into  the  air-cells.  Thence,  crawling 
up  the  bronchi,  they  get  over  into  the  oesophagus  and  reach  the  stomach 
and  intestine,  where  after  other  moults  they  become  mature  worms. 

Of  course,  the  irritation  felt  by  Looss  (who  thus  produced  a  general  in- 
fection in  himself  and  long  harbored  the  worms  in  his  intestine)  was  iden- 
tical with  the  ground  itch  or  "mazamorra,"  which  comes  on  after  walking 
barefoot  in  infected  mud  or  smearing  the  hands  with  it,  and  there  seems 
no  doubt  that  this  is  the  ordinary  mode  of  infection.  Of  course,  the  larvae 
may  be  swallowed  if  muddy  water  or  mud-covered  vegetables  are  taken 
into  the  stomach  or  if,  as  sometimes  happens  to  these  people,  a  craving 
for  bulk  in  their  food  is  satisfied  by  eating  mud  or  clay.  But  although 
this  infection  by  mouth  has  been  regarded  as  the  chief  mode  of  entrance 
it  seems  now,  in  the  light  of  Looss'  work,  to  be  less  important  and  perhaps 
even  uncommon. 


UNCINARIASIS 


791 


The  mature  worms  attach  themselves  to  the  walls  of  the  intestine  and 
draw  into  their  capacious  mouths  some  part  of  the  mucosa  (Fig.  390 A). 
They  seem  to  be  actual  blood-suckers,  although  there  is  still  difference  of 
opinion  about  this.  Sometimes  haemorrhage  can  be  found  about  the  point 
at  which  they  were  applied,  and  it  has  been  thought  that  much  loss  of 
blood  might  occur  after  they  dropped  off  or  changed  to  another  place. 
But  little  blood  is  found  in  the  stools,  and  it  is  not,  as  a  rule,  found  in  the 


l?pSS»f^lp^ 

^^~-^fci_!iii^»^^^ 


^""^"-— — il_* 

Fig.  390 A. — Head  of  ankylostome  in  secti 
tine  is  drawn  up  into 


— — -  T-^...       I, 

ikylostome  in  section  showing  how  t 
te  is  drawn  up  into  the  mouth  cavity 


intestine  of  the  worm.  The  impression  is,  therefore,  that  they  do  not 
cause  the  profound  anaemia  by  merely  mechanically  removing  blood,  and 
this  is  strengthened  by  the  character  of  the  anaemia,  which  is  peculiar 
and  marked  by  an  outspoken  eosinophilia.  This,  together  with  the  nervous 
phenomena  and  the  symptoms  of  general  intoxication,  point  rather  to  a 
toxic  substance  produced  by  the  worm  as  the  cause  of  the  anaemia. 

The  worms  are  found  hanging  to  the  wall  of  the  small  intestine  and  are 
pretty  tightly  attached.     Hundreds  of  them  occur  in  one  case.     Aside 


792  TEXT-BOOK    OF    PATHOLOGY 

from  the  pallor,  changes  in  the  other  organs  are  not  especially  charac- 
teristic. The  spleen  is  not  enlarged.  The  bone-marrow  shows  a  response 
to  the  anaemia.  The  kidneys  are  found  to  present  some  exudate  of  blood 
and  epithelial  degeneration. 

LITERATURE 
Ashford  and  Igaravidez:   Uncinariasis   in  Porto  Rico,   U.  S.   Senate  Document  No. 

808,  1911,  (Literature). 

Stiles:   "Hookworm  Disease,"  Hygienic  Laboratory  Bull.,  No.  10,  Washington,  1903. 
Looss:   Centbl.  f.  Bakt.  u.  Paras.,  Abth.  i,  1901,  xxix,  733. 

OTHER  NEMATODE  INFECTIONS 

Brief  mention  may  be  made  of  certain  other  very  common  infections 
with  nematode  worms. 

Ascaris  lumbricoides  is  the  common  round  worm  found  in  the  intestine 
of  children,  which,  by  its  presence  in  numbers,  exercises  an  irritating 
influence.  It  does  not  actually  fix  itself  to  the  intestinal  wall,  but  lies  free 
or  in  convoluted  masses  in  the  lumen.  The  effects  of  its  wanderings  into 
other  localities  have  been  mentioned.  Apparently  it  may  secrete  a  toxic 
material,  for  there  are  general  and  nervous  symptoms  due  to  its  presence. 

The  life-history  of  the  Ascaris  has  been  shown  more  clearly  in  the  recent 
work  of  Stewart,  and  of  Ransom  and  Foster.  Stewart  found  that  when 
eggs  were  fed  to  rats  and  mice  the  larvae  hatched  in  the  intestine,  reached 
the  lung,  and  developed  there,  passing  thence  into  the  intestine,  from  which 
they  were  discharged.  He  thought  that  these  animals  must  act  as  inter- 
mediate hosts,  and  that  infection  of  the  final  host  must  arise  from  the 
ingestion  of  the  partly  developed  worms  thus  excreted.  Ransom  and 
Foster  show  clearly,  however,  that  these  larvae  are  discharged  from  the 
intestine  of  the  rat  or  mouse  only  because  they  are  unsuitable  hosts.  In 
pigs  and  children,  if  young  enough,  larvae  which  are  hatched  in  the  intestine 
from  ingested  eggs  wander  into  the  lungs  through  the  diaphragm  and 
pleura.  There  they  develop  further,  causing  serious  pneumonic  phenom- 
ena, and  later,  passing  up  the  trachea,  they  go  down  into  the  intestine, 
where  they  complete  their  development.  The  larvae,  as  shown  also  by 
Yoshida,  have  a  remarkable  power  of  wandering  through  all  the  tissues 
and  can  penetrate  the  skin. 

LITERATURE 
Stewart,  F.  H.:   Brit.  Med.  Jour.,  1916,  ii,  474,  486,  753.     Parasitology,  1917,  ix,  213; 

1918,  x,  189,  197. 

Ransom  and  Foster:  Jour.  Agric.  Research,  1917,  xi,  395.  Jour.  Parasitol.,  1919,  v,  93. 
Yoshida:  Ibid.,  1919,  vi,  19. 

Oxyuris  vermicularis,  a  small  worm  with  pointed  extremities,  3  to 
5  mm.  long,  is  a  frequent  inhabitant  of  the  colon,  where  it  attacks  the 
mucosa,  and  by  its  bites  produces  haemorrhagic  points,  and  an  inflam- 


OTHER   NEMATODE    INFECTIONS  793 

matory  reaction  with  intense  itching  of  the  anal  region.  Its  eggs  develop 
on  vegetables,  etc.,  or  the  embryos  which  quickly  leave  the  shell  may  be 
transferred  to  the  mouth  and  an  extensive  autoinfection  produced.  In- 
vasion of  the  oxyuris  into  the  mucosa  of  the  appendix »has  been  shown  to 
be  responsible  for  a  considerable  number  of  cases  of  appendicitis  (17  in 
a  series  of  129  cases,  Cecil  and  Bulkley). 

The  Trichocephalus  trichiurus,  or  dispar,  is  a  similar  worm  with  long, 
thread-like  anterior  end.  It  buries  this  anterior  end  in  the  mucosa  of  the 
caecum  and  absorbs  blood.  No  very  marked  symptoms  are  produced,  but 
it  can  occasionally  be  the  cause  of  appendicitis.  More  important  than 
these  is  the  Filaria  Bancrofti,  whose  embryos  are  found  in  the  circulating 
blood  in  the  form  of  delicate,  actively  motile  threads  which  appear  there 
only  at  night.  They  are  transferred  by  the  mosquitoes  (culex),  in  which 
they  undergo  a  certain  development,  reaching  the  salivary  glands  or 
oesophagus,  so  that  they  are  injected  with  another  bite  into  another  host. 


Fig  390B. — Elephantiasis  affecting  both  legs  (Singapore). 

The  mature  worm,  developing  in  the  human  body,  invades  and  lodges 
itself  in  the  lymphatic  channels,  where  it  produces  great  distension,  haemor- 
rhage, and  inflammation.  Huge  masses  of  lymphatic  varicosities  are  the 
result  and  much  obstruction  to  the  flow  of  lymph.  The  effect  of  this  is 
evident  in  nearly  every  tropical  country  in  the  occurrence  of  the  so-called 
elephantiasis  (Fig.  390B),  which  affects  the  legs  or  the  scrotum,  causing 
huge  enlargements  due  to  lymph  stasis  and  new  formation  of  tissue  which 
are  traceable  to  the  presence  of  the  worm.  Chyluria,  or  milky  urine,  and 
chylous  ascites  are  also  characteristic  features.  In  the  Fiji  Islands,  where 
Bahr  showed  that  the  Stegomyia  acts  as  intermediate  host  and  carrier 
of  the  infection,  I  saw  several  cases  of  elephantiasis  affecting  the  arms 
alone.  The  most  frequently  observed  lesion  in  those  islands  is,  however, 
a  great  swelling  and  induration  of  the  lymph-nodes  in  the  inguinal  region 


794  TEXT-BOOK    OF    PATHOLOGY 

or  elsewhere,  and  in  the  disintegrated  centre  of  each  of  these  the  filarise 
are  to  be  found. 

LITERATURE 

Braun:  Thierischen  Parasiten  des  Menschen,  Wiirzburg,  4  Aufl.,  1908. 
Cecil  and  Bulkley:  Jour.  Exp.  Med.,  1912,  xv,  225. 

Opie:  "Filarial  Lymphatic  Varix,"  Amer.  Jour.  Med.  Sci.,  1901,  cxxii,  251. 
Manson:  Tropical  Diseases,  London,  1903,  545. 
Looss:  Mense's  Handb.  d.  Tropenkrankheiten,  1914,  ii,  312. 
Bahr:  Jour.  London  School  of  Tropical  Med.,  Suppl.  i,  1912. 


CHAPTER  XL 

THE  EFFECTS  OF  INJURIES  UPON  THE  BLOOD  AND  BLOOD- 
FORMING  ORGANS 

Importance  of  changes  in  blood-forming  organs.  The  bone-marrow :  its  regenerative 
changes.  The  spleen.  The  lymphoid  tissues  with  the  hcemolymph  nodes.  Injuries  of  red 
corpuscles  and  erythrogenic  tissue.  Polycythcemia.  Anaemia  or  oligocythcemia.  Pest- 
hcBmorrhagic  and  other  secondary  anosmias.  Pernicious  anosmia.  Aplastic  ancemia. 
Hcemochromatosis.  Hcemolytic  icterus.  Osteosclerotic  ancemia.  Banti's  disease.  Spleno- 
megaly of  Gaucher. 

THE  fact  that  in  the  many  disorders  of  the  blood  and  of  the  blood-forming 
organs  we  are  as  yet  in  most  cases  ignorant  of  the  cause,  makes  it  seem 
preferable  to  discuss  these  conditions  together  and  quite  objectively.  It 
is  true,  of  course,  that  nearly  all  of  the  injuries  which  have  already  been 
considered  cause  changes  in  the  blood  and  its  sources,  and  sometimes  we 
can  trace  these  effects  with  the  greatest  accuracy,  so  as  to  derive  enlight- 
enment with  regard  to  the  principles  which  are  probably  concerned  in  the 
more  obscure  affections. 

The  blood,  in  virtue  of  its  rapid  circulation  and  of  the  powerful  sifting 
and  cleansing  effect  exerted  upon  it  by  the  very  blood-forming  organs 
which  are  its  source,  does  not  show  the  direct  effect  of  local  injury  except 
after  very  gross  damage  by  haemorrhage  or  by  chemical  agents.  Then 
it  becomes  diluted  by  the  inflow  of  fluid  from  the  tissues,  or,  in  the  second 
case,  it  shows  the  effect  of  the  chemical,  as  in  the  formation  of  carbon 
monoxide  haemoglobin,  methaemoglobin,  etc.).  Instead,  the  changes 
which  appear  in  the  circulating  blood  are  essentially  those  which  depend 
upon  the  activity  of  the  blood-forming  organs,  and  may  consist  in  an 
incomplete  new  formation  of  cells  of  the  same  type  as  those  which  were 
lost,  or  in  the  introduction  of  greatly  increased  numbers  of  some  of  the 
cells  (leucocytes),  or  even  in  the  appearance  of  cells  which  are  not  normally 
present  in  the  blood  (erythroblasts,  myeloblasts,  etc.).  Thus  it  is  clear 
that  we  shall  have  to  deal  but  little  with  the  direct  effects  of  injurious 
agents  upon  the  blood  itself.  On  the  other  hand,  the  changes  brought 
about  in  the  blood-forming  organs  by  direct  injury  or  through  the  neces- 
sity of  restoring  to  normal  the  injured  blood,  must  interest  us  quite  as 
much  as  the  remarkable  changes  in  the  blood  which  then  follow.  It  is  as 
though  an  army  during  the  battle  should  rapidly  circle  back  into  the  mother 
country  carrying  the  dead  and  wounded,  returning  to  the  battle  with  ever 
new  reserves.  In  time  there  would  come  a  change  in  the  character  of  the 
army,  depending  upon  the  ability  of  the  mother  country  to  recruit. 

795 


796  TEXT-BOOK   OF   PATHOLOGY 

BLOOD-FORMING  ORGANS 

Leaving  aside  the  conditions  found  in  embryonic  life,  it  is  clear  that  the 
bone-marrow  constitutes  the  essential  seat  of  the  formation  of  most  of  the 
elements  of  the  blood,  although,  as  we  have  seen  in  the  outline  given  in 
Chapters  IX  and  XII,  the  cells  of  the  lymphoid  series  are  furnished  to 
the  blood  by  the  lymphoid  tissues  scattered  everywhere  throughout  the 
body.  Under  stress  of  great  need,  tissue  of  the  character  of  the  bone- 


>* 


I* 

f/  "  '"r~G     '" 

I  *  >->  >      *  * 


s^ 

*, 


.»       .* 


L>^J 


Fig.  391.— Bone-marrow  from  femur  of  normal  adult,  showing  chiefly  fat  with  very 

little  myeloid  tissue. 

marrow  appears  in  situations  far  removed  from  the  bones,  and  cells  swept 
into  the  general  circulation  may  settle  as  colonies  in  the  capillaries  of 
various  organs  and  there  multiply  to  some  extent  (Tanaka).  The  part 
played  by  the  spleen  in  blood  formation  is  still  disputed,  and  although 
some  writers  assign  to  it  a  most  important  role,  others  regard  it  as  chiefly 
concerned  in  the  purification  of  the  blood.  This  matter  must  for  the 
present  be  left  undecided. 


BLOOD-FORMING   ORGANS 


797 


The  Bone-marrow. — Throughout  life  the  marrow  of  the  cancellous 
framework  of  the  short  and  flat  bones  maintains  its  cellular  character  and 
is  active  in  blood  formation.  In  childhood  this  is  true  of  the  marrow  of 
the  long  bones  too,  but  with  advancing  age  fat  increases  in  amount  there 
and  replaces  the  marrow,  often  even  in  the  cancellous  regions  of  the  ends 
of  the  bone.  The  microscopical  study  of  the  marrow  shows  only  a  delicate 
framework  with  blood-vessels  among  the  closely  packed  fat-holding  cells. 
In  the  angles  and  crevices  one  may  find  a  few  cells  of  myelocyte  or  ery- 


Fig.  392. — Bone-marrow  from  normal  infant.  It  shows  quite  well-defined  blood- 
channels,  neutrophile  and  eosinophile  myelocytes,  megalocaryocytes,  etc.  There  are 
numerous  normoblasts  which  do  not  show  well  in  this  drawing. 

throblast  type  (Fig.  391).  It  seems  that  these  are  the  cells  which  multiply 
at  an  astounding  rate  when  special  activity  of  the  bone-marrow  is  de- 
manded. In  the  marrow  of  the  child's  femur  (Fig.  392)  or  in  that  of  the 
short  cancellous  bones  a  very  different  condition  exists.  There  is  relatively 
little  fat,  and  the  delicate  vascular  reticulum  is  loaded  with  loose  cells.  Of 
course,  as  mentioned  before,  the  osteoblasts  and  osteoclasts  which  are 
closely  applied  to  the  bone  hold  aloof  and  are  concerned  only  in  bone  for- 
mation and  destruction.  The  capillaries  are  wide  and  variable  in  diameter, 


798  TEXT-BOOK   OF   PATHOLOGY 

and  it  is  frequently  difficult  to  trace  their  endothelial  outlines,  Indeed,  one 
does  not  receive  the  impression  that  they  are  stout-walled  tubes  capable 
of  carrying  blood  safely  at  a  considerable  pressure,  but  rather  that  their 
walls  are  extremely  thin  if  not  actually  lacking  in  places.  At  times  it 
seems  as  though  the  mass  of  cells  in  the  reticulum  were  continuous  with 
those  within  the  capillaries,  and  one  must  suppose  that  some  such  relation 
may  exist,  to  explain  the  phenomenally  rapid  delivery  of  cells  into  the 
blood-stream.  For  a  discussion  of  the  histogenesis  of  the  cells  concerned 
the  student  is  referred  to  the  papers  of  Maximow,  Jackson,  and  others. 


Fig.  393.— Bone-marrow  of  rabbit  after  long  treatment  with  benzol.     Practically  all  the 
blood-forming  elements  are  destroyed. 

In  such  cellular  marrow  there  are  found,  side  by  side,  the  following 
kinds  of  cells: 

1.  Those  concerned  in  the  production  of  red  corpuscles:   Megaloblasts, 
normoblasts,  and  the  erythrocytes  themselves. 

2.  Those  concerned  in  the  formation  of  the  neutrophile,  eosinophile  and 
basophile   granular  leucocytes:     Myeloblasts  without   granules,   myelo- 
cytes  with  neutrophile,  eosinophile  and  basophile  granules,  and  the  mature 
leucocytes  themselves  with  these  different  types  of  granule. 


BLOOD-FORMING   ORGANS 


799 


3.  An  indefinite  but  limited  number  of  large  and  small  lymphoid  cells, 
situated  usually  about  the  blood-vessels  and  capable  of  giving  rise  to 
lymphocytes  and  to  their  derivatives,  including  plasma  cells. 

4.  Megalocaryocytes  which,  by  constricting  off  portions  of  their  granular 
cytoplasm,  form  blood-platelets,  which  they  discharge  into  the  blood. 

In  ordinary  sections  these  cells  are  so  intermingled  that  one  cannot 
make  out  their  relations  to  one  another,  but  Bunting  puts  forward  the 


Fig.  394. — Bone-marrow  of  rabbit.     Beginning  regeneration  after  benzol  poisoning; 
islands  of  myelocytes  and  normoblasts. 

statement  that  they  occur  in  definite  groups  or  colonies  at  the  margins  of 
which  the  perfected  cells  are  set  free.  This  he  has  found  especially  striking 
in  experimental  anaemias  in  rabbits  in  which  the  bone-marrow  had  been 
injured  by  the  injection  of  ricin  or  other  substance  used  to  produce  the 
anaemia.  So,  too,  Selling  described  the  appearance  of  such  colonies  or 
pure  cultures  of  the  various  cells  in  bone-marrow  rendered  practically 
cell-free  (Fig.  393)  with  injections  of  benzol  and  then  allowed  to  regenerate. 
These  preparations  I  have  studied  and  the  truth  of  the  statement  is  very 


800 


TEXT-BOOK   OF   PATHOLOGY 


striking.  There  are  isolated  groups  composed  in  one  case  entirely  of 
nucleated  red  cells  (Fig.  394),  in  another  entirely  of  myelocytes  or  of 
megalocaryocytes  (Fig.  395),  and  in  the  later  stages  each  of  these  comes 
to  be  accompanied  by  the  mature  cells  which  they  produce  (Fig.  396). 
Bunting  explains  that  with  further  development  the  groups  become  so 
interwoven  that  it  is  impossible  to  outline  them  clearly,  but  in  the  bone- 
marrow  of  his  rabbits  made  anemic  with  ricin  he  finds  such  islands  with 
a  central  group  of  megaloblasts  surrounded  by  normoblasts  and  these  in 


Fig.  395. — Bone-marrow  of  rabbit  after  benzol  poisoning.     Beginning  regeneration; 
islands  of  megalocaryocytes. 

turn  by  ordinary  red  corpuscles.  It  is  on  the  basis  of  these  observations 
that  he  regards  the  megaloblasts  as  normal  constituents  of  the  bone-marrow 
and  the  immediate  ancestors  of  the  normoblasts.  It  is  well  known  that 
this  is  not  the  view  of  German  haematologists  (Naegeli),  who  hold  to 
Ehrlich's  statement  that  megaloblasts  are  embryonic  cells  occurring  only 
under  pathological  conditions  in  adult  bone-marrow,  and  that  therefore 
pernicious  anaemia,  in  which  they  become  abundant  in  the  marrow,  rep- 
resents a  pathological  return  to  embryonic  conditions.  It  seems,  however, 
that  one  may  convince  oneself  of  their  common  occurrence  in  normal  and 


BLOOD-FORMING   ORGANS 


801 


regenerating  bone-marrow  and  of  the  probability  of  Bunting's  view  that 
they  represent  the  earlier  stage  in  the  formation  of  red  corpuscles.  The 
occasional  sweeping  of  these  nucleated  cells  into  the  blood  will  call  for 
discussion  below. 

In  quite  the  same  way  the  myeloblasts  and  myelocytes  of  each  kind 
grow  in  colonies  and  shed  into  the  blood  their  polymorphonuclear  de- 
scendants. These  cells,  even  in  their  earlier  non-granulated  stages,  give 
an  intense  blue  reaction  with  alpha-naphthol  and  dimethylparaphenylene 


Fig.  396. — Bone-marrow  of  rabbit  after  benzol  poisoning.     Later  stage  of  regeneration. 
Mixed  islands  of  myelocytes,  normoblasts,  with  occasional  megalocaryocytes. 

diamine,  which  in  the  presence  of  an  oxydizing  ferment  produce  indophenol 
blue  (oxydase  reaction).  This  reaction  is  also  given  by  all  the  granulated 
leucocytes  of  the  blood,  including  the  large  mononuclear  and  transitional 
forms  of  Ehrlich.  The  latter  are  thereby  shown  to  be  related  to  the  my- 
elocyte  group  rather  than  to  the  lymphoid  cells,  since  none  of  the  lym- 
phocytes or  related  cells  give  the  reaction.  (The  mast  cells  of  the  tissue 
fail  to  give  it  despite  their  basophilic  granules.) 

Ordinarily  the  lymphoid  cells  of  the  bone-marrow  form  an  inconspicuous 
52 


802 


TEXT-BOOK    OF   PATHOLOGY 


element  of  the  cell  mass  and  are  sometimes  collected  in  groups  or  lymph 
nodules.  In  those  cases  in  which  the  injurious  agent  causes  the  isolated 
overproduction  of  lymphoid  cells  they  may,  however,  increase  to  such  an 
extent  as  to  crowd  aside  all  the  other  cells.  Theirs  is  probably  under 
ordinary  circumstances  the  least  prominent  role  among  the  bone-marrow 

cells. 

The  megalocaryocytes  which  maintain  the  platelet  content  of  the  blood 
are,  like  the  other  cells,  vulnerable,  and  may  be  greatly  reduced  in  number 
by  toxic  substances.  They  regenerate  themselves  in  little  colonies  just 
as  do  the  other  cells  (Fig.  395). 

The  Spleen. — The  studies  of  Weidenreich  and  Mollier  have  made  clear 
the  structure  of  the  spleen  as  far  as  concerns  its  vascular  arrangement, 
but  there  is  still  much  to  be  learned  with  regard  to 
the  cellular  structure  of  the  splenic  pulp. 

The  smaller  branches  of  the  splenic  artery  are  sur- 
rounded for  some  distance  by  mantles  of  lymphoid 
tissue  which  constitute  the  Malpighian  bodies. 
These  are  in  every  respect  like  nodules  of  lymphoid 
tissue  found  elsewhere  and  show  the  same  reactions. 
Aside  from  them  the  tissue  between  the  fibrous 
trabeculse  belongs  entirely  to  the  splenic  pulp  and 
into  this  the  arteriole  passes,  to  branch  and  empty 
into  the  wide  venules,  which  form  a  sort  of  feltwork 
making  up  most  of  the  pulp.  In  the  interstices  be- 
tween these  venules  is  the  reticulum  of  the  pulp,  in 
which  are  held  great  numbers  of  free  cells.  For  our 
purposes  the  most  interesting  features  are  the  struc- 
ture of  the  walls  of  the  venules  and  the  nature  of  the 
cells  in  the  pulp  reticulum.  The  walls  of  the  venules 
(Fig.  397)  are  very  loose  in  texture,  so  that  it  seems 
extremely  easy  for  cells  to  wander  in  and  out.  The 
lining  endothelial  cells  are  quite  unlike  those  seen 
elsewhere,  and  instead  of  being  flat  and  polygonal 
and  uniformly  adherent  by  their  edges  to  the  edges 
of  the  next  cell,  they  are  greatly  elongated,  thick,  and  pointed  at  each  end, 
with  a  large  and  prominent  nucleus  which  projects  into  the  lumen  of  the 
venule.  In  many  places  the  cells,  which  lie  parallel  to  one  another  and 
lengthwise  in  the  venule,  have  their  nuclei  side  by  side,  so  that  between 
these  rows  of  nuclei  the  wall  is  formed  by  the  bodies  only  of  the  cells.  A 
cross-section  at  that  point  shows  only  the  unstained  bodies  of  the  cells, 
like  little  cogs  on  the  inside  of  the  venule,  while  at  another  level  the  venule 
may  be  lined  all  round  with  the  prominent  nuclei  (Fig.  398).  Outside  the 
venule  there  is  a  delicate  cylindrical  basketwork  of  elastic  fibrils;  whether 
there  is  any  other  structureless  membrane  between  is  still  disputed. 

The  reticulum  between  the  venules  shows  a  few  elongated  nuclei  which 


Fig.  397.— Diagram- 
matic drawing  of  sple- 
nic venule  showing  the 
elongated  endothelial 
cells,  the  structureless 
membrane,  and  the  cir- 
cular reticulum  fibres 
(Mollier). 


BLOOD-FORMING    ORGANS  803 

belong  to  the  cells  of  the  connective-tissue  framework.  In  chronic  passive 
congestion  and  similar  conditions  these  are  very  conspicuously  increased 
in  number  and  the  fibrous  reticulum  is  correspondingly  denser.  In  the 
meshes  there  are  great  numbers  of  red  corpuscles,  the  actual  quantity 
varying  with  different  conditions,  so  that  in  the  fibroid  spleen  of  chronic 
passive  congestion  there  are  hardly  any,  while  in  the  acute  splenic  tumor  of 
typhoid  fever  they  are  present  in  overwhelming  numbers.  The  majority 
of  the  other  cells  are  lymphocytes,  and  these  can  be  found  wandering 


J 


!'*L  ^ 


Fig.  398. — Section  of  spleen  showing  venules  with  endothelial  cells  and  network  of  pro- 
toplasmic and  reticulum  strands  (Mollier). 

through  the  walls  of  the  venules  as  well  as  within  the  venules  themselves. 
There  are  other  rather  larger  mononuclear  cells  ("pulp  cells "),  some  of 
which  reach  the  size  of  myelocytes.  It  is  indeed  not  uncommon  to  find 
both  eosinophile  and  neutrophile  myelocytes  in  small  numbers,  but  this 
is  not  a  feature  of  perfectly  normal  spleens.  Plasma  cells,  polymorpho' 
nuclear  neutrophile,  and  eosinophile  leucocytes  are  occasionally  present, 
but  are  in  very  small  numbers.  Thus  under  ordinary  circumstances  the 
cells  seem  to  be  essentially  of  the  lymphoid  type.  One  is  especially  im- 
pressed with  the  complete  ease  with  which  all  these  cells  pass  in  and  out 


§04  TEXT-BOOK   OF   PATHOLOGY 

through  the  walls  of  the  venules,  and  it  is  easy  to  understand  that,  under 
these  circumstances,  modifications  of  the  passing  blood  might  readily  change 
the  character  of  the  splenic  tissue. 

As  to  the  function  of  the  spleen,  it  is  even  yet,  after  centuries  of  ex- 
periment and  speculation  (Malpighi  attempted  to  discover  this  function 
by  extirpating  the  spleen  of  a  dog),  impossible  to  say  anything  very  defi- 
nite. It  is  generally  supposed  to  be  an  organ  active  in  destroying  injured 
blood-corpuscles  and  sifting  out  of  the  circulating  blood  the  debris  of  such 
cells,  the  haemoglobin  of  which  it  prepares  for  use  by  the  liver  in  the  for- 
mation of  bile-pigments.  This  idea  depends  chiefly  upon  the  finding  of 
pigment  in  the  spleen,  but  there  is  little  to  show  that  all  of  this  cannot  be 
equally  well  accomplished  after  the  spleen  is  removed.  It  is  stated  by 
many  that  the  spleen  is  an  active  blood-forming  agent,  and  Pearce  and  his 
co-workers  have  shown,  among  others,  that  there  is  a  temporary  anaemia 
after  splenectomy,  apparently  compensated  for  by  hyperplasia  of  bone- 
marrow  and  lymphoid  tissues.  Lymphocyte  production  is  perhaps  de- 
creased for  a  time  by  splenectomy,  but  is  soon  reinstated  (Murphy). 
Studies  of  the  blood  of  the  splenic  vein  as  contrasted  with  that  of  the  ar- 
tery have  been  referred  to,  but  they  are  open  to  criticism  and  give  very  con- 
tradictory results.  Since  these  methods  are  unsatisfactory,  it  is  difficult  to 
prove  that  the  spleen  actually  contributes  cells  to  the  blood  (although  that 
seems  probable),  because  new  cells  from  any  source  added  to  the  circulating 
blood  tend  to  lodge  in  its  pulp. 

The  Lymphoid  Tissue. — The  lymphoid  tissue  is  almost  universally 
distributed,  since  it  occurs  in  conspicuous  accumulations  throughout  the 
whole  digestive  tract,  in  the  walls  of  the  respiratory  tract,  in  lymph- 
glands  in  orderly  arrangement  everywhere  throughout  the  body,  in  the 
Malpighian  bodies  of  the  spleen,  and  in  inconspicuous  nodules  in  the  skin, 
bone-marrow,  and  other  organs  such  as  the  thyroid,  parathyroid,  adrenal, 
kidney,  liver,  pancreas.  The  lymphatic  channels  lead  its  cells  into  the 
blood  but  are  interrupted  by  others  of  its  masses  arranged  as  sieves  to 
retain  impurities.  Everywhere  the  architecture  of  the  lymphoid  tissue  is 
the  same  in  principle  although  slightly  more  elaborate  in  those  places  where 
lymph  sinuses  surround  the  more  compact  masses  of  lymphoid  tissue. 
There  is  in  this  tissue  a  reticulum  with  many  associated  cells  of  large  size 
and  pale  vesicular  nucleus  and,  very  commonly,  in  the  follicles  a  central, 
palely  staining  mass  of  large  cells  related  to  if  not  identical  with  the  retic- 
ulum cells.  These  have  been  looked  upon  since  Flemming's  work  as  the 
direct  antecedents  of  the  lymphoid  cells.  The  latter,  which  are  identical 
with  the  lymphocytes  of  the  blood,  are  accumulated  in  quantities  in  the 
meshes  of  the  reticulum.  That  they  wander  far  and  wide  in  the  crevices 
of  the  tissues  and  develop  there  into  larger  phagocytic  mononuclear  wan- 
dering cells  has  been  mentioned  in  a  previous  chapter.  That  the  ad- 
ventitial  cells  which  lurk  about  the  vessels,  and  the  plasma  cells  which 
with  other  lymphoid  cells  are  so  abundant  in  the  stroma  of  all  the  mucosae 


BLOOD-FORMING   ORGANS  805 

and  are  so  extensively  concerned  in  inflammatory  processes,  are  part  of 
this  same  group  has  been  made  clear  before. 

Accumulations  of  such  cells  in  unaccustomed  situations,  but  still  capable 
of  reproducing  themselves  and  increasing  their  numbers,  are  found  in 
various  conditions,  dependent  upon  stimuli  which  lead  to  the  hyperplasia 
of  the  original  lymphoid  tissue,  just  as  accumulations  of  the  cells  charac- 
teristic of  the  bone-marrow  may  occur  in  various  organs  when  that  tissue 
is  caused  to  undergo  hyperplasia.  Much  discussion  has  taken  place  as  to 
whether  such  lymphoid  and  myeloid  foci  are  due  to  the  transportation  of 
lymphoid  or  myeloid  cells  to  these  situations  or  to  an  autochthonous  or 
independent  origin  in  the  place  where  they  are  found  (Meyer  and  Heineke, 
Sternberg).  Probably  both  may  occur,  but  from  our  knowledge  of  the 
possibilities  of  the  transportation  of  cells  and  tissues  and  from  our  obser- 
vations of  the  way  in  which  such  cells  maintain  themselves  in  good  con- 
dition in  the  capillaries  of  foreign  organs,  it  seems  perhaps  more  probable 
that  in  most  cases  they  are  colonies  descended  from  emigrating  cells. 
Nevertheless,  when  bone  with  a  marrow  cavity  is  formed  in  a  calcined 
area  of  the  lung  or  aorta,  it  is  hard  to  escape  the  impressions  that  the 
myeloid  tissue  which  appears  in  such  a  marrow  cavity  is  due  to  a  recrudes- 
cence of  the  whole  process  of  bone  and  bone-marrow  formation. 

Other  lymphoid  collections  in  the  form  of  deep  red  lymph-nodes  are 
found  in  the  prevertebral  region,  neck,  thorax,  etc.  These  are  the  hcemo- 
lymph  nodes  whose  sinuses  contain  blood.  Aside  from  their  supposed 
function  of  destroying  injured  blood-corpuscles,  they  seem  to  behave  like 
other  lymph-nodes  (cf.  Warthin). 

EFFECT   OF  INJURIES  TO  THE  RED   CORPUSCLES  AND   THEIR   FORMA- 
TIVE  ORGANS 

It  is  naturally  impossible  that  there  should  be  any  extensive  alterations  in 
the  red  corpuscles  without  some  accompanying  changes  in  the  closely 
associated  white  corpuscles  and  vice  versa;  nevertheless  the  disturbances 
affect  so  predominantly  one  type  of  cell  or  the  other  that  we  may  confidently 
speak  of  these  diseased  conditions  with  regard  to  the  cells  chiefly  affected, 
referring  to  the  changes  in  the  others  as  accessory. 

In  the  normal  blood  the  number  of  red  corpuscles  per  cubic  millimetre 
is  about  five  million,  while  the  number  of  white  corpuscles  taken  together 
is  about  five  or  six  thousand.  Any  great  variation  from  these  numbers 
usually  indicates  the  influence  of  some  abnormal  condition.  An  increase 
in  the  number  of  red  corpuscles  or  polycythcemia  may  occur,  but  is  by  no 
means  so  common  as  the  opposite  effect,  a  decrease  in  their  number, 
bligocythcemia,  loosely  called  ancemia. 

Polycythsemia. — The  rapid  loss  of  fluid  from  the  body,  such  as  may 
occur  with  severe  diarrhoea  or  Asiatic  cholera  or  even  with  profuse  sweating, 
leads  to  such  inspissation  or  concentration  of  the  blood  as  to  raise  the 
number  of  red  corpuscles  per  cubic  millimetre  to  six  or  seven  million. 


806  TEXT-BOOK   OF   PATHOLOGY 

This  is  naturally  a  transitory  phenomenon  if  the  patient  survives,  since 
with  the  absorption  of  water  from  the  digestive  tract  the  blood  returns  to 
its  normal  concentration.  There  are  other  conditions,  however,  such  as 
chronic  cyanosis  from  cardiac  insufficiency  or  from  emphysema,  in  which 
there  is  a  lasting  polycythaemia  apparently  due  to  the  actual  need  for 
more  blood  to  nourish  and  oxygenate  the  tissues  properly.  This  is  espe- 
cially marked  when  the  chronic  passive  congestion  has  existed  since  in- 
fancy, as  in  congenital  heart  lesions.  In  persons  who  live  at  high 
altitudes  there  is  a  similar  increase  in  the  number  of  red  corpuscles  which 
appears  after  even  a  short  stay  in  the  mountains  or,  it  is  said,  after  or 
during  a  balloon  voyage.  More  interesting  still  and  more  difficult  to 
explain  are  those  cases  of  polycythcemia  rubra  (Osier),  or  erythrcemia,  in 
which  the  blood  becomes  actually  thick  and  viscous  from  the  presence 
of  such  enormous  numbers  of  red  corpuscles  (10  millions  or  more).  There 
is  increase  in  the  total  volume  of  blood,  cardiac  hypertrophy,  great  en- 
largement of  the  spleen,  and  hyperplasia  of  the  bone-marrow.  The  cause 
is  quite  unknown  and  the  patients  go  on  to  die  of  haemorrhage  or  of  some 
intercurrent  infection.  It  is  a  very  curious  phenomenon,  perhaps  analogous 
to  leukaemia,  since  in  spite  of  the  fact  that  the  blood-vessels  are  everywhere 
turgid  with  blood,  the  erythroblastic  tissues  of  the  bone-marrow  are  found 
to  be  in  process  of  active  hyperplasia  and  blood  formation,  as  though 
behaving  quite  independently  of  the  needs  of  the  blood  which  usually 
govern  them. 

Anaemia. — On  the  other  hand,  agencies  which  destroy  and  diminish  the 
red  corpuscles  are  extremely  common,  and  their  action  far  more  easily 
understood. 

Decrease  in  the  number  of  red  corpuscles  in  the  blood  may  be  brought 
about  in  a  very  great  variety  of  ways  which  perhaps  fall  into  the  following 
divisions : 

1.  Actual  loss  of  blood  through  haemorrhage. 

2.  Destruction  of  blood  and  injury  of  the  bone-marrow  by  poisons 
which  are  often  those   produced   by  bacteria  or    other  parasites,  often 
chemical  substances  taken  as  drugs  or  absorbed  by  workers  in  certain 
industries.     Long-continued  infections  and  the   presence    of   malignant 
tumors  are  factors  especially  likely  to  bring  about  such  results. 

3.  A  peculiar,  sharply  denned  disease  known  as  pernicious  ancemia,  in 
which,  despite  the  most  active  efforts  toward  regeneration,  the  red  cor- 
puscles continue  to  decrease  in  number. 

4.  Osteosclerotic  Ancemia.— The  attack  may  be  more  serious  in  that  it  is 
directed  against  the  bone-marrow  itself.     While  it  is   difficult  to  show 
that  this  is  so  in  the  case  of  poisons  and  infections  which  may  also  destroy 
the  circulating  red  corpuscles,  it  is  quite  clear  in  those  cases  in  which 
metastases  from  cancers  of   the  prostate  or  breast    occupy  the  whole 
marrow  cavity  of  every  bone  to  the  mechanical  exclusion  of  bone-marrow, 
or  even   in  the  cases  of   leukaemia   in  which  the  whole  of   the  bone- 


BLOOD-FORMING   ORGANS  807 

marrow  is  given  over  to  the  production  of  the  forerunners  of  white 
corpuscles,  so  that  the  erythroblastic  tissue  is  crowded  out  of  existence. 
In  such  cases  there  is  extreme  anaemia  in  spite  of  efforts  toward  extra- 
medullary  blood  formation. 

Secondary  Anaemias. —  1.  Post-hcemorrhagic  anaemias  depend  in  their 
severity  upon  the  extent  of  the  haemorrhage  and  upon  the  frequency  with 
which  it  is  repeated.  A  single  great  haemorrhage  is  followed  by  a  series 
of  symptoms  due  to  the  incomplete  filling  of  the  blood-vessels, — fainting, 
nausea,  weakness,  collapsing  pulse,  etc., — but  the  concentration  of  the 
blood  and  the  proportion  of  corpuscles  immediately  after  the  haemorrhage 
is  naturally  exactly  what  it  was  before.  Very  rapidly,  however,  fluid 
passes  from  the  tissues  or  from  the  digestive  tract  to  dilute  the  blood 
and  make  up  its  quantity.  Within  a  few  days  after  such  haemorrhage 
the  fatty  bone-marrow  of  the  long  bones  becomes  so  filled  with  newly 
formed  cells  that  the  fat  is  crowded  out  and  the  marrow  assumes  a  red 
color  and  cellular  consistency.  In  such  marrow  there  are  found  abundant 
nucleated  red  cells  rapidly  giving  rise  to  red  corpuscles,  and  also  quanti- 
ties of  myelocytes;  this  is  not  followed,  however,  by  the  pouring  out  of 
any  extraordinary  number  of  leucocytes,  although  the  proportion  of  these 
cells  in  the  blood  is  somewhat  increased. 

Such  extensive  haemorrhages  occur,  of  course,  in  mechanical  injuries 
in  which  large  blood-vessels  are  cut  or  torn,  but  they  also  occur  in  advanced 
pulmonary  tuberculosis  from  the  erosions  of  a  branch  of  the  pulmonary 
artery,  in  ulcers  of  the  stomach  or  in  cases  of  cirrhosis  of  the  liver  in  which 
there  is  a  rupture  of  the  dilated  veins  in  the  oesophagus,  in  the  rupture  of 
an  extra-uterine  pregnancy,  or  in  ordinary  pregnancy  at  childbirth.  But 
even  more  profound  degrees  of  anaemia  may  be  produced  by  slighter  but 
frequently  repeated  haemorrhages,  such  as  those  which  come  from  re- 
current nose-bleed,  bleeding  haemorrhoids,  and  ulcerated  submucous  myo- 
mata  of  the  uterus,  and,  possibly,  in  the  case  of  certain  intestinal  para- 
sites which  suck  the  blood,  although,  as  has  already  been  said,  this  is  of 
somewhat  doubtful  occurrence  in  human  beings  and  the  anaemia  caused  by 
these  parasites  seems  rather  due  to  a  poison  which  they  produce. 

2.  Destruction  of  the  blood-corpuscles  (haemolysis)  may  be  caused  by  a 
great  variety  of  chemical  substances,  of  which  ricin  and  benzol  have  already 
been  mentioned.  Nitrobenzol,  toluylenediamine,  lead,  and  a  host  of  other 
substances  have  a  similar  effect.  Particularly  interesting  are  the  specific 
haemolytic  sera  which  have  been  experimentally  produced,  and  we  are 
even  yet  very  imperfectly  informed  as  to  the  part  which  similar  elusive 
substances  may  play  in  human  pathology.  There  are  many  bacteria 
which  produce  strong  haemolytic  poisons,  and  acute  infections  are  there- 
fore common  causes  of  intense  anaemia.  For  example,  the  haemolytic 
streptococci  can  cause  the  destruction  of  a  great  proportion  of  the  blood- 
corpuscles  in  a  brief  period,  and  even  the  less  actively  haemolytic  S.  viridans 
produces  an  endocarditis  and  general  infection  which  runs  its  course  with 


808  TEXT-BOOK   OF   PATHOLOGY 

the  development  of  extreme  grades  of  anaemia.  The  anaemia  which  ac- 
companies typhoid  fever,  chronic  tuberculosis,  and  syphilis  is  apparently 
due  to  similar  processes,  while  in  chronic  nephritis  and  the  cachexias  which 
accompany  the  presence  of  tumors,  especially  perhaps  when  they  are 
ulcerated,  the  nature  of  the  poison  is  more  difficult  to  ascertain. 

The  extreme  anaemia  brought  about  by  malaria  is  in  great  part  due  to 
the  mechanical  destruction  of  the  corpuscles  by  the  parasites,  but  in  the 
case  of  bothriocephalus  and  uncinaria  it  appears  that  a  recognizable 
haemolytic  material  can  be  extracted  from  the  worms  and  that  this  is 
probably  diffused  into  the  blood  and  tissues. 

Such  anaemias,  which  together  with  those  caused  by  haemorrhage,  are 
often  called  secondary,  since  their  cause  is  known,  resemble  one  another 
closely  in  the  character  of  the  blood  changes.  The  red  corpuscles  may  be 
reduced  to  less  than  a  million  per  cubic  millimetre,  and  tend  to  be  rather 
small  and  pale,  or  poor  in  haemoglobin,  and  show  some  irregularities  in 
size  or  form.  Normoblasts  are  present  in  the  circulation,  often  appearing 
in  great  numbers,  at  intervals  corresponding  with  what  seem  to  be  crises 
of  activity  in  the  bone-marrow.  Megaloblasts  are  seldom  seen.  There  is 
nearly  always  an  accompanying  leucocytosis  except  in  the  case  of  such 
diseases  as  typhoid  fever  and  malaria,  in  which  the  leucocytes  are  de- 
creased in  number. 

The  changes  in  the  bone-marrow  are  those  already  described  as  charac- 
teristic of  hyperplasia,  which  appears  in  response  to  the  dearth  of  red 
cells,  but  associated  with  similar  hyperplastic  changes  in  the  myelocytic 
group  (Fig.  399).  When,  however,  the  anaemia  is  caused  by  some  poison 
which  attacks  the  bone-marrow  itself,  the  reparatory  changes  are  even 
more  striking,  as  shall  be  detailed  later.  In  the  spleen,  which  may  be 
somewhat  enlarged,  one  finds  no  especial  change  in  the  Malpighian  bodies, 
but  in  the  splenic  pulp,  myelocytes,  erythroblastic  cells,  and  other  elements 
corresponding  to  those  of  the  bone-marrow  are  to  be  found.  Similarly  in 
the  capillaries  of  the  liver,  and  sometimes  outside  them  in  the  liver  sub- 
stance itself,  such  groups  of  cells  may  occur.  The  lymph-glands  and 
lymphoid  tissues  are  practically  unaffected  in  secondary  anaemias.  Scat- 
tered haemorrhages  are  common,  and  oedema  of  the  ankles  or  of  the  tissues 
under  the  eyes  forms  a  characteristic  accompaniment.  Other  anatomical 
changes,  aside  from  the  pallor  of  the  organs  in  which  little  or  no  blood 
pigment  is  deposited,  are  inconstant.  Very  often  there  is  an  accumulation 
of  fat  globules  in  the  heart  muscle  and  in  the  kidneys.  The  disabilities 
produced  by  such  anaemia  are  those  consequent  upon  diminution  of  the 
bulk  of  the  blood  and  of  its  oxygen-carrying  capacity.  Weakness,  faint- 
ness,  etc.,  have  been  mentioned,  but,  curiously  enough,  whether  from  the 
increased  efforts  of  the  heart  and  more  rapid  circulation,  or  other  cause, 
the  respiratory  interchange  is  not  decreased  and  the  nitrogenous  output 
not  characteristically  altered. 

A  secondary  anaemia  is  the  banal  result  of  all  sort  of  injuries  which 


BLOOD-FORMING   ORGANS 


809 


destroy  the  blood-corpuscles,  just  as  cardiac  decompensation  may  arise 
from  the  most  varied  injuries  to  the  heart.  The  changes  in  the  bone- 
marrow  are  the  ordinary  or  routine  efforts  of  the  body  to  repair  this  injury, 
just  as  new  epithelium  grows  to  cover  a  defect.  We  need  not  feel  surprised, 
therefore,  in  finding  the  type  of  the  reparatory  reaction  the  same  in  all. 
If  we  can  remove  the  cause  by  stopping  hemorrhage,  by  expelling  para- 
sites, by  extirpating  tumors  or  withdrawing  chemical  poisons,  the  rapid 


®c©  ©* 


Fig.  399. — Bone-marrow  in  secondary  anaemia,  showing  intense  regenerative  hyper- 
plasia:  (a)  Myelocytes;  (6)  normoblasts  with  occasional  megaloblasts;  (c)  eosinophile 
myelocytes;  (d)  lymphoid  cells. 

production  of  red  corpuscles  in  the  bone-marrow  proceeds  until  the  anaemic 
circulation  once  more  has  its  normal  amount  of  normal  blood,  after  which 
it  quiets  down  and  the  cellular  marrow  resumes  its  fatty  character  in  the 
long  bones. 

Pernicious  Anaemia. — This,  although  so  difficult  to  distinguish  from  other 
types  of  severe  anaemia  by  any  single  criterion,  is  quite  obviously  an  indepen- 
dent and  definite  disease  which  we  recognize  with  certainty,  and  of  which  we 
can  foretell  the  course  as  surely  as  we  can  in  a  case  of  typhoid  fever.  It 


TEXT-BOOK   OF   PATHOLOGY 

may  be  said  that  nothing  is  known  of  its  cause  although  numerous  theories 
have  been  put  forward,  but  the  complex  of  changes  in  the  blood,  the 
anatomical  changes  in  the  organs,  and  the  symptoms  and  the  course  of  the 
disease  are  monotonously  uniform.  From  the  fact  that  we  have  not  dis- 
covered its  cause  it  has  often  been  called  primary  or  essential  anaemia,  in 
contrast  with  secondary  anaemias,  but  it  seems  by  no  means  impossible 
that  when  we  presently  discover  this  cause  and  find  that  its  removal 
allows  the  otherwise  progressive  anaemia  to  be  repaired  there  will  be  no 
justification  for  such  a  name  as  primary  anaemia.  That  it  is  different  from 
the  ordinary  secondary  anaemias  is  shown  at  once,  however,  by  the  con- 
dition of  the  blood,  which  is  simulated  closely  only  in  the  bothriocephalus 
anaemia.  Briefly,  there  is  extreme  decrease  in  the  number  of  red  cor- 
puscles, each  of  which,  however,  contains  an  abnormally  large  amount  of 
haemoglobin,  so  that,  sometimes,  in  spite  of  the  oligocythaemia,  the  haemo- 
globin of  the  whole  blood  is  not  greatly  lowered.  The  corpuscles  are  very 
irregular  in  form  (poikilocytosis)  and  in  size  (anisocytosis),  there  being 
not  only  small  forms  but  very  large  or  giant  corpuscles,  also  tinged  deeply 
with  haemoglobin.  The  presence  of  these  large  forms  together  with  the 
high  color  index  is  distinctive,  since  these  do  not  occur  in  secondary  anaemias 
where  the  color  index  is  low.  Nucleated  red  corpuscles  are  found  some- 
times in  large  numbers  and  megaloblasts  are  often  abundant.  Indeed, 
the  finding  of  megaloblasts  in  the  circulating  blood  is  much  relied  on  in 
the  diagnosis  of  this  disease.  The  leucocytes  are  decreased  in  number 
and  there  maybe  only  1500-2000  per  cubic  millimetre.  Since  the  lymphoid 
structures  in  the  body  are  unaltered,  the  percentage  of  lymphocytes  rises 
and  they  may  assume  a  proportion  of  as  much  as  60  per  cent.  The  great 
decrease  is  in  the  polymorphonuclear  neutrophiles.  Myelocytes  and 
myeloblasts  are  occasionally  found.  The  decrease  in  the  red  cells  is 
often  such  as  to  give  the  blood  a  peculiar  watery  appearance,  although 
the  high  color  index  tends  to  keep  it  red.  In  actual  numbers  the  red  cells 
may  sink  far  below  one  million.  (For  details  of  the  blood  changes  consult 
the  works  of  Cabot,  Naegeli,  Lazarus.)  This  distinctive  alteration  of  the 
blood  is  perhaps  not  enough  to  mark  out  pernicious  anaemia  as  an  inde- 
pendent disease,  but  the  occurrence  in  middle-aged  people,  the  complete 
lack  of  any  recognizable  cause,  the  continued  good  nutrition  of  the 
patient,  the  progressive  deepening  of  the  anaemia  with  intermissions  during 
which  great  improvement  occurs,  the  yellow  pigmentation  of  the  skin,  and 
the  practically  uniform  fatal  outcome  are  enough  to  establish  its  identity. 
At  autopsy  the  body  is  found  well  nourished,  the  subcutaneous  fat  and 
indeed  all  the  fat  tinged  a  rather  deep  yellow.  The  muscles  are  dark  red. 
The  diminution  in  the  amount  of  blood  is  striking,  and  there  may  be  found 
minute  ecchymoses  and  local  cedemas,  especially  in  the  lungs.  The  heart 
is  soft,  and  through  the  myocardium  there  shines  the  yellow  streaking 
which  indicates  the  presence  of  much  fat  in  the  muscle-fibres.  The 
liver,  cortex  of  the  kidneys,  heart  muscle,  and  the-  lungs  are  pigmented 


BLOOD-FORMING    ORGANS  811 

with  iron-containing  blood-pigment,  even  to  the  extent  of  assuming  a 
rather  distinct  chestnut-brown  color.  Immersed  in  ferrocyanide  of  potas- 
sium and  weak  hydrochloric  acid,  they  become  gray-blue  in  color.  The 
mucosa  of  the  stomach  is  often  atrophic  and  smooth  and  there  may  be 
achylia.  Indeed,  many  writers  have  thought  this  to  be  in  some  way  the 
cause  of  the  disease,  but  the  evidence  is  insufficient  to  uphold  this  view. 
In  the  mouth,  too,  there  are  often  lesions  of  the  mucosa  of  an  inflammatory 
character  associated  with  haemorrhages  which  cause  pain,  especially  when 
acids  are  taken  into  the  mouth.  On  the  tongue  there  are  brownish  patches 


Fig.  400. — Bone-marrow  in  pernicious  anaemia.  Normoblasts  and  numerous  mega- 
loblasts  occur,  together  with  many  neutrophile  myelocytes.  There  are  phagocytic  cells 
and  some  finely  granular  pigment. 

at  the  site  of  haemorrhages.  Hunter  has  especially  emphasized  this  glossitis 
and  regards  it  as  the  primary  lesion,  or  portal  of  entry  of  the  causative 
agent  of  the  disease.  The  blood-forming  organs  show  changes  which  are 
primarily  distinctive  of  the  reaction  to  a  severe  anaemia. 

The  bone-marrow  is  dark  red  and  rather  gelatinous.  Its  fat  is  replaced 
by  the  abundant  hyperplastic  tissue  which  in  general  resembles  that  found 
in  secondary  anaemias.  The  character  of  this  can  be  conveyed  better  by 
a  drawing  than  a  description  (Fig.  400).  There  is  extensive  new  formation 
of  myelocytes  and  myeloblasts.  Newly  formed  lymphoid  cells  are  present, 
and  there  are  abundant  groups  or  islands  of  erythroblastic  cells  among 


812  TEXT-BOOK   OF    PATHOLOGY 

which  megaloblasts  are  conspicuous.  Ehrlich  made  the  statement  that 
the  presence  of  megaloblasts  in  the  hyperplastic  bone-marrow  was  peculiar 
to  pernicious  anaemia  and  that  it  indicated  a  return  to  a  distinctly  em- 
bryonic type  of  erythrocyte  formation,  in  sharp  contrast  with  the  normal 
formation,  which  is  by  way  of  the  normoblasts.  The  appearance  of  megalo- 
blasts in  the  blood  and  of  megalocytes  or  large,  deeply  colored,  non-nucleated 
red  corpuscles  was  equally  characteristic,  and  one  must  regard  pernicious 
anaemia  as  a  condition  in  which  there  was  being  formed  a  different  sort  of 
blood  derived  largely  from  abnormal  cells,  the  megaloblasts,  proper  to 
embryonic  life  but  obsolete  in  adult  life.  Nsegeli  and  Lazarus  and  most 


Fig.  401. — Bone-marrow  in  pernicious  ansemia.     An  island  or  group  of  megaloblasts 
with  adjacent  myelocytes  and  a  few  normoblasts. 

German  writers  have  accepted  this  view  of  the  obsolete  nature  of  megalo- 
blasts and  the  consequent  peculiarity  of  the  bone-marrow  in  pernicious 
anaemia.  Certainly  the  presence  of  megaloblasts  in  the  circulating  blood 
is  indicative  of  very  severe  anaemia,  and  although  these  cells  occur  in 
other  forms  of  anaemia,  they  are  far  more  common  in  pernicious  ansemia. 
But  any  one  can  convince  himself  of  the  presence  of  megaloblasts  in  any 
hyperplastic  bone-marrow,  and  the  experiments  of  Bunting,  in  which,  by 
repeatedly  injuring  the  bone-marrow  with  ricin,  he  produced  an  anaemia 
practically  identical  with  pernicious  anaemia,  showed  further  that  in  the 
bone-marrow  there  were  quantities  of  megaloblasts  which  formed  the 


BLOOD-FORMING   ORGANS  813 

centres  of  erythrogenetic  islands.  They  formed  red  corpuscles  by  de- 
velopment through  the  intermediate  normoblasts  which  lay  peripherally. 
It  is  Bunting's  idea  that  this  is  practically  the  normal  relation,  and  that 
the  erythrocytes  are  given  off  peripherally,  but  that  in  the  case  of  such 
serious  injury  to  the  bone-marrow  as  may  be  produced  with  ricin  or  as 
exists  in  pernicious  anaemia,  not  only  the  more  peripheral  normoblasts, 
but  the  central  megaloblasts  themselves,  may  be  hurriedly  discharged. 
It  is  quite  true  that  in  the  bone-marrow  of  pernicious  anaemia  it  is  ex- 
ceedingly difficult  to  outline  any  such  groups  of  cells,  since  they  are  in- 
timately intermingled  with  adjacent  groups  of  other  sorts  of  cells.  Never- 
theless, the  relative  concentration  which  can  be  made  out,  and  the  analogy 
with  the  perfectly  clear-cut  islands  of  regenerating  cells  in  bone-marrow 
made  aplastic  with  benzol,  leads  us  to  believe  that  Bunting's  conception 


Fig.  402. — Pernicious  anaemia.    Lymph-gland  with  phagocytes  in  the  peripheral  sinus, 

containing  red  corpuscles. 

is  a  true  one  (Fig.  401).  Numerous  large  phagocytic  cells  are  found  in 
the  sections,  loaded  with  red  corpuscles  and  with  the  shadows  of  such 
corpuscles,  together  with  occasional  fragments  of  nucleated  cells.  These 
have  been  described  by  Sternberg  and  are  conspicuous  also  in  the  spleen 
and  in  the  hsemolymph  glands  (Fig.  402).  They  at  least  indicate  the 
activity  of  blood  destruction. 

The  spleen  is  usually  slightly  enlarged,  and  in  some  cases,  but  by  no 
means  all,  shows  a  rusty  tint  on  its  cut  surface.  The  Malpighian  bodies 
can  be  seen  plainly  and  the  splenic  pulp  is  not  very  greatly  increased 
in  bulk.  Occasionally  the  organ  is  larger  and  firmer  than  normal,  the 
increase  being  evidently  in  the  splenic  pulp.  Microscopically  there  is 
strikingly  little  change  from  the  normal  (Fig.  403).  The  venules  are 
clearly  outlined  with  intact  endothelial  cells;  the  intervening  reticulum  of 


814 


TEXT-BOOK    OF    PATHOLOGY 


the  pulp  is  more  abundantly  loaded  with  red  corpuscles  than  in  the  normal, 
and  many  of  these  appear  to  be  disintegrating.  The  lymphoid  cells  which 
normally  occupy  this  position  seem  to  be  relatively  few.  Both  within  and 
between  the  venules  there  are  moderate  numbers  of  large  phagocytic  cells 
with  debris  of  red  corpuscles  in  their  protoplasm.  The  myeloid  change 
described  by  Meyer  and  Heineke  and  others  is  by  no  means  so  conspicuous 
as  one  might  be  led  to  expect  from  the  severity  of  the  anaemia;  indeed, 
it  is  necessary  to  search  through  the  sections  to  find  any  myelocytes,  and 


Fig.  403. — Pernicious  anaemia.     Spleen  showing  distorted  red  corpuscles  between  the 
venules  and  small  group  of  myelocytes  in  the  reticulum  of  the  pulp. 

then  they  occur  only  in  small  groups  of  two  or  three,  both  inside  and  out- 
side the  venules.  Many  of  them  are  found  in  the  margins  of  the  Mal- 
pighian  bodies  or  in  the  walls  of  the  larger  blood-vessels.  Nucleated  red 
cells  are  also  inconspicuous,  but  are  occasionally  found  in  the  splenic  pulp. 
In  reality,  the  alterations  of  the  spleen  in  severe  secondary  anaemias  may 
be  much  more  marked  than  in  this  condition,  both  with  regard  to  the 
increased  number  of  wandering  cells  in  the  pulp  and  the  accumulation  of 
myeloid  cells,  but  that  is  probably  to  be  explained  by  the  influence  of  the 
infectious  or  toxic  process  which  stands  as  the  cause  of  such  secondary 


BLOOD-FORMING    ORGANS  815 

anaemia  and  which  in  itself  may  produce  changes  in  the  spleen  (cf.  acute 
splenic  tumor  in  infectious  diseases). 

The  lymph-glands  show  no  striking  alterations,  but,  as  stated  above, 
the  hsemolymph  glands  contain  in  their  blood-filled  sinuses  many  of  the 
large  phagocytic  cells  loaded  with  red  corpuscles.  The  immunity  of  the 
lymphoid  tissue  from  alteration  in  pernicious  anaemia  is  evident  in  some 
cases  in  the  presence  of  a  slight  degree  of  lymphoid  hyperplasia  in  the 
bone-marrow  and  in  the  relative  increase  in  the  numbers  of  lymphoid 
cells  in  the  blood. 

The  liver  is  said  by  Meyer  and  Heineke  to  show  accumulations  of 
myelocytes  and  erythroblastic  cells.  Much  more  striking  is  the  fine,  dust- 
like  sprinkling  of  iron-containing  pigment  in  the  liver-cells  themselves 
(Fig.  52,  page  124).  This  pigment,  which  is  readily  colored  blue  by  the 
ferrocyanide  method,  lies  about  the  fine  bile  canaliculi  in  the  centre  of 
each  strand  of  liver-cells.  There  may  be  some  pigment  also  in  the  endo- 
thelial  cells  of  the  capillaries  but  it  is  far  less  noticeable. 

Another  lesion  characteristic  of  pernicious  anaemia  is  found  in  the 
white  matter  of  the  spinal  cord.  Especially  in  the  posterior  tracts  there 
occur  focal  areas  of  degeneration  of  the  nerve-fibres  and  neuroglial  scar- 
ring which,  by  interrupting  these  tracts,  produce  irregular  ascending  sec- 
ondary degenerations.  These,  described  by  Lichtheim,  Minnich,  Nonne, 
Milne,  and  others,  bring  about  very  distinct  sensory  disturbances  during 
life,  sometimes  amounting  to  ataxic  phenomena  closely  resembling  those 
of  tabes. 

On  the  whole,  taking  into  consideration  the  various  lesions  here  de- 
scribed, it  appears  that  the  autopsy  findings  in  pernicious  anaemia  are  so 
constant  and  peculiar  that  a  diagnosis  can  be  made  with  security  from  them 
alone,  but  when  taken  together  with  the  typical  course  of  the  disease  and 
the  alterations  of  the  blood,  there  remains  no  doubt  as  to  the  independence 
of  the  disease.  It  seems  reasonably  certain,  too,  that  before  long  some 
simple  explanation  of  the  pathogenesis  of  this  disease  will  be  found. 

Some  mention  should  be  made  of  the  rather  rare  cases  of  aplastic  ancemia 
which  is  practically  identical  with  pernicious  anaemia  except  in  that  it 
runs  a  more  precipitate  downward  course  to  the  fatal  result  because  no 
effort  toward  regeneration  of  the  blood  takes  place  in  the  bone-marrow. 
Instead,  the  marrow  of  the  long  bones  is  found  at  autopsy,  in  spite  of  the 
most  profound  anaemia,  to  be  entirely  yellow  and  fatty  without  any  of 
the  cell  hyperplasia  seen  in  the  ordinary  cases. 

In  some  degree  allied  to  pernicious  anaemia,  although  in  most  respects  essentially 
different,  is  the  curious  affection  hcemochromatosis.  This  has  been  referred  to  in  connection 
with  pigmentation  and  perhaps  also  in  other  associations.  Inasmuch  as  it  is  not  a 
form  of  anaemia  it  has  no  place  here,  but  the  deposition  of  blood  pigment  is  so  striking 
that  it  is  unconsciously  associated  with  that  just  described  in  pernicious  anaemia.  As 
a  result  of  some  process  of  unknown  nature,  and  without  great  blood  destruction,  the 
organs  become  laden  with  hsemosiderin  and  haemofuscin.  Incidentally  there  is  injury 


816 


TEXT-BOOK   OF   PATHOLOGY 


and  scarring  of  the  liver  and  pancreas,  and  usually  diabetes.  All  these  organs  assume 
a  bright  chestnut-brown  color.  Whether  the  accumulation  of  iron  is  due  to  some  in- 
ability of  the  mucosa  of  the  colon  to  excrete  the  usual  excess,  remains  to  be  determined. 

Another  form  of  anaemia  which  may  be  touched  upon  is  that  which 
accompanies  the  so-called  hcemolytic  icterus.  It  is  either  congenital  or 
arises  later  in  life  and  appears  to  be  due  to  an  excessive  fragility  of  the  red 


Ph. 


N.M. 


E.M. 


E.M. 


Fig.  404. — Myeloid  alteration  of  the  splenic  pulp  in  osteosclerotic  anaemia  from 
destruction  of  bone-marrow  by  metastases  from  a  carcinoma  of  the  prostate.  N.  M., 
Neutrophile  myelocytes;  E.  M.,  eosinophile  myelocytes;  Ph.,  pigment  holding  phagocytic 
cells. 

corpuscles  which,  in  liberating  their  haemoglobin,  furnish  the  material  for  the 
production  of  j  aundice.  There  is  no  obstruction  of  the  bile-passages ,  but  the 
spleen  becomes  greatly  enlarged  and  filled  with  red  corpuscles.  It  is  said 
that  removal  of  the  spleen  brings  the  disease  to  a  stop  and  that  the  cor- 
puscles recover  their  normal  resistance.  No  adequate  explanation  is 
offered  for  this  any  more  than  for  the  similar  beneficial  effect  of  extirpation 


BLOOD-FORMING   ORGANS 


817 


of  the  spleen  in  pernicious  anaemia,  which  seems  to  relieve  the  patient  for 
a  time. 
Anaemia  Following  Mechanical  Destruction  of  the  Bone-marrow.—- 

Although  the  technically  impossible  experimental  destruction  of  all  the 
bone-marrow  has  often  been  discussed,  the  only  light  on  such  a  condition 
is  furnished  by  those  cases  in  which  a  tumor,  such  as  a  carcinoma  of  the 
prostate  or  breast,  metastasizes  to  the  marrow  cavity  of  practically  every 
bone  in  the  body,  and  there,  by  occupying  space  in  the  rigidly  enclosed 


Fig.  405. — Osteosclerotic  ansemia  following  destruction  of  bone-marrow  by  metastatic 
carcinoma.  Clumps  of  myelocytes  in  the  liver  capillaries.  The  endothelial  cells  are 
intact. 

cavity,  destroys  the  bone-marrow.  There  is  much  uniformity  in  these 
cases,  and  we  have  recently  studied  two  in  which  literally  every  bone  was 
found  to  be  completely  occupied  by  the  tumor.  The  cavities  of  all  the 
long  bones  were  filled  with  a  solid  tissue,  for  these  tumors  cause  the  forma- 
tion of  enormously  thick  laminae  of  new  cancellous  bone  which  lie  in  a 
close  network  and  contain  in  their  meshes  only  the  epithelial  cells  of  the 
tumor.  The  ribs,  vertebrae,  pelvic  and  other  bones  were  also  solidly  in- 
filtrated by  the  bone-forming  tumor.  The  effect  was  to  produce  the  most 
53 


818 


TEXT-BOOK   OF   PATHOLOGY 


profound  anaemia  in  which  the  red  blood-corpuscles  sank  to  600,000  per 
c.mm.  There  was  a  parallel  reduction  of  the  granular  leucocytes.  It  is 
in  such  cases  that  the  greatest  need  arises  for  extramedullary  blood  for- 
mation and,  indeed,  they  furnish  the  best  and  least  complicated  examples 
of  myeloid  change  in  the  spleen  and  liver.  The  development  of  blood  in 
the  spleen  and  liver  in  one  of  these  cases  is  shown  in  Figs.  404  and  405. 

A  similar  effect,  as  far  as  the  red  corpuscles  are  concerned,  is  produced 
by  the  crowding  out  of  the  erythrogenic  tissues  by  the  enormous  over- 
growth of  myeloid  cells  in  myeloid  leukaemia  and  of  the  lymphoid  cells 
in  lymphoid  leukaemia.  Of  course  the  destruction  is  by  no  means  so  com- 
plete in  these  cases,  and  the  existence  of  the  myeloid  change  in  other 


Fig.  406. — Spleen  in  Banti's  disease. 

tissues  is  less  clearly  defined  since  they  are  already  overwhelmed  with  the 
hyperplastic  elements  from  the  bone-marrow  itself. 

Banti's  Disease.— There  is  a  form  of  anaemia  with  great  swelling  of  the 
spleen  and  usually  accompanied  by  haemorrhages  which  has  long  been 
described  by  clinicians  as  ancemia  splenica.  Banti  has  studied  these  cases 
anatomically  and  his  name  is  associated  with  the  complex  of  lesions,  al- 
though it  is  claimed  by  others  that  not  all  the  cases  progress,  as  Banti 
describes  them,  to  a  stage  in  which  cirrhosis  of  the  liver  and  ascites  are 
features.  Nothing  is  known  of  the  cause:  the  spleen  becomes  greatly 
enlarged  and  there  is  a  secondary  type  of  anaemia  intensified  by  haemor- 
rhages from  the  stomach.  There  may  or  may  not  be  cirrhosis  of  the  liver, 
but  there  is  a  peculiar  and  specific  type  of  alteration  in  the  spleen  which  is 
not  like  that  due  to  chronic  passive  congestion  nor  even  like  the  one  asso- 


BLOOD-FORMING   ORGANS 


819 


elated  with  forms  of  cirrhosis  of  the  liver  which  do  not  obstruct  the  portal 
blood-stream  (Fig.  406).  It  may  reach  a  weight  of  1  to  3  kg.,  and  during 
life  is  distended  with  blood.  The  veins  are  enormously  enlarged  and 
numerous  huge  collateral  channels  appear,  especially  in  adhesions  between 
the  spleen,  the  stomach,  and  the  diaphragm.  There  is  often  thrombosis 
of  the  main  splenic  vein,  a  condition  which  I  have  seen  three  times.  When 
the  spleen  is  extirpated,  it  shrinks  and  collapses  with  the  escape  of  blood 


Fig.  407. — Portion  of  spleen  and  liver  from  case  of  Banti's  disease.    Spleen  fibrous  and 
elastic.     Extreme  cirrhosis  of  the  liver. 

and  becomes  a  rather  flabby  elastic  mass  which,  on  section,  shows  a  grayish- 
pink  translucent  cut  surface  that  sinks  a  little  below  the  capsule  (Fig. 
407).  The  Malpighian  bodies  are  not  visible.  Microscopically  there  is 
found  to  be  moderate  atrophy  and  scarring  of  the  Malpighian  bodies,  and 
in  the  pulp  the  venules  are  separated  by  quite  abundant  loose  fibrous 
tissue  in  which  there  remain  very  few  of  the  original  pulp  cells.  The  whole 
spleen  is  thus  impoverished  in  cells  and  has  assumed  an  empty  appearance, 


820  TEXT-BOOK  OF  PATHOLOGY 

being  composed  essentially  of  fibrous  tissue  in  which  the  venules  are  em- 
bedded. The  liver,  in  the  late  stages,  is  said  by  Banti  to  become  distinctly 
cirrhotic.  In  our  rather  numerous  cases  it  has  frequently  appeared  normal 
and  in  few  instances  has  shown  advanced  cirrhosis.  The  bone-marrow  is 
moderately  hyperplastic.  We  are  thus  very  ignorant  of  this  condition, 
but  it  is  quite  clear  that  it  is  a  definite  and  constantly  recurring  disease 
and  that  it  is  easy  to  recognize  the  typical  anatomical  changes.  Ex- 
tirpation of  the  spleen  appears  to  cure  the  whole  malady,  if  it  does  not 
kill  the  patient  through  uncontrollable  haemorrhage  at  the  operation. 

There  is  another  type  of  splenomegaly  known  as  Gaucher's  splenomegaly 
in  which  a  totally  different  condition  exists.  Details  must  be  read  in  the 
papers  of  Bovaird,  Brill,  Mandelbaum,  Risel,  and  others,  but  the  essential 
facts  are  that  it  occurs  in  families,  affecting  several  children,  that  it  pro- 
duces great  enlargement  of  the  spleen  without  enlargement  of  the  lymph- 
glands,  jaundice,  or  ascites.  There  is  no  change  in  the  blood,  but  in  the 
spleen,  lymph-glands,  bone-marrow,  and  liver  there  are  giant  multinuclear 
phagocytic  cells  the  origin  of  which  has  been  much  disputed.  Marchand 
and  Risel  think  they  arise  from  the  reticulum  cells  through  the  absorp- 
tion of  a  hyaline  foreign  protein-like  substance. 

LITERATURE 
General— Paltauf,  Freund,  and  Sternberg:    Handb.  allg.  Path.,  Krehl  and  Marchand, 

1912,  ii,  1. 

Naegeli:  Blutkrankheiten  u.  Blutdiagnostik,  Leipzig,  1907. 
Bone-marrow — Maximow:  Arch.  f.  mikr.  Anat.,  1910,  Ixxvi,  1. 

Jackson:  Arch.  f.  Anat.  u.  Phys.,  Anat.  Abth.,  1904,  33. 

Bunting:  Johns  Hopkins  Hosp.  Bull.,  1905,  xvi,  222.  Jour.  Exp.  Med., 

1906,  viii,  625. 
Myeloid  metaplasia — Tanaka:  Ziegler's  Beitr.,  1912,  liii,  338,  Lit. 

Meyer  and  Heineke:  Verb.  Dtsch.  Path.  Gesellsch.,  1906,  ix,  224- 
Sternberg:  Ziegler's  Beitr.,  1909,  xlvi,  586. 
Domarus:  Arch.  f.  exp.  Path.  u.  Phar.,  1908,  Iviii,  319. 
Morris:  Johns  Hopkins  Hosp.  Bull.,  1907,  xviii,  200. 
Benzol  ancemia— Selling:  Ziegler's  Beitr.,  1911,  li,  576. 
Oxydase  reaction— Loele :  Ergebn.  d.  allg.  Path.,  1913,  xvi2,  760. 

Schultze:  Ziegler's  Beitr.,  1909,  xlv,  127. 

Anatomy  of  spleen— Weidenreich:  Arch.  f.  mikr.  Anat.,  1901,  Iviii,  247. 
Mollier:  Ibid.,  1910-11,  Ixxvi,  608. 

Pearce,  Austin,  Krumbhaar,  Eisenbrey:  "Spleen  and  Blood  De- 
struction," Jour.  Exp.  Med.,  1912,  xvi;  ibid.,  1913,  xviii;  ibid., 
1914,  xx,  et  seq. 

Lymphocytes— Marchand:  Verb.  Dtsch.  Path.  Gesellsch.,  1913,  xvi,  5. 
Polycyth&mia  rubra— Osier:  Amer.  Jour.  Med.  Sci.,  1903,  cxxvi,  187.    Brit.  Med.  Jour., 

1904,  1,  121. 

Lucas:  Arch.  Int.  Med.,  1912,  x,  597. 

Typhoid  bone-marrow— Longcope:  Bull.  Ayer  Clin.  Lab.,  1905,  ii,  1. 
Hoemolymph  nodes— Warthin :  Amer.  Jour.  Anat.,  1901,  i,  63. 
Pernicious  ancemia— Cabot :  Osier  and  McCrae's  Modern  Medicine,  1915,  iv,  619. 
Lazarus:  Die  Ansemie,  Wien,  1913. 
Sternberg:  Verh.  Dtsch.  Path.  Gesellsch.,  1907,  x,  114. 


BLOOD-FORMING    ORGANS  821 

Pernicious  anosmia — Ziegler:  Dtsch.  Arch.  f.  kl.  Med.,  1910,  xcix,  431. 
Aplastic  ancemia — Lavenson:  Amer.  Jour.  Med.  Sci.,  1907,  cxxxiii,  100. 

Stone:  Ohio  State  Med.  Jour.,  1907,  iii,  243,  Lit. 
Osteosclerotic  ancemia — Assmann:  Ziegler's  Beitr.,  1907,  xli,  565. 

Askanazy:  Verhandl.  Dtsch.  Path.  Gesellsch.,  1904,  vii,  58. 
Hcemolytic  jaundice — Guizzetti:  Ziegler's  Beitr.,  1912,  Iii,  15. 
Primary  splenomegaly — Banti:  Riforma  Medica,  1901,  xvii,  i,  590. 
Rolleston:  Practitioner,  1914,  xcii,  470. 
Leon-Kindberg:  Annales  de  Medicine,  1914,  i,  189. 
Gaucher's  splenomegaly — Bovaird:  Amer.  Jour.  Med.  Sci.,  1900,  cxx,  377. 

Brill  and  Mandelbaum:  Ibid.,  1909,  1913,  cxlvi,  863.  Jour. 

Exp.  Med.,  1912,  xvi,  797. 

Marchand:  Munch,  med.  Woch.,  1907,  liv,  1102. 
Risel:  Ziegler's  Beitr.,  1909,  xlvi,  241. 


CHAPTER  XLI 

EFFECTS  OF  INJURIES  TO  THE  BLOOD  AND  BLOOD-FORMING 

ORGANS  (Continued) 

Leucocytosis;  Leucopenia.  Lymphocytosis.  Eosinophilia:  Corresponding  changes  of 
hcematopoietic  organs.  Independent  disease  of  the  blood-forming  organs:  General  characters; 
Classification  in  lack  of  information  as  to  aetiology.  Chronic  lymphoid  leukaemia.  Acute 
lymphoid  leukaemia.  Leucosarcoma,  or  chloroleucosarcoma  (chloroma).  Lymphoid 
myeloma.  Pseudoleukcemia.  Lymphosarcoma.  Status  lymphaticus. 

THE  blood-forming  organs  respond  promptly  in  the  production  of  white 
corpuscles  when  the  occasion  demands  it,  just  as  they  do  in  the  case  of 
red  corpuscles.  But  in  this  case  the  causes  of  their  activity  are  different 
and  it  is  toward  the  flooding  of  the  blood  with  abnormally  great  numbers 
of  these  white  corpuscles  that  their  efforts  tend,  rather  than  to  the  mere 
replacement  of  those  which  have  been  destroyed  in  the  circulation. 

The  appearance  of  an  excessive  number  of  white  corpuscles  in  the 
circulation  is  called  hyperleucocytosis,  commonly  shortened  to  leuco- 
cytosis, while  their  decrease  is  known  as  leucopenia.  So  specific  are  the 
different  types  of  white  cell  of  the  blood  that  each  may  separately  be  thus 
affected,  and  it  is  necessary,  in  order  to  understand  the  nature  of  the  change, 
to  know  not  only  how  many  white  cells  are  present  in  each  cubic  milli- 
metre of  the  blood,  but  in  what  proportion  the  different  cells  are  present. 
Through  common  use  the  far  more  frequent  excess  in  the  absolute  number 
of  polymorphonuclear  neutrophile  leucocytes  has  come  to  be  spoken  of 
loosely  as  "  leucocytosis "  par  excellence.  But  the  terms  lymphocytosis, 
eosinophilia,  myelocytosis,  etc.,  are  also  used  to  express  the  predominant 
increase  in  the  corresponding  cells,  and  these  terms  may  be  properly  used 
even  though  the  total  number  of  leucocytes  is  not  increased.  In  the  fol- 
lowing we  shall  use  the  term  leucocyte  to  refer  to  any  of  the  circulating 
white  cells  of  the  blood,  specifying  in  each  case  the  particular  type  meant. 
The  details  of  the  changes  in  the  relative  proportions  and  absolute  num- 
bers of  leucocytes  must  be  studied  in  the  special  works  on  the  clinical 
examination  of  the  blood,  and  only  an  outline  shall  be  given  here  in  con- 
nection with  the  description  of  the  changes  in  the  blood-forming  tissues. 

LEUCOCYTOSIS  AND  LEUCOPENIA 

Neutrophile  leucocytosis  is  the  common  outpouring  of  polymorphonuclear 
neutrophiles  into  the  blood,  so  familiar  in  almost  every  sort  of  acute  in- 
flammatory process.  These  cells  have  to  a  great  extent  the  function  of 
attacking  and  engulfing  bacteria  and  other  injurious  substances  and  of 

822 


LEUCOCYTOSIS   AND    LEUCOPENIA  823 

producing  a  proteolytic  ferment  which  acts  best  in  an  alkaline  medium. 
They  appear  in  increased  numbers  in  the  course  of  digestion  after  the  use 
of  certain  drugs  (quinine,  etc.),  after  haemorrhage,  during  some  forms  of 
toxic  injury  to  the  tissues,  but  especially  and  in  greatest  abundance  as  a 
response  to  the  invasion  of  bacteria.  Thus  in  pneumonia,  endocarditis, 
septic  infection,  and  in  nearly  every  sort  of  acute  inflammatory  process, 
the  neutrophile  leucocytes  rise  in  number  until  the  white  corpuscle  count 
reaches  20,000  to  30,000  or  40,000,  or  in  some  cases  as  much  as  150,000, 
per  c.mm.  In  such  cases  the  other  leucocytes  are  not  correspondingly 
increased,  and  the  neutrophile  cells  assume  a  proportion  of  90  or  95  per 
cent.  There  are  notable  exceptions  to  this  in  the  case  of  typhoid  fever, 
measles,  tuberculosis,  and  protozoan  infections,  such  as  malaria,  in  which 
the  leucocyte  count  does  not  rise,  or  in  the  case  of  trichiniasis  and  allied 
parasitic  infections  in  which  the  eosinophile  cells  are  especially  increased. 

Lymphocytosis. — The  lymphocytes  are  relatively  and  sometimes  ab- 
solutely increased  in  number  in  typhoid  fever  and  several  other  infections, 
and  the  important  work  of  Murphy*  has  recently  shown  that  their  presence 
is  really  of  the  very  greatest  value  in  antagonizing  such  infections.  Animals 
deprived  of  their  lymphocytes  by  exposure  to  z-rays,  etc.,  are  much  more 
susceptible  to  tuberculosis  than  normal  animals,  and  the  zone  of  lympho- 
cytes which  is  so  constantly  found  gathered  about  growing  tumors  is 
evidently  of  great  importance,  for  in  animals  without  lymphocytes  im- 
planted tumors  grow  rapidly,  although  they  are  destroyed  in  the  controls. 
Hence  v/e  must  assume  that  the  so-called  round-cell  infiltration  which  is 
so  striking  a  feature  of  the  late  stage  of  an  inflammatory  reaction  and 
predominant  in  the  more  chronic  forms,  is  an  expression  of  the  ability  of 
the  lymphocytes  to  act  in  the  process  of  warding  off  and  annulling  injuries. 
Relative  lymphocytosis  occurs  not  only  in  typhoid  fever  but  in  malaria, 
small-pox,  exophthalmic  goitre,  and  in  many  affections  of  childhood. 

Eosinophilia  has  been  mentioned  as  occurring  in  trichiniasis,  uncin- 
ariasis,  and  other  infections  with  parasitic  worms,  in  asthma,  in  various 
skin  diseases,  in  scarlet  fever,  etc.  Other  cells,  such  as  myelocytes,  myelo- 
blasts,  and  mast  cells  are  found  at  times  in  the  circulating  blood  but 
usually  only  in  connection  with  leukaemias,  except  in  certain  severe  in- 
fections in  which  myelocytes  are  swept  into  the  blood  in  the  wake  of 
the  leucocytes. 

The  changes  in  the  blood-forming  organs  in  these  states  of  the  blood  are 
not  so  satisfactorily  studied  as  one  could  wish.  Descriptions  of  the  spleen 
and  bone-marrow  are  particularly  meagre  except  in  a  few  instances. 

In  neutrophile  leucocytosis  there  is  a  strong  hyperplastic  reaction  in 
the  bone-marrow,  which  naturally  consists  essentially  in  a  great  new 
production  of  neutrophile  myelocytes,  which  leads  to  the  formation  of  the 
leucocytes.  As  a  rule,  the  leucocytes  are  discharged  so  rapidly  that  the 

*  Murphy  and  Ellis:  Jour.  Exp.  Med.,  1914,  xx,  397. 


824 


TEXT-BOOK   OF   PATHOLOGY 


myelocytes  become  the  most  prominent  feature  of  the  bone-marrow  section 
(Fig.  408).  Undoubtedly  the  spleen  is  deeply  affected  in  this  process  and 
commonly  assumes  the  peculiar  softness  and  richness  in  cells  which  has 
already  been  described  as  the  acute  splenic  tumor  of  infectious  or  septic 
diseases.  It  appears  that  in  such  spleens  there  is  a  form  of  myeloid  meta- 
plasia combined  with  an  accumulation  of  the  debris  of  cells,  and  phagocytes 
loaded  with  such  fragments.  The  lymph-glands  and  lymphoid  tissues  are 


Fig.  408. — Bone-marrow  from  a  case  of  staphylococcus  septicaemia  with  leucocytosis. 
Myelocytes  are  abundant,  but  there  are  few  leucocytes  in  the  marrow. 

not  necessarily  much  affected  except  by  local  conditions  in  which  they 
take  up  the  products  of  inflammation. 

The  cause  of  the  changes  in  the  bone-marrow  in  inflammatory  leuco- 
cytosis has  been  much  discussed.  It  is  evident  that  the  appearance  of 
such  great  numbers  of  leucocytes  must  depend  upon  the  ability  of  the 
bone-marrow  to  produce  them  rapidly.  The  idea  that  the  leucocytosis 
is  a  response  to  the  need  caused  by  the  destruction  of  many  of  their  number 
is  scarcely  different  from  the  idea  that  they  are  drawn  to  the  general  cir- 
culation and  thence  to  the  site  of  the  inflammation  by  a  chemotactic 


LEUCOCYTOSIS   AND    LEUCOPENIA 


825 


substance  which  itself  gains  entrance  into  the  circulation.  That  some  such 
chemical  stimulant  must  not  only  attract  the  leucocytes  but  also  stir  the 
bone-marrow  to  increased  formation  of  these  cells  seems  to  be  clearly 
shown  by  the  extremely  rapid  and  ready  increase  which  takes  place  in 
infections  as  contrasted  with  the  much  less  striking  leucocytosis  which 
appears  after  a  severe  haemorrhage,  that  is,  after  the  actual  mechanical 
removal  of  the  leucocytes.  It  is  most  important  to  realize  the  fact  that 
an  extremely  violent  poisoning,  such  as  occurs  in  many  severe  infections, 


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Fig.  409. — Bone-marrow  in  typhoid  fever. 


may  not  be  followed  by  any  leucocytosis.  On  the  contrary,  the  bone- 
marrow  seems  to  be  so  injured  by  the  strong  stimulus  as  to  be  incapable  of 
producing  the  cells.  It  is  probably  exactly  the  same  thing  on  a  somewhat 
different  plane  when,  in  a  debilitated  old  person,  there  is  no  leucocytosis 
in  pneumonia  or  other  infection,  for  then  a  degree  of  poisoning  which 
might  be  readily  met  by  a  leucocytosis  in  a  young  and  strong  person  is 
sufficient  to  paralyze  the  feebly  reacting  bone-marrow  of  the  old  man. 
Clearly  then  the  prognosis  in  any  infection  may  be  judged  to  some  extent 
by  the  efficiency  of  the  leucocytic  response;  when  there  is  a  failure  on  the 


826  TEXT-BOOK   OF   PATHOLOGY 

part  of  the  bone-marrow  to  produce  abundant  leucocytes  the  disease  is 
likely  to  prove  fatal. 

In  lymphocytosis  of  infectious  diseases  the  spleen  and  lymph-glands  are 
usually  enlarged,  but  this  enlargement  is  generally  due  to  local  causes,  as 
in  typhoid  fever,  and  not  especially  to  their  participation  in  the  production 
of  lymphocytes,  although  the  lymphoid  tissue  is  undoubtedly  active  in 
this  way.  In  the  bone-marrow  there  is  very  definite  hyperplasia  and  the 
bone-marrow  of  the  femur  becomes  red  or  grayish-red  and  cellular.  Here, 
however,  the  new  formation  of  myelocytes  and  neutrophile  cells  is  found 
to  have  sunken  to  a  relatively  far  less  important  position.  It  is  true  that 
the  typhoid  marrow  still  shows  numerous  myelocytes,  but  the  striking 
feature,  as  Longcope  has  shown,  is  the  relatively  abundant  new  formation 
of  lymphoid  cells  there.  A  comparison  of  Figs.  408  and  409  will  show 
this.  In  typhoid  fever  the  myelocytes  seem  unable  to  respond  to  such 
stimuli  as  usually  produce  neutrophile  leucocytosis.  The  advent  of 
pneumonia  or  other  similar  infection  in  the  course  of  the  disease  does  not 
necessarily  bring  out  the  corresponding  leucocytosis,  and,  indeed,  those 
things  which  usually  produce  an  abscess  have  failed  to  do  so  in  a  person 
sick  with  typhoid  fever,  although  the  occurrence  of  furunculosis  with 
typhoid  fever  is  familiar.  This,  however,  comes  on  in  a  late  stageiand  cor- 
responds with  the  experiment  of  Bauer  who  could  produce  no  abscess  by 
injecting  turpentine  subcutaneously  during  the  height  of  the  typhoid  fever, 
although  when  the  fever  disappeared  in  convalescence  the  belated  abscess 
appeared  at  the  site  of  the  injection. 

In  eosinophilia  there  is  a  relative  and  absolute  increase  in  the  eosinophile 
myelocytes  of  the  bone-marrow.  This  statement  is  made  without  hesitation 
since  it  has  been  shown  experimentally  by  Opie  to  be  so,  although  there 
are  as  yet  no  conclusive  reports  as  to  the  appearance  of  the  bone-marrow 
in  human  beings  in  those  infections  (trichiniasis,  etc.)  in  which  the  eosino- 
philes  are  so  abundant  in  the  blood.  With  regard  to  the  analogous  con- 
ditions in  leukaemia  we  shall  speak  presently. 

INDEPENDENT  DISEASE  OF  THE  BLOOD-FORMING  ORGANS 

We  approach  in  this  section  a  series  of  extraordinary  affections  involving 
the  blood-forming  organs,  and  consequently  the  blood,  in  which  the  morpho- 
logical changes  from  normal  are  very  minutely  studied,  but  in  no  single 
one  of  which  we  know  anything  of  the  cause.  The  study  of  these  diseases 
is  made  more  difficult  by  the  fact  that  while  there  are  type  forms  which 
are  fairly  distinct,  one  meets  with  many  individual  cases  in  which  there 
are  wide  variations  from  these  types.  They  are  affections  of  the  lymphoid 
tissue  on  the  one  hand,  or  of  myeloid  tissue  on  the  other,  and  such  is  the 
specific  distinction  between  these  tissues  that  we  find  no  mixture  of  the 
two.  They  are  essentially  hyperplasias  of  the  blood-forming  tissues,  and 
while  in  some  cases  this  does  not  involve  any  striking  change  in  the  cir- 
culating blood,  in  others  such  quantities  of  new  cells  are  emptied  into  the 


INDEPENDENT  DISEASE    OF   THE   BLOOD-FORMING   ORGANS     827 

blood-stream  as  to  be  completely  subversive  of  its  ordinary  composition.* 
Perhaps  this  should  not  be  regarded  as  a  distinction  of  importance  between 
these  cases,  because  it  is  said  to  happen  that  in  some  forms  the  blood, 
after  having  been  normal  through  a  long  period  in  which  disease  of  the 
myeloid  or  lymphoid  tissue  was  well  developed,  may  suddenly  be  flooded 
with  an  excessive  number  of  cells  representing  the  particular  hyperplastic 
element.  Such  cases,  however,  are  rare,  although  great  modifications  in 
the  quantity  of  cells  poured  into  the  blood  occur  from  time  to  time  in 
those  in  which  the  blood  shows  distinct  changes.  It  is  probably  correctly 
claimed  that  the  classification  of  such  diseases  should  be  based  not  upon 
the  number  of  cells  swept  into  the  blood,  but  upon  their  character  and 
therefore  upon  the  character  of  the  hyperplasia  in  the  blood-forming  organ 
concerned.  Still,  the  setting  free  of  the  cells  or  their  retention  in  the  place 
of  their  formation  is  so  nearly  a  constant  feature  of  each  form  that  we 
must  assume  that  there  is  something  peculiar  about  the  way  these  cells 
are  held  together  in  the  tissue,  which  brings  about  these  different  results. 
It  is  difficult,  if  not  impossible,  to  see  in  the  sections  of  bone-marrow  or 
lymphoid  tissue  anything  which  in  one  case  would  make  the  escape  of 
cells  impossible,  in  another  facilitate  it;  but  perhaps  with  finer  technique 
this  may  be  discerned. 

In  some  types  it  appears  that  the  hyperplasia  of  one  sort  of  cell  occurs 
strictly  within  the  normal  limits  of  the  myeloid  or  lymphoid  tissue,  as 
the  case  may  be,  even  though  these  cells  may  escape  into  the  blood.  In 
others  the  hyperplastic  tissue  extends  like  a  tumor,  so  as  to  invade  and 
destroy  adjacent  tissue,  even  breaking  through  the  cortex  of  the  bone  or 
spreading  far  and  wide  from  the  normal  limits  of  the  lymphoid  tissue. 
On  account  of  this  many  authors  have  looked  upon  these  hyperplasias 
as  tumor  growths.  Indeed,  even  when  there  is  no  obvious  tumor  but 
great  quantities  of  cells  are  found  circulating  in  the  blood,  it  seems  that 
these  cells  may  form  colonies  in  other  organs  and  there  give  rise  to  new 
cells  of  the  same  sort.  This  is  the  point  in  dispute  in  the  question  of  mye- 
loid metaplasia,  other  investigators  holding  that  such  colonies  of  cells  are 
formed  in  situ  by  a  true  metaplasia,  and  not  derived  from  the  usual  site 
of  their  formation  in  the  blood-forming  organs.  The  question  is  hard 
to  settle  satisfactorily,  but  in  the  one  case  the  new  formation  of  cells 
in  an  unaccustomed  organ,  such  as  the  liver,  would  resemble  the  mode  of 
distribution  and  proliferation  of  a  tumor;  in  the  other  we  must  assume 
that  the  tissues  of  the  capillary  walls  of  the  liver,  the  splenic  pulp,  etc., 
are  capable  of  reacquiring  the  power  of  blood  formation  which,  as  all  agree, 
they  possessed  during  embryonic  life.  To  me  the  idea  of  the  transplant- 


*  Leukaemia,  or  leucocythaemia,  was  first  observed  almost  simultaneously  by  Bennet 
in  Scotland  and  by  Virchow  in  Germany  (1848).  Virchow  recognized  the  lymphoid 
nature  of  the  cells  in  one  type  and  their  granular  character  in  the  other,  and  called  them 
lymphatic  and  lienal  forms.  Neumann  first  pointed  out  the  importance  of  the  bone- 
marrow  in  their  production. 


828  TEXT-BOOK    OF    PATHOLOGY 

ation  and  growth  of  cells  seems  more  plausible,  although  there  is  some 
good  evidence  in  favor  of  the  idea  of  metaplasia. 

It  appears,  then,  that  if  we  know  accurately  all  the  cellular  types  existent 
in  the  bone-marrow  and  in  the  lymphoid  tissue,  which  are  the  blood- 
forming  tissues  concerned,  and  if  we  assume  that  each  is  capable  of  under- 
going an  independent  hyperplasia,  we  should  be  able  to  construct  a  tabu- 
lation of  all  the  possible  diseases  arising  in  this  way.  This  has  indeed 
been  done,  just  as  it  was  possible  for  Rokitansky  to  foretell  what  types 
of  malformation  of  the  heart  might  occur  on  the  basis  of  the  embryo- 
logical  development  of  that  organ  and  then  years  later  to  meet  with  cases, 
hitherto  unknown,  which  realized  each  member  in  his  scheme.  The 
possible  existence  of  unknown  tumors  has  been  foretold  in  the  same  way 
on  a  histogenetic  basis. 

Sternberg  has  made  such  a  table,  which  I  shall  quote  in  brief : 

A — Local  limited  homologous  hyperplasias : 
a — With  escape  of  cells  into  the  blood 

(1) — of  the  lymphatic  tissue Lymphatic  leukcemia. 

(2) — of  the  myeloid  tissue Mixed-cell  leukcemia. 

b — With  slight  or  no  escape  of  cells 

(3) — of  the  whole  lymphatic  tissue  (diffuse) Pseudoleukcemia. 

(4) — of  lymphatic  tissue  of  bone-marrow  (tumor- 
like) Lymphatic  myeloma. 

(5) — of  myeloid  tissue  of  bone-marrow  (tumor-like) . M yeloid  myeloma. 
B — Atypical    growths    invading    surrounding    tissue    with 

heterotopic  or  distant  nodules: 
a — With  escape  of  cells  into  the  blood 

(6) — of  the  lymphatic  tissue Leucosarcoma    or     chloro- 

leucosarcoma. 

(7) — of  the  myeloid  tissue Chloromyelosarcoma. 

b — Without  escape  of  cells  into  the  blood 

(8) — of  the  lymphatic  tissue Lymphosarcoma. 

B — 6 — (9)  which  would  be  an  atypical  growth  of  myeloid 
tissue,  invasive  but  without  escape  of  cells,  has  not 
yet  been  observed. 

While  this  classification  seems  logical,  it  is  not  an  aBtiological  classification, 
and  therefore  open  to  criticism.  I  should  prefer  another  division,  perhaps 
equally  open  to  criticism,  but  separating  as  the  main  groups  the  affections 
of  the  lymphoid  from  those  of  the  myeloid  tissue.  The  subordination  of 
the  main  basis  of  Sternberg's  grouping  is  made  for  reasons  explained  above. 

A— Hyperplasia  of  lymphoid  tissues: 
a — With  leukaemic  blood — 

(1) — with  swelling  of  lymphoid  tissue  and  lymphoid 

infiltration  of  organs Chronic  lymphoid  leukcemia; 

Acute  lymphoid  leukcemia. 
(2) — with  tumors  originating  in  various  situations 

and  invading  tissues Leucosarcoma;  Chloroleuco- 

sarcoma   (Chloroma). 


INDEPENDENT  DISEASE    OF   THE    BLOOD-FORMING   ORGANS     829 

6 — Without  leuksemic  blood — 

(3) — with  tumors  involving  bone-marrow Lymphoid     or     plasma-cell 

myeloma. 
(4) — with  general  swelling  of  lymphoid  tissue ....  Pseudoleukcemia. 

(5) — with  regional  invasive  tumor-like  growth Lymphosarcoma. 

(6) — with  stigmata  of  general  maldevelopment. . .  .Status  lymphaticus. 
B — Hyperplasia  of  myeloid  tissue: 
a — With  leuksemic  blood — 

(7) — with  myeloid  infiltration  of  organs Myeloid  leukaemia;  Myelo- 

blastic  leukaemia. 

(8) — with  tumors  of  the  myeloid  tissue Chloromyelosarcoma    (Mye- 
loid chloroma). 
b — Without  leuksemic  blood — 

(9) — with  tumors  of  the  myeloid  tissue Myeloid  myeloma. 

C — (Included  here  though  probably  not  related.)  Tumor- 
like  swelling  of  lymph-glands  with  nodules  in  spleen, 
liver,  lungs,  etc.,  granulomatous  alteration  of  lymphoid 
tissue  of  specific  morphology,  apparently  infectious  in 

origin Lymphogranulomatosis     or 

Hodgkin's  disease. 

Chronic  Lymphoid  Leukaemia. — The  onset  is  insidious,  with  painless 
enlargement  of  some  of  the  lymph-glands  and  occasionally  with  haemor- 
rhages from  the  mucosae.  Examination  of  the  blood  shows  an  increase 
in  the  leucocytes  without  necessarily  any  change  in  the  red  corpuscles. 
Among  the  leucocytes  the  small  lymphocytes  occupy  the  important  place 
and  are  proportionately  greatly  increased.  This  state  may  continue  for 
years  with  gradually  progressing  anaemia,  continuous  intermittent  increase 
in  the  number  of  white  cells,  and  slow  enlargement  of  the  lymph-glands, 
spleen,  and  sometimes  of  the  liver.  The  leucocytes  may  constitute  90 
or  95  per  cent,  of  all  the  white  cells  and  there  may  be  several  hundred 
thousand  of  these  per  c.mm.  Naegeli  mentions  one  case  in  which  the  haemo- 
globin was  25  per  cent,  and  there  were  621,000  leucocytes,  of  which  99.6 
per  cent,  were  lymphocytes  with  only  0.14  per  cent,  of  neutrophiles.  The 
symptoms  are  due  chiefly  to  the  presence  of  infiltrations  of  these  lympho- 
cytes in  various  places  where  they  often  produce  pressure  phenomena, 
and  to  haemorrhage.  In  the  nervous  system  and  eyes,  destructive  changes 
may  occur  in  this  way.  Dyspnoea  follows  similar  obstruction  in  the  lungs, 
which,  together  with  the  changed  character  of  the  blood,  makes  aeration 
difficult.  In  the  skin  there  are  sometimes  tumor-like  masses.  Death 
follows  from  the  cachectic  condition  itself  or  from  acute  exacerbation  or 
intercurrent  bacterial  infection. 

At  autopsy  the  lymph-glands  are  found  enlarged  and  converted  into 
homogeneous  masses  of  soft,  grayish-white  cellular  tissue,  without  any 
marks  remaining  to  indicate  their  structure.  In  one  case  which  I  watched 
for  several  years  the  axillary,  inguinal,  and  retroperitoneal  glands  finally 
formed  huge  masses  in  which  the  separate  glands  had  grown  to  the  size 
of  apples.  They  were  so  large  as  to  hold  the  arms  away  from  the  sides, 


830 


TEXT-BOOK    OF    PATHOLOGY 


but  showed  no  tendency  to  invade  the  surrounding  tissue.  In  that  case 
the  spleen  was  large  and  hard  and  there  were  scattered  infiltrations  of  the 
lymphoid  cells  along  the  portal  branches  in  the  liver  (Fig.  410).  The 
tonsils  and  pharyngeal  lymphoid  tissue  may  become  enlarged  late  in  the 
disease,  but  this  is  not  invariable.  The  intestinal  lymphoid  tissue  is  aston- 
ishingly little  affected.  The  spleen  is  generally  enlarged,  although  not  to 
the  maximum  degree.  It  may  still  show  Malpighian  bodies  on  section 


«,  -v  *w  "•  is,*?,  s  -**  «»7  c  -;  *  -.tw?  y . ; 


Fig.  410.— Chronic  lymphoid  leukaemia.    Infiltration  about  the  gall-ducts  and  portal 

vessels. 


or  these  can  become  so  indistinctly  outlined  as  to  merge  in  the  rest  of  the 
tissue  which  is  of  a  grayish  or  brownish  red.  The  bone-marrow  is  no  longer 
fatty  in  the  shaft  of  the  long  bones,  but  forms  a  solid  cellular  tissue  of 
gray  or  grayish-red  color,  often  with  patches  of  dark  red.  The  liver, 
which  is  usually  rather  swollen,  shows  grayish  lines  accompanying  the 
bile-ducts  and  portal  veins.  Gray  infiltrations  are  found  elsewhere  too, 
as  in  the  thymus,  which  may  be  markedly  enlarged,  or  in  the  kidneys, 


INDEPENDENT  DISEASE    OF   THE    BLOOD-FORMING   ORGANS       831 

adrenals,  testes,  etc.    Following  the  blood-vessels  in  the  retina  are  sheaths 
of  lymphocytes  with  which  hemorrhages  are  often  associated. 

The  histological  changes  are  all  occasioned  by  the  extraordinary  over- 
production of  lymphocytes  from  the  lymphoid  tissue,  wherever  that  occurs, 
in  the  lymph-glands,  lymphoid  apparatus  of  the  respiratory  or  digestive 
tracts  or  skin,  or  in  the  bone-marrow.  It  is  impossible,  as  a  rule,  to  make 
out  just  where  it  started  to  undergo  hyperplasia  in  these  chronic  cases, 
although  there  is  a  better  opportunity  in  the  acute  cases  to  be  described  later. 


iplll''^8®^^  --'  c*  8>%v 


Fig.  411. — Chronic  lymphoid  leukaemia.     Spleen  showing  a  Malpighian  body  and  part 
of  the  pulp  in  which  there  is  much  induration  and  infiltration  with  lymphoid  cells. 

Nsegeli  makes  a  special  point  of  saying  that  such  hyperplasia  cannot 
occur  in  the  bone-marrow  lymphoid  tissue  alone,  but  that  all  the  lymphoid 
tissue  is  equally  involved. 

The  cells,  in  most  of  the  chronic  cases,  are  small  lymphocytes.  Never- 
theless, in  the  lymphoid  tissue  in  which  they  are  being  formed  one  finds 
almost  always  a  mixture  of  these  with  rather  larger  lymphoid  cells. 

In  the  lymph-glands  all  signs  of  the  original  architecture  with  lymph- 
nodules  and  sinuses  have  disappeared,  being  swamped  and  covered  in  or 
pushed  aside  by  the  overwhelming  growth  of  one  kind  of  cell,  so  that  the 


832  TEXT-BOOK    OF    PATHOLOGY 

tissue  appears  as  a  solid,  uniform  mass  of  lymphocytes.  In  the  spleen,  at 
first  sight,  it  seems  that  the  same  thing  is  true,  as  though  the  Malpighian 
bodies  had  spread  to  occupy  everything,  but  closer  examination  shows  that 
the  structure  of  the  pulp  is  still  discernible  and  the  venules  and  interspaces 
are  found  filled  with  lymphocytes.  In  the  older  cases,  in  which  the  spleen 
is  hard,  there  is  much  new  fibrous  tissue  between  the  venules.  This  was 
true  in  the  very  chronic  case  mentioned  above  and  is  shown  in  Fig.  411. 
In  the  bone-marrow  there  is  usually  almost  complete  replacement  of  the 
ordinary  cells  by  spreading  masses  of  lymphoid  tissue,  but  in  many  cases 
there  are  areas  of  myeloid  tissue  left  unchanged  with  erythroblastic  and 
myeloblastic  cells.  These  appear  to  be  the  dark-red  patches  which  are 
visible  in  the  gross  and  are  no  doubt  responsible  for  the  relatively  good  main- 
tenance of  the  red  cell  content  of  the  blood. 

Acute  Lymphoid  Leukaemia. — In  our  experience  this  is  a  more  common 
affection  than  the  chronic  form,  and  must  be  distinguished  from  it  because 
of  its  more  violent  and  severe  symptoms  and  rapid  course,  and  also  because 
the  cells  concerned  are  in  most  cases  larger.  In  relatively  few  cases  only 
are  they  of  the  same  small  size  as  in  the  chronic  forms.  It  must  be  noted 
here  that  certain  of  the  cases  which  were  formerly  classed  as  acute  lymphoid 
leukaemia  are  now  known  to  be  not  lymphoid  leukaemia  at  all,  but  myeloid 
leukaemia  in  which  the  non-granular  myeloblast  is  the  cell  that  is  especially 
abundant. 

In  contrast  to  the  chronic  form  of  lymphoid  leukaemia  this  one  begins 
suddenly  with  intense  symptoms :  fever,  haemorrhages  from  the  mucosae, 
and  rapidly  developing  anaemia.  Haemorrhages  in  the  retinae  are  almost 
constant,  while  those  in  the  conjunctivae,  over  the  face  and  over  the  whole 
body,  are  often  very  extensive  and  gradually  pass  through  the  ordinary 
changes  of  color  to  become  pigment  spots  that  finally  disappear.  The 
haemorrhages  in  the  mouth,  vagina,  and  digestive  tract  often  become  con- 
verted into  gangrenous  areas  which  leave  deep  ulcers.  The  tonsils  and 
the  rest  of  the  pharyngeal  adenoid  tissue  frequently  become  greatly  enlarged 
and  deeply  ulcerated.  The  lymph-glands  may,  in  some  cases,  even  in  a 
rather  advanced  stage,  be  relatively  slightly  enlarged,  but  usually  they  are 
palpable  or  even  form  prominent  packets.  In  a  case  now  under  observa- 
tion what  seems  to  be  the  thymus  has  become  greatly  enlarged  in  the  course 
of  a  few  days.  A  radiograph  reveals  the  fact,  however,  that  this  is  a 
retrosternal  mass  of  lymph-glands.  The  spleen  is  generally  enlarged  but 
does  not  reach  as  a  rule  the  huge  dimensions  seen  in  some  other  forms. 
The  blood  in  some  instances  shows  no  decrease  in  red  corpuscles  but  usually 
the  anaemia  advances  rapidly  and  in  the  case  mentioned  is  already  under 
1,000,000.  Occasionally  such  blood  shows  regenerative  forms  resembling 
those  of  pernicious  anaemia,  but  often  there  seems  to  be  no  attempt  at 
regeneration.  The  leucocytes  reach  high  numbers,  ranging  from  50,000  to 
250,000  or  more,  and  the  increase  is  represented  by  the  lymphocytes,  which 
may  constitute  98  or  99  per  cent,  of  the  cells.  As  stated  above,  these 


INDEPENDENT   DISEASE    OF   THE    BLOOD-FORMING   ORGANS      833 

lymphocytes  are  in  most  cases  larger  than  those  of  normal  blood.  Death 
results  from  a  terminal  infection,  from  haemorrhage,  or  from  the  disease 
itself. 

At  autopsy  the  lesions  are  found  to  resemble  those  of  the  chronic  form 
except  that  since  the  course  of  the  disease  is  so  much  briefer,  there  is  not 
time  for  the  development  of  such  great  accumulations  of  lymphoid  tissue. 
The  lymph-glands  are  nevertheless  enlarged,  and  show  on  section  a  homo- 


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Fig.  412. — Splenic  pulp  in  acute  lymphoid  leukaemia.    The  cells  of  the  pulp  are  practi- 
cally entirely  replaced  by  large  lymphoid  cells. 

geneous,  grayish-white  cellular  tissue  rather  softer  than  that  found  in  the 
chronic  cases.  The  presence  of  hemorrhages  in  these  glands  is  very 
characteristic.  Microscopically  one  may  find  the  architecture  still  rec- 
ognizable although  the  sinuses  contain  great  quantities  of  lymphocytes. 
Occasionally,  however,  the  whole  structure  appears  as  a  mass  of  lymphoid 
cells.  There  are  usually  similar  changes  in  the  adenoid  tissues  of  the 
throat,  and  sometimes  in  those  of  the  digestive  tract,  so  that  swellings  com- 
parable to  those  in  typhoid  fever  are  found  in  the  solitary  nodules  and 
54 


834 


TEXT-BOOK   OF   PATHOLOGY 


Peyer's  patches.     Since,  with  haemorrhages,  these  may  become  ulcerated, 
the  resemblance  may  be  close. 

The  spleen  is  fairly  firm,  moderately  enlarged,  and  dark  grayish-red  in 
color.  Sometimes  one  can  see  the  Malpighian  bodies  distinctly,  but  in 
other  cases  they  are  not  to  be  outlined.  There  are  occasional  infarctions. 
Microscopically  it  is  difficult  to  outline  the  Malpighian  bodies  because  the 
splenic  pulp  is  filled  with  quite  similar  cells.  These  lie  in  great  numbers 
between  the  venules,  to  the  exclusion  of  most  of  the  other  cells  (Fig.  412). 


, 

:" 


Fig.  413. — Spleen  in  acute  lytmphoid  leukaemia.  The  splenic  pulp  and  blood-vessels 
are  filled  with  large  lymphoid  cells  contrasting  with  the  lymphocytes  of  the  Malpighian 
bodies. 

It  is  noteworthy  that  in  this,  as  in  other  forms  of  leukemia,  the  endothelium  of  the 
venules  of  the  spleen  to  which  so  many  functions  have  been  ascribed  is  perfectly  intact 
and  shows  no  evidence  of  playing  any  part  in  the  extraordinary  changes  going  on  round 
about. 

In  a  case  before  me,  however,  the  Malpighian  bodies  do  stand  out  with 
fair  distinctness  because  their  cells  are  rather  smaller  and  more  closely 
packed  than  those  in  the  pulp  (Fig.  413).  In  the  bone-marrow  (Fig.  414)> 


INDEPENDENT   DISEASE    OF   THE    BLOOD-FORMING    ORGANS      835 

which  is  gray  or  grayish-red  and  cellular,  often  with  red,  gelatinous 
patches,  the  conditions  vary.  Usually  practically  all  the  myeloid  elements 
are  crowded  out  of  existence,  except  perhaps  in  the  red  patches  just  men- 
tioned, by  the  great  compact  swarms  of  lymphoid  cells.  Nevertheless, 
there  are  some  cases  in  which  these  lymphoid  cells  occur  at  the  time  of 
death  in  patches  only,  as  though  they  were  still  in  process  of  aggression. 
Naegeli  is  very  dogmatic  in  stating  that  there  are,  and  can  be,  no  cases  in 
which  this  process  begins  in  the  bone-marrow  alone — that  it  is  essentially 
a  systemic  disease  affecting  all  the  lymphoid  tissue.  Nevertheless,  in  one 


^O^®       «3<£P    6 

&X1**" 


Fig.  414. — Bone-marrow  in  acute  lymphoid  leukaemia. 

such  case  reported  by  Dr.  Reed  we  found  the  lymphoid  tissue  throughout 
the  body  entirely  unaffected  except  that,  in  the  manner  of  a  sieve,  it  had 
retained  many  of  the  circulating  lymphocytes  in  its  vessels.  The  bone- 
marrow  was  practically  entirely  composed  of  lymphocytes.  Ehrlich,  in 
studying  the  preparations  from  that  case,  expressed  his  opinion  (1902) 
that  such  a  leukaemia  might  originate  from  any  substratum  of  lymphoid 
tissue,  such  as  that  in  the  skin,  in  the  intestinal  wall,  or  in  the  bone-marrow. 
The  other  changes  are  the  effects  of  infiltration  and  localization  of  large 
quantities  of  lymphocytes  in  the  organs.  In  the  liver  this  deposit  does  not, 


836  TEXT-BOOK   OF   PATHOLOGY 

in  the  brief  span  of  the  disease,  reach  macroscopical  dimensions,  but  in  the 
kidneys  there  have  been  cases  in  which  such  quantities  of  cells  have 
gathered  in  the  interstices  as  to  enlarge  the  organ  greatly  and  give  it  the 
appearance  of  a  huge  white  kidney.  In  the  nervous  system  and  retinae 
similar  accumulations  accompanied  by  haemorrhages  cause  functional  and 
anatomical  disturbances.  It  is  important  to  note  that  in  neither  of  the 
forms  of  lymphoid  leukaemia  do  the  circulating  lymphoid  cells,  or  the  cells  of 
this  sort  in  the  tissues,  give  the  oxydase  reaction  which  is  shown  by  Schultz 
to  be  characteristic  of  the  myeloid  cells.  Nor,  according  to  Longcope, 
are  they  capable  of  producing  a  proteolytic  ferment.  The  contrast  in  the 
case  of  other  forms  of  leukaemia,  to  be  described  later,  is  very  striking. 

Leucosarcoma  or  Chloroleucosarcoma. — This  term,  introduced  by  Stern- 
berg,  is  meant  to  designate  those  cases  in  which  a  definite,  tumor-like  mass 
is  developed  in  some  organ  or  tissue  and  is  composed  of  lymphoid  cells 
which  seem  to  escape  into  the  blood-stream,  giving  rise  to  leuksemic  altera- 
tions of  the  blood.  Naegeli  and  others  refuse  to  recognize  this  as  anything 
distinct  from  lymphoid  leukaemia,  in  which,  as  they  say,  there  may  be 
extensive,  tumor-like  infiltrations  of  the  tissues.  Sternberg,  who  finds  the 
tumors  in  the  dura  mater,  in  the  mediastinum,  in  the  breast  or  in  connec- 
tion with  the  tissues  of  the  orbit,  denies  that  such  growths  occur  in  ordinary 
leukaemia  and  brings  forward  the  cases  studied  by  Paltauf  and  by  Buschke 
and  Hirschfeld  in  which  the  tumor  was  well  developed  before  any  changes 
occurred  in  the  blood.  Several  cases  which  we  have  studied,  even  though 
this  very  point  was  neglected,  have  seemed  to  me  to  occupy  so  distinct  a 
position  and  to  begin  so  definitely  with  the  formation  of  a  localized  tumor- 
like  mass  that  I  am  inclined  to  accept  Sternberg's  nomenclature.  In  one 
of  these  cases  there  were  two  circumscribed  "  lymphomatous "  nodules  in 
the  breast,  which  were  removed  by  the  surgeon.  It  was  only  after  their 
removal  that  examination  of  the  blood  was  made  and  revealed  the  presence 
of  250,000  lymphocytes  per  c.mm.  Another  case  showed  a  lymphoid  nod- 
ule in  the  cervix  uteri  (Fig.  415)  extending  to  the  vagina,  with  ulceration 
and  bleeding.  It  was  at  first  thought  to  be  a  carcinoma,  but  the  autopsy 
revealed  areas  of  infiltration  of  lymphoid  cells  in  many  of  the  organs  in 
association  with  the  leukaemic  condition  of  the  blood.  The  cells  in  this 
form  also  fail  to  show  the  oxydase  reaction. 

Intimately  related  to  this,  if  not  identical  with  it,  is  one  of  the  forms  of 
chloroma,  so  named  for  the  green  color  which  the  tumor-like  nodules  show 
when  first  exposed  at  autopsy.  There  are  two  sorts  of  chloroma,  one  com- 
posed of  large  lymphoid  cells,  the  other  of  myeloid  cells.  The  lymphoid 
type  differs  in  no  important  particular  from  the  leucosarcoma  except  in  its 
green  color,  and  perhaps  in  its  arising  usually  in  connection  with  the  peri- 
osteum, and  especially  with  that  of  the  bones  of  the  face  and  head.  The 
green  color  is  inconstant,  failing  in  some  parts  of  the  same  nodule,  and  is 
not  to  be  regarded  as  sufficient  basis  for  the  separation  of  these  cases;  hence 
Sternberg  classifies  them  as  chloroleucosarcoma.  No  good  explanation  of 


INDEPENDENT   DISEASE    OF   THE    BLOOD-FORMING   ORGANS     837 

the  bright  green  color  has  been  found,  and  efforts  at  the  isolation  of  the 
pigment  have  failed,  perhaps  partly  because  it  fades  very  quickly  on 
exposure  and  disappears.  The  myeloid  form  is  named  by  Sternberg  on  the 
same  basis  chloromyelosarcoma;  it  will  be  referred  to  later. 

Lymphoid  or  Plasma  Cell  Myeloma. — A  myeloma  is  a  growth  springing 
up  in  the  bone-marrow  and  evidently  occurring  as  a  systemic  affection  of 
the  marrow-cells,  since  it  appears  simultaneously  in  many  bones  and  nowhere 
else.  Unless  we  assume  the  existence  of  cells  which  can  grow  only  in  bone- 
marrow,  it  is  hard  to  imagine  such  wide-spread  multiple  growths  as  due  to 


Fig.  415. — Leucosarcoma.     Tumor-like  nodule  in  the  substance  of  the  cervix  uteri. 
This  was  associated  with  lymphoid  leukaemia. 

transportation  of  cells.  There  are  again  two  kinds,  this  one  composed  01 
lymphoid  cells  and  another,  to  be  described  later,  composed  of  myeloid 
cells.  In  their  biological  behavior  they  are  almost  exactly  alike.  The 
lymphoid  myeloma  is  gray  or  reddish-gray  on  section,  while  the  myeloid 
form  is  deep  red  and  soft,  but  both  encroach  upon  the  cortex  of  the  bone 
and  erode  it,  causing  fractures  at  such  weakened  spots.  In  both  types 
there  occurs  in  the  urine  a  peculiar  albumose  (Bence  Jones  protein),  the 
mode  of  formation  of  which  is  much  debated.  In  neither  form  is  there  any 
constant  or  characteristic  alteration  of  the  blood  in  the  sense  of  a  leuksemic 


838 


TEXT-BOOK    OF   PATHOLOGY 


flooding  with  lymphoid  or  myeloid  cells,  but  in  one  of  the  three  cases 
of  the  lymphoid  form  which  we  observed  this  winter  there  were  excessive 
numbers  of  large  lymphoid  cells  with  the  morphology  of  plasma  cells,  in 
the  circulating  blood. 

In  two  of  these  cases  there  were  prominent  tumors  projecting  from  the 
ribs,  vertebrae,  and  long  bones.  On  sawing  through  the  bones  it  was  found 
that  the  involvement  of  the  marrow  was  far  greater  than  coul'd  be  realized 
from  the  surface.  Where  the  tumors  showed,  the  enlargement  was  partly 
due  to  lifting  up  of  the  cortex,  partly  to  its  actual  erosion  and  the  protrusion 


Fig.  416. — Lymphoid  myeloma.     The  cells  closely  resemble  plasma  cells. 

of  the  tumor.  There  were  several  fractures  of  the  weakened  bones.  In  the 
third  case,  in  which  the  albumosuria  was  absent,  there  were  no  tumors 
springing  from  the  bones,  but  nearly  all  the  ribs  were  broken  and  the  thorax 
collapsed.  The  marrow  was  entirely  replaced  by  masses  of  lymphoid 
cells  and  the  same  was  true  of  the  marrow  of  the  long  bones  where  the  bony 
cortex  had  become  greatly  thinned.  There  was  no  leuksemic  change  in  the 
blood.  The  cells  (Fig.  416)  are  non-granulated  mononuclear  cells  with 
basophilic  protoplasm,  and  are  very  similar  to  the  plasma  cells,  with  which 
they  are  regarded  by  most  writers  as  identical. 


INDEPENDENT   DISEASE    OF   THE    BLOOD-FORMING   ORGANS      839 

Pseudoleuksemia. — Cohnheim  employed  this  term  to  describe  a  case  in 
which  there  was  marked  lymphoid  hyperplasia  in  the  lymph-glands  and 
other  lymphoid  tissue  but  no  leukaemia;  in  other  words,  a  condition  identical 
with  lymphoid  leukaemia,  but  without  the  blood  changes.  Since  that  time 
every  sort  of  obscure  affection  of  the  lymph-glands  has  been  called  by  this 
name,  usually  in  the  lack  of  any  clear  idea  of  the  nature  of  the  case,  and  it 
has  been  particularly  confusing  in  the  case  of  Hodgkin's  disease.  At  the 
1912  meeting  of  the  German  Pathological  Association  in  Strassburg  this 
was  made  the  subj  ect  of  discussion.  Frsenkel  and  Sternberg  agreed  that 
such  a  condition  as  Cohnheim  described  existed,  and  that  it  differed  from 
lymphosarcoma  and  Hodgkin's  disease,  but  that  in  some  cases  there  arose  a 
sublymphsemic  condition  of  the  blood  or  even  a  leukaemic  condition,  after 
which  it  could  no  longer  be  distinguished  from  leukaemia.  In  the  long  dis- 
cussion which  followed  no  one  referred  specifically  to  any  case  of  this  dis- 
ease nor  did  any  one  seem  familiar  with  it.  It  is  unquestionably  a  very 
uncommon  affection,  and  the  instances  which  are  referred  to  are  usually 
those  in  which  there  has  been  clinical  study  only.  Nevertheless,  one  does 
meet  with  cases  in  which  there  is  swelling  of  the  glands  which  form  bulky 
packets,  enlargement  of  the  spleen,  and  no  blood  change.  If  such  cases  at 
autopsy  prove  to  be  due  to  a  true  hyperplasia  of  lymphoid  tissue  without 
leukaemia  and  without  invasion  of  the  tissues,  they  will  fulfil  the  definition 
of  pseudoleukaemia. 

Lymphosarcoma. — Kundrat  was  the  first  to  give  a  clear  description  of  the 
disease  which  he  outlined  as  lymphosarcomatosis.  In  this  he  recognized  a 
more  or  less  wide-spread  growth  arising  from  a  group  of  lymph-glands  (more 
rarely  from  a  single  one)  or  from  a  tract  of  lymphoid  tissue  such  as  occurs  in 
the  intestinal  wall,  pharynx,  etc.  Such  a  growth  is  composed  of  a  delicate 
reticulum  in  the  meshes  of  which  lie  cells  of  a  lymphoid  character.  It  fails 
to  respect  the  capsules  of  the  lymph-glands  but  grows  rapidly  and  invades 
and  infiltrates  adjacent  tissues.  Isolated  metastases  in  distant  organs  are 
rare,  but  the  adjacent  lymph -glands  may  be  involved;  otherwise  the  growth 
tends  to  spread  in  loose  tissue  and  in  film  or  plate  form  over  serous  surfaces. 
Throughout,  Kundrat  recognized  the  regional  character  of  the  growth. 
Where  the  tumor  appears  in  the  form  of  a  metastatic  nodule  in  such  organs 
as  the  heart  or  kidney,  the  sharply  outlined  nodule  seen  with  the  naked 
eye  proves  to  be  a  localized  infiltration  of  cells  between  the  muscle-fibres 
or  tubules  (Fig.  417).  Eight  cases  which  I  was  able  to  study  seemed 
to  fall  into  two  groups.  Three  showed  thoracic  masses  apparently  derived 
from  mediastinal  lymph-glands  and  limited  in  their  extension  to  the  thorax, 
while  five  were  equally  limited  to  the  abdominal  cavity.  They  differed 
slightly  in  the  form  of  the  cells,  which  in  the  thoracic  type  were  small 
(4-6  n),  while  in  the  abdominal  type  they  measured  8-12  /j,  and  were 
associated  with  a  fev^  scattered  phagocytic  cells  of  large  size.  The  thoracic 
type  formed  great  masses  of  solid  tissue  surrounding  the  heart  and  com- 
pressing the  lungs.  In  one  case  these  had  actually  penetrated  the  heart-wall 


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TEXT-BOOK    OF    PATHOLOGY 


and  hung  in  polypoid  lobules  in  the  cavity  of  the  right  ventricle.  The  abdom- 
inal or  intestinal  type,  as  already  mentioned,  either  formed  great  ring-shaped 
masses  at  intervals  along  the  intestine,  penetrating  into  its  lumen  and 
obstructing  it  until  ulceration  again  opened  the  channel,  or  else  they 
infiltrated  the  whole  wall  diffusely  for  a  long  way,  and  by  making  it 
rigid  and  inactive  might  have  caused  a  so-called  paralytic  ileus.  The 
intestine  comes  to  look  like  a  stiff  piece  of  garden  hose,  and  the  folds  of 
mucosa  are  all  greatly  swollen  and  stand  up  stiffly  (Fig.  418).  In  such 


Fig.  417.— Lymphosarcoma.  Infiltrating  mass  appearing  as  a  quite  sharply  outlined 
nodule  in  the  kidney.  This  was  a  case  in  which  the  intestine  was  probably  the  point 
of  origin. 

intestinal  cases  it  is  not  uncommon  to  find  organs  such  as  the  adrenal  and 
pancreas  completely  buried  in  an  infiltrating  mass  of  the  tissues.  The 
mesenteric  glands  are  usually  greatly  enlarged  by  a  similar  infiltration. 
The  spleen  shows  no  especial  alteration  in  either  of  these  types,  nor  do  the 
more  distant  lymph-glands.  It  is  generally  stated  that  the  bone-marrow 
is  quite  unaffected  and  that  there  are  no  alterations  of  the  blood.  In  two 
of  our  cases  there  was  hyperplastic  bone-marrow  in  the  long  bones  and 
there  were  many  cells  which  resembled  precisely  those  of  the  tumor  growth, 


INDEPENDENT   DISEASE    OF   THE    BLOOD-FORMING    ORGANS      841 

and  formed  solid  masses  of  tumor  tissue.  Further  and  more  modern 
study  of  the  bone-marrow  in  such  cases  must  be  made.  Lymphosarcoma 
arising  from  other  groups  of  lymph-glands  occurs  as  mentioned  above  and 
presents  similar  characteristics. 

The  characters  which  distinguish  a  lymphosarcoma  from  other  condi- 
tions which  resemble  it  in  a  confusing  way  may  be  best  set  down  in  a  com- 
parative form.  From  a  single  section  it  would  probably  be  impossible  from 
a  study  of  the  cells  to  distinguish  between  an  involvement  of  a  gland  by 
chronic  lymphoid  leukaemia,  leucosarcoma,  lymphosarcoma,  and  small 
round-cell  sarcoma.  In  chronic  leukaemia  the  glands  become  enlarged 
but  remain  discrete,  there  is  dissemination  of  lymphoid  cells  in  the  capil- 


II 

1 

Fig.  418. — Lymphosarcoma.     Infiltration  of  valvulae  conniventes  of  the  jejunum. 

laries  of  organs  otherwise  practically  unchanged,  and  there  is  the  leukaemic 
state  of  the  blood.  In  leucosarcoma  there  is  an  invasive  lymphoid  tumor 
and  there  may  be  nodular  infiltrations,  but  once  more  there  is  the  leukaemic 
state  of  the  blood.  In  lymphosarcoma  there  is  an  invasive  or  infiltrating 
lymphoid  growth  which  has  a  peculiar  regional  way  of  spreading  and  is 
rather  limited  either  to  the  thorax  or  the  abdomen.  It  is  much  like  leuco- 
sarcoma except  that  there  is  no  leukaemic  change  of  the  blood.  Round- 
cell  sarcomata  offer  much  less  difficulty :  they  start  anywhere  in  the  con- 
nective tissue  (not  in  the  lymph-glands  especially)  as  a  single  tumor  nodule 
which  invades  the  surroundings  and  metastasizes  by  way  of  the  blood- 
stream, forming  new  discrete  nodules  in  distant  organs,  such  as  the  lungs, 


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TEXT-BOOK    OF    PATHOLOGY 

\ 


Fig.  419.-Intestine  in  status  lymphaticus,  showing  great  enlargement  of  lymphoid 

nodules. 


INDEPENDENT  DISEASE    OF   THE    BLOOD-FORMING   ORGANS      843 


liver,  etc.  When  they  lodge  in  a  lymph-gland  they  produce  a  solid  nodule 
with  an  outline,  outside  which  some  remnant  of  the  gland  may  be  found 
unchanged.  All  the  others  cause  a  complete  replacement  of  the  gland, 
although  occasionally  a  localized  lymphosarcomatous  infiltration  may  leave 
the  rest  of  the  gland  intact.  With  round-cell  sarcoma  there  is  no  leukaemia. 
Status  Lymphaticus  or  Thymico-lymphaticus. — In  many  young  persons 
and  children  who  have  died  suddenly  after  some  slight  shock  or  infection 
which  seemed  insufficient  to  cause  death,  there  is  found,  at  autopsy,  a  general 
swelling  of  the  lymphoid  structures  and  persistence  or  enlargement  of  the 
thymus.  Paltauf  was  the  first  to 
point  out  clearly  that  this  lym- 
phoid hyperplasia  is  only  part  of  a 
general  constitutional  abnormal- 
ity which  amounts  to  a  physical 
inferiority  of  the  persons  affected. 
The  whole  complex  is  best  seen  in 
young  persons,  since  only  part  of 
it  is  as  yet  evident  in  children, 
while  the  lymphoid  changes  fade 
in  old  people.  In  men  there  is 
an  incomplete  development  of  the 
secondary  sexual  characteristics 
with  a  tendency  toward  the  femi- 
nine type — the  hair  on  the  face  is 
scanty  or  lacking,  the  pubic  hair 
has  the  feminine  distribution, 
being  sharply  limited  toward  the 
abdomen,  the  external  genitals 
are  small,  the  thighs  round  and 
arched  anteriorly,  and  the  skin 
smooth  and  velvety.  In  women, 
thorax  and  extremities  are  slen- 
der, the  genitals  are  hypoplastic, 
menstruation  is  irregular  or  ab- 
sent, and  there  may  be  a  tendency 

to  growth  of  hair  on  the  face.  In  such  persons  the  musculature  may  be 
flabby  and  weak,  though  sometimes  well  developed,  but  the  heart  is  weak 
and  soft  and  the  large  blood-vessels  are  relatively  narrow  and  thin  walled. 
It  appears  that  failure  of  this  inadequate  circulatory  mechanism  may  be 
one  at  least  of  the  causes  of  sudden  death  and  probably  the  most  impor- 
tant. Emerson  finds  such  cases  most  common  among  alcoholics  and  drug 
habitue's,  but  it  is  by  no  means  limited  to  mental  degenerates.  Persons 
with  this  constitutional  abnormality  are  evidently  far  more  exposed  than 
others  to  destruction  by  the  injuries  and  infections  incidental  to  life,  and 
if  they  reach  mature  age,  it  is  through  especial  care  or  good  fortune. 


Fig.  420. — Status  lymphaticus.  Enlarge- 
ment of  tonsils  and  lymphoid  nodules  at  the 
root  of  the  tongue. 


§44  TEXT-BOOK   OF  -PATHOLOGY 

At  autopsy  one  finds  the  lymphoid  nodules  throughout  the  digestive 
tract  especially  enlarged  and  prominent  (Fig.  419).  In  the  throat  and  at 
the  base  of  the  tongue  the  adenoid  tissue  is  swollen  too  (Fig.  420),  although 
Emerson  makes  little  of  this  point.  The  lymph-glands  in  general  may  be 
larger  than  normal,  although  this  is  not  constant.  The  spleen  is  not 
particularly  affected  except  that  the  Malpighian  bodies  are  enlarged. 
There  is  often  red  bone-marrow.  The  thymus  is  commonly  persistent  and 
often  greatly  enlarged,  so  as  to  weigh  forty  to  fifty  grams  and  extend  far 
down  over  the  pericardium.  The  narrowness  and  delicacy  of  the  aorta  and 
the  smallness  of  the  heart  are  striking.  Wiesel  has  described  in  many 
cases  hypoplasia  of  the  adrenals  and  chromaffin  system  and  thinks  that 
the  condition  of  the  circulatory  apparatus  is  connected  with  that.  The 
lymphoid  tissue  shows  no  such  hyperplasia  as  is  seen  in  leukemia,  but 
maintains  its  architecture  and  the  relations  of  lymphoid  cells  to  germinal 
centres.  Details  of  this  affection  should  be  read  in  the  papers  of  Neusser, 
Bartel  and  Bauer,  and  others.  It  may  be  interesting  to  quote  Neusser 's 
division  of  constitutions  into  two  categories.  One,  the  bearer  of  a 
good  heart,  good  blood-vessels,  good  bone-marrow,  good  sympathetic 
and  chromafnn  system,  and  good  genitals,  is  like  a  folio  edition  of  the 
genus  Homo;  while  the  other  shows  just  the  opposite,  with  its  poor  heart, 
poor  hypoplastic  vessels,  poor  bone-marrow,  poor  genitals,  poor  chromafnn 
and  sympathetic  system. 

LITERATURE 

General — Sternberg:  Ergebnisse  d.  allg.  Path.,  1903,  ix,  IP6  Abt.,  360. 
Leukcemia — Nsegeli:  Leukaemia  u.  Pseudoleukaemia,  Wien,  1913. 

Sternberg:  Ztschr.  f.  Heilkunde,  1904,  xxv,  Path.  Abth.,  170. 
Reed:  Amer.  Jour.  Med.  Sci.,  1902,  cxxiv,  653. 
Leucosarcoma— Sternberg:  Wien.  kl.  Woch.,   1908,  xxi,  475.     Ziegler's  Beitr.,   1915, 

lxi,75. 
Myeloma — Christian:  Jour.  Exp.  Med.,  1907,  ix,  325. 

Sherman:  Edin.  Med.  Jour.,  1913,  n.  s.  x,  321. 
Hoffman:  Ziegler's  Beitr.,  1904,  xxxv,  317. 
Sternberg:  Ztsch.  f.  Heilk.,  1904,  xxv,  Path.  Abth.,  89. 
Hedinger:  Frankf.  Ztsch.  f.  Path.,  1911,  vii,  343. 
MacCallum:  Jour.  Exp.  Med.,  1901-05,  vi,  53. 
Pseudoleukcemia— Frsenkel:  Verh.  d.  Dtsch.  Path.  Gesellsch.,  1912,  xv,  5. 

Sternberg:   Ibid.,  22;  discussion,  82. 
Lymphosarcoma — Kundrat:  Wien.  kl.  Woch.,  1893,  vi,  211. 

Paltauf :  Ergebn..  d.  allg.  Path.,  1896,  iii,  652. 

MacCallum:  Johns  Hopkins  Hosp.  Bull.,   1907,  xviii,  337.     Trans. 

Assoc.  Am.  Phys.,  1907,  xxii,  350. 

Status  lymphaticus — Neusser:  Diagnose  des  Status  Thymico-lymphaticus,  Wien,  1911. 
Bartel:  Status  Thymico-lymphaticus,  Leipzig,  1912. 
Paltauf:  Wien.  kl.  Woch.,  1889,  ii,  876;  1890,  iii,  172. 
Emerson:  Arch.  Int.  Med.,  1914,  xiii,  169. 
ZeUweger:  Ztsch.  f.  angew.  Anat.  u.  Konstitutionslehre,   1913, 

i,  192. 
v.  Werdt:   Berl.  kl.  Woch.,  1910,  xlvii,  2383. 


CHAPTER  XLII 

EFFECTS  OF  INJURIES  TO  THE  BLOOD  AND  BLOOD-FORMING 

ORGANS  (Continued) 

Chronic  myeloid  leukcemia.  Acute  myeloid  leukaemia,  myeloblastic  leukcemia.  Myeloid 
chloroma  or  chloromyelosarcoma.  Myeloid  myeloma.  Hodgkin's  disease  or  lympho- 
granulomatosis . 

CHRONIC  MYELOID  LEUKEMIA 

THE  beginning  of  this  disorder  is  usually  gradual  and  unnoticed,  with 
weakness  and  loss  of  weight,  after  which  anaemia  and  slight  haemorrhages 
appear.  Many  of  the  patients  suffer  no  particular  discomfort  and  show  no 
anaemia  until  late  in  the  disease,  but  apply  for  relief  from  a  large  abdominal 
tumor  which  proves  to  be  the  enormously  enlarged  spleen.  Examination 
of  the  blood  shows  a  very  great  increase  in  the  number  of  white  cells  which 
are  easily  seen  to  be  large  granular  cells.  They  may  reach  a  count  of  over 
1,000,000  per  c.mm.  More  careful  study  reveals  the  fact  that  while  at 
first  the  polymorphonuclear  neutrophiles  are  still  the  predominant  cells, 
there  is  later  a  great  increase  in  the  neutrophile  myelocytes  which  usually 
become  the  most  numerous  cells.  Eosinophile  myelocytes  also  appear  in 
great  numbers,  while  eosinophile  leucocytes,  though  absolutely  increased, 
like  the  neutrophile  leucocytes,  do  not  attain  to  any  great  proportion  among 
all  the  cells.  Mast  leucocytes  with  their  basophile  granulations  and 
basophilic  myelocytes  are  abundant  and  conspicuous.  Lymphocytes  are 
present  in  small  numbers  and  form  a  very  small  proportion  of  the  total. 
Normoblasts  and  rarely  megaloblasts  appear  in  later  stages  when  the 
anaemia  becomes  more  marked.  The  appearance  of  such  blood  with  its 
huge  numbers  of  large  granular  myelocytes  is  most  astonishing  even  when 
compared  with  the  much  altered  blood  of  the  lymphoid  forms  of  leukaemia. 
In  late  stages  when  the  alterations  have  become  most  intense,  non-granular 
myeloblasts  may  appear  in  considerable  numbers.  These,  like  the  granular 
cells  just  mentioned,  give  the  oxydase  reaction  most  brilliantly,  and,  as 
might  be  expected,  the  blood  in  these  cases  is  rich  in  proteolytic  ferments. 
There  may  be  no  reduction  in  the  red  corpuscles  until  quite  late  in  the 
disease.  Then,  partly  as  a  result  of  the  haemorrhages,  their  number  sinks 
and  normoblasts  appear  in  the  circulation.  In  some  cases  megaloblasts 
are  found  and  the  form  of  the  red  corpuscles  (anisocytosis,  poikilocytosis) 
recalls  that  seen  in  pernicious  anaemia.  Megalocaryocytes  are  sometimes 
found. 

With  the  advance  of  the  disease  there  often  occur  rather  extensive 
haemorrhages  from  the  mucosae  or  into  the  retinae  or  other  organs.     Death 

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from  apoplexy  seems  to  be  relatively  common.  Extensive  necrotic  and 
gangrenous  processes  sometimes  appear  here  just  as  in  the  lymphoid  cases. 
There  have  been  reported  a  few  instances,  such  as  those  of  Thompson 
and  Ewing,  Burckhardt,  and  others,  in  which  such  myeloid  leukaemia 
with  predominant  myelocytes  in  the  blood  has  arisen  acutely  and  quickly 
led  to  sudden  death,  and  in  these  cases  evidences  of  hemorrhage  and 

necrotizing  processes  are  most  striking. 
They  are  mentioned  here  because  there  is 
another  group  of  acute  myeloid  leukaemias 
to  be  discussed  later  in  which  myeloblasts 
form  the  predominant  cell  in  the  blood. 

At  autopsy,  in  cases  of  chronic  myeloid 
leukaemia,  the  blood  is  found  clotted  in  the 
heart  and  large  vessels  and  is  so  peculiar  in 
appearance  that  it  suggested  to  Virchow 
the  name  leukaemia  or  white  blood.  When 
it  clots  slowly,  as  in  the  heart,  the  upper  part 
of  the  clot  is  whitish  or  greenish  and  rather 
opalescent  on  account  of  the  great  number 
of  leucocytes.  In  a  typical  case  which  we 
have  studied,  the  clots  evidently  formed 
more  rapidly  for  they  were  of  a  quite  uni- 
form pale  chocolate  color.  The  most  strik- 
ing phenomenon  at  autopsy  is  the  great 
enlargement  of  the  spleen  (Fig.  421),  which 
is  smooth  and  firm  and  often  deeply  notched 
at  its  edge.  In  some  cases  it  is  adherent 
to  the  diaphragm  and  abdominal  wall.  It 
stretches  downward  toward  the  right  and 
may  reach  the  symphysis  pubis,  filling  a 
great  part  of  the  abdominal  cavity  and  ap- 
pearing to  rest  on  the  right  ilium.  In  the 
case  just  mentioned  it  weighed  1550  grams 
but  it  may  weigh  as  much  as  10,000  grams. 
On  section  it  is  grayish-red  and  finely  gran- 
ular and  opaque;  the  Malpighian  bodies 
have  disappeared  but  the  trabeculae  can 

usually  be  fairly  clearly  seen.  Sometimes,  however,  in  the  later  stages  it 
is  very  fibrous  and  dense  and  the  whole  structure  assumes  a  rather  uni- 
form appearance.  Infarcts  are  quite  common.  The  bone-marrow  in  the 
long  bones  is  no  longer  fatty  but  firm,  opaque  yellowish  gray  or  pinkish- 
gray,  and  homogeneous.  It  can  be  cut  out  in  blocks  and  is  evidently  a  solid 
mass  of  cells.  The  liver  is  enlarged  and  rather  pale  but  usually  without 
any  grossly  visible  change  in  the  structure.  However,  in  the  case  men- 
tioned there  were  several  opaque  grayish  nodules  embedded  in  its  sub- 


W 


Fig.  421. — The  spleen  in  chronic 
myeloid  leukaemia. 


CHRONIC   MYELOID    LEUKAEMIA 


847 


stance  and  reaching  5  to  8  mm.  in  diameter,  which  proved  to  be  masses  of 
myeloid  tissue.  The  other  organs  show  no  characteristic  gross  changes 
except  the  effects  of  the  anaemia,  which  are  seen  in  the  general  pallor  of 
the  organs  and  in  accumulations  of  fat  in  the  heart,  kidneys,  etc.  The 
lymph-glands  are  not  enlarged  and  with  the  rest  of  the  lymphoid  tissue 
appear  to  play  no  part  in  the  process.  Apoplectic  hemorrhages  in  the 
brain  have  already  been  mentioned.  Thrombosis  of  various  veins  is  not 
uncommon.  When  complicating  infections  occur  the  leucocytosis  which 
attends  them  may  be  quite  normal  and  the  reaction  about  the  bacteria 
and  injured  tissue  typical.  In  such  cases  the  whole  blood  picture  can 
change  so  that  the  leuksemic  character  disappears,  and  in  place  of  the 


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^®^^r 

«;  V 


Fig.  422. — Bone-marrow  in  chronic  myeloid  leuksemia.  There  are  very  abundant 
neutrophile  (B)  and  eosinophile  (C)  myelocytes,  megalocaryocytes  (A),  and  a  few 
normoblasts  (D). 


horde  of  myelccytes  there  are  found  the  neutrophile  leucocytes.  Such  a 
change  does  not  last,  however,  and  when  the  occasion  for  leucocytosis  is 
over  the  leukemia  returns.  I  have  not  seen  such  a  case  but  it  would 
appear  to  offer  an  interesting  field  for  study  of  the  nature  of  leuksemia. 

Microscopically  the  bone-marrow  is  the  tissue  of  prime  interest.  It 
appears  as  a  solid  array  of  cells  among  which  the  capillary  vessels  can  be 
made  out  with  some  difficulty  (Fig.  422).  Within  these  vessels  there  are 
great  numbers  of  neutrophile  myelocytes,  eosinophile  myelocytes,  leucocytes 
of  all  kinds,  and  red  corpuscles.  Outside,  but  evidently  able  to  enter  the 
blood-channels  pretty  easily,  are  masses  of  neutrophile  myelocytes  with 
somewhat  smaller  numbers  of  eosinophile  myelocytes.  Basophile  myelo- 


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cytes  are  also  present  in  great  numbers,  and  there  are  other  non-granular 
mononuclear  cells  of  rather  large  size  which  are  probably  myeloblasts. 
Neutrophile  leucocytes  are  there  in  rather  large  quantities  too,  but  there  is 
not  much  to  be  seen  of  red  blood-cells  or  of  erythroblastic  tissue.  Normo- 
blasts  are  present  here  and  there  in  small  groups  but  must  be  searched  for. 
From  this  it  seems  that  the  progressive  anemia  in  this,  as  in  other  types  of 
leukaemia,  may  be  due  to  the  actual  crowding  out  of  the  erythroblastic  tissue 


Fig.  423 — Spleen  in  chronic  myeloid  leukaemia.  Space  between  two  adjacent 
venules,  showing  numerous  myelocytes  of  neutrophile  and  eosinophile  type.  Many 
cells,  emigrating  from  the  venules,  of  which  some  appear  to  be  nucleated  red  corpuscles. 

rather  than  to  the  haemorrhages,  which  are  not  always  very  evident.  In 
this  respect  it  would  resemble  the  osteosclerotic  anaemia  mentioned  above. 
The  spZeen  (Fig.  423)  in  this  disease,  has  almost  the  same  composition  in 
respect  to  the  cells  present  as  the  bone-marrow;  it  resembles  in  an  exagger- 
ated way  the  myeloid  spleen  found  in  the  osteosclerotic  anaemia.  As  shown 
in  the  drawing,  the  venules  of  the  splenic  pulp  (Malpighian  bodies  are  not 
found)  are  intact  and  in  themselves  unaffected.  They  are  full  of  myelo- 
cytes and  in  the  intervening  spaces  myelocytes  of  all  kinds  are  crowded 


CHRONIC   MYELOID    LEUKAEMIA 


849 


together  with  some  red  corpuscles  and  a  few  nucleated  red  cells.  Myelo- 
blasts,  nucleated  red  cells,  and  even  lymphocytoid  cells  are  constantly 
found  passing  through  the  walls  of  the  venules  which  seem  to  be  as  open  as 
so  much  mosquito  netting. 

In  all  the  other  organs  the  microscopical  alterations  consist  essentially 
in  the  filling  of  the  capillaries  with  myelocytes,  etc.,  from  the  leukaemic 
blood  (Fig.  424).  In  the  liver  the  capillaries  may  be  hugely  distended 


°«*  «* 


e  -^, 


.**«?£ 


Fig.  424. — Myeloid  leukaemia.     General  infiltration  of  the  liver  with  myeloid  cells. 


with  clumps  and  masses  of  these  cells.  It  is  interesting  to  note  that 
no  necroses  occur  in  the  liver-cells  or  even  among  the  packed  myelocytes 
themselves.  In  this  the  myelocytes  differ  from  the  cells  found  distending 
these  capillaries  in  typhoid  fever,  which  seem  unused  to  life  within  the 
vessels  and  in  addition  carry  seeds  of  death  with  them.  In  the  nodules 
mentioned  above  there  are  huge  pools  of  myeloid  cells  and  the  liver-cells 
are  compressed  into  flattened  rows  or  squeezed  out  of  existence  entirely. 
55 


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Some  of  the  wide  capillaries  contain  megalocaryocytes  in  groups,  and  the 

whole  area  has  assumed  the  exact  appearance  of  bone-marrow  (Fig.  425). 

Other  organs  are  also  thickly  infiltrated  with  myelocytes  (Fig.  426),  but 

as  a  rule  show  little  of  actual  myeloid  colonization.     The  lymph-glands 


Fig.  425. —  Myeloid  leukaemia.  Myeloid  area  in  the  liver,  showing  displacement  of 
liver-cells  by  the  abundant  myelocytes,  and  in  the  endothelium-lined  capillaries  many 
megalocaryocytes. 

merely  participate  passively  in  this  process— occasionally  their  sinuses  are 
stuffed  with  the  cells  of  the  blood. 

The  nature  of  the  process  is  quite  obscure  as  in  the  other  forms,  but  it 
seems  clear  that  the  changes  are  primary  in  the  bone-marrow,  and  that 
those  of  the  spleen  and  other  organs  are  secondary.  Nevertheless  it  is  also 
pretty  clear  that  new  formation  of  cells  goes  on  in  the  myeloid  accumula- 


ACUTE   MYELOID    LEUKAEMIA. — MYELOBLASTIC    LEUKAEMIA      851 

tions  of  tissue  in  spleen  and  liver,  although  not,  it  seems  to  me,  as  the  result 
of  activity  on  the  part  of  splenic  or  hepatic  endothelium. 

ACUTE  MYELOID  LEUKAEMIA.— MYELOBLASTIC  LEUKAEMIA 

We  have  already  mentioned  the  existence  of  cases  in  all  respects  like  the 
chronic  myeloid  leukaemia  except  that  their  fatal  course  is  very  rapid  and 
marked  by  the  occurrence  of  more  extensive  hemorrhages  and  ulcerations  of 
mueosae.  In  another  and  larger  group  of  these  acute  cases  whose  symptoms 


Fig.  426. — Myeloid  leukaemia.     Heart  showing  the  overfilling  of  the  capillaries  with  mye- 
loid cells. 

are  not  to  be  easily  distinguished  from  those  of  acute  lymphoid  leukaemia, 
the  differences  lie  in  the  fact  that  the  non-granular  mononuclear  cells  which 
are  predominant  in  the  blood  and  tissues  are  not  lymphocytes,  but  myelo- 
blasts,  as  shown  by  their  possession  of  a  proteolytic  ferment  action  in  an 
alkaline  medium  and  by  their  positive  oxydase  reaction.  In  these  cases 
there  is  a  great  overflooding  of  the  blood  with  white  cells,  most  of  which  are 
myeloblasts;  the  bone-marrow  shows  a  myeloid  hyperplasia  in  which  they 
are  prominent,  and  there  are  myeloid  changes  in  the  spleen  and  liver. 
Haemorrhages,  necrotic  and  ulcerative  stomatitis,  etc.,  are  common. 


852  TEXT-BOOK   OF   PATHOLOGY 

Lymph-glands  may  be  enlarged,  but  commonly  are  not.  The  whole  condi- 
tion has  the  appearance  of  an  acute  infectious  process,  and  indeed  infections 
often  exist,  but  whether  as  cause  or  as  incidental  accompaniment  it  is  difficult 
to  say.  Sternberg,  however,  is  so  impressed  by  this  that  he  proposes  to 
exclude  the  myeloblastic  leukaemia  completely  from  the  group  of  leukaemias 
and  to  regard  it  as  an  infectious  process — the  more  so  since  it  has  been 
shown  that  a  number  of  extremely  severe  infections  can  cause  the  appear- 
ance of  huge  numbers  of  myeloblasts  or  myelocytes  in  the  circulating  blood. 
These,  however,  are  not  progressive  processes,  and  the  myeloid  cells  dis- 
appear with  recovery  from  the  infection. 

The  question  of  the  relation  of  infection  to  the  whole  group  of  leukaemias 
is  one  which  we  can  hardly  discuss  as  yet  with  profit.  All  of  them  have 
something  of  the  character  of  infections  and  although  we  have  no  facts  to 
go  on  it  seems  impossible  to  single  out  one  form  as  definitely  infectious  on 
such  inadequate  evidence.  Only  when  we  have  a  firmer  knowledge  of  their 
aetiology  shall  we  be  able  to  make  a  rational  classification. 

MYELOID  CHLOROMA.     CHLOROMYELOSARCOMA 

The  justification  for  the  isolation  of  this  group  is  much  the  same  as  in  the 
case  of  the  lymphoid  chloroma  or  chloroleukosarcoma  and  the  same  argu- 
ments have  been  raised  against  it.  The  peculiar  feature  consists  in  the 
formation  of  tumor-like  growths  within  the  bone-marrow  or  extending 
through  the  cortex  of  the  bone  to  spread  over  the  periosteal  surface.  Some 
of  them  spring  apparently  from  the  periosteum.  They  may  or  may  not 
have  a  bright  grass  green  color,  and,  as  in  the  lymphoid  chloroma,  the  in- 
constancy of  this  color  makes  it  seem  an  inadequate  basis  of  classification. 
The  tumors  allow  the  myeloid  cells  to  escape  in  great  numbers  into  the 
circulation  and  are  thus  accompanied  by  a  leukaemic  state  of  the  blood. 
The  bone-marrow,  in  Meixner's  case,  was  partly  red,  partly  occupied  by 
masses  of  myelocytes  which  in  the  gross  looked  green.  The  lymph-glands 
were  unaffected;  the  spleen  much  infiltrated  with  myelocytes. 

MYELOID  MYELOMA 

In  the  previous  chapter  we  spoke  of  multiple,  rather  invasive,  tumor-like 
growths  springing  from  the  bone-marrow  and  composed  of  mononuclear 
cells  which  have  been  regarded  as  plasma  cells.  There  are  other  cases, 
however,  in  which  the  tumors  have  in  general  the  same  distribution  but 
differ  in  appearance,  being  very  soft  and  deep  red  in  most  parts.  They 
infiltrate  and  destroy  the  bones  and  give  rise  to  repeated  fractures.  As  in 
the  other  type  there  is  found  the  Bence- Jones  albumose  in  the  urine. 

Boggs  and  Guthrie  have  shown  that  this  albumose  is  by  no  means  limited  to  cases 
of  myeloma,  and  even  that  it  may  be  absent  in  some  well-defined  cases  of  this  affection. 
On  the  other  hand  it  is  present  in  cases  of  carcinomatous  invasion  of  the  bone-marrow 
and  in  cases  of  chronic  myeloid  leukaemia.  The  mechanism  of  its  production  is  as  yet 
too  uncertain  to  discuss  here. 


HODGKIN'S  DISEASE  OR  LYMPHOGRANULOMATOSIS          853 

The  cells  which  form  these  tumors  have  occasionally  been  demonstrated 
to  be  myelocytes  or  even  erythroblasts  (Ribbert) ,  but  in  most  cases  they 
correspond  with  myeloblasts.  In  a  case  which  I  studied  ten  years  ago 
I  thought  that  their  identity  with  myeloblasts  was  proven  (Fig.  427). 
It  is  to  be  hoped  that  in  future  the  oxydase  reaction  will  be  applied  to  these 
cases  to  settle  this  point  definitely.  No  leuksemic  changes  occur  in  the 
blood. 


Fig.  427. — Myeloid  myeloma.  The  cells  are  larger  than  those  of  the  lymphoid 
myeloma  (Fig.  416),  which  are  drawn  to  the  same  scale.  They  show  no  definite  granules, 
but  would  probably  give  the  oxydase  reaction. 

HODGKIN'S  DISEASE  OR  LYMPHOGRANULOMATOSIS 

While  not  an  example  of  the  hyperplasia  of  either  myeloid  or  lymphoid 
tissue,  the  clinical  and  gross  anatomical  difficulties  in  diagnosis  make  it 
desirable  that  Hodgkin's  disease  should  be  considered  in  this  connection. 
Described  by  Hodgkin  together  with  a  number  of  other  conditions  in  1832, 
much  confusion  existed  as  to  the  nature  of  the  process  until  the  work  of 
Sternberg,  Reed,  Longcope,  Ziegler,  and  others  established  the  fact  that 
there  is  a  peculiar  and  specific  histological  picture  which  sets  it  apart  as  a 
separate  disease. 

The  affection  is  commonly  found  in  rather  young  persons  and  far  more 
frequently  in  men  than  in  women.  Beginning  with  painless  swelling  of  the 
superficial  lymph-glands,  it  progresses  with  gradual  enlargement  of  these 


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glands  and  signs  of  similar  enlargement  of  others  within  the  thorax  or  ab- 
domen, and  usually  with  increase  in  size  of  the  spleen.  Anaemia  appears 
and  may  reach  a  profound  degree.  There  may  be  evidences  of  mechan- 
ical pressure  exerted  by  the  enlarged  glands  upon  the  veins,  producing 
oedema  of  the  face  or  other  regions,  upon  the  trachea,  leading  to  emphysema 
in  some  cases,  or  upon  some  part  of  the  alimentary  tract,  causing  character- 
istic effects.  Death  is  the  result  of  one  of  these  mechanical  influences,  of 
some  intercurrent  infection,  or  of  the  anaemia  and  cachexia  produced  by  the 
disease  itself.  It  may  be  well  to  describe  the  peculiar  change  in  the  tis- 


Fig.  428. — Hodgkin's   disease;   early  stage.      Lymphoid   and   epithelioid    cells   with 
scattered  eosinophiles  and  large  multinuclear  cells. 

sues,  which  is  the  same  wherever  it  occurs,  before  discussing  in  detail  the 
distribution  of  the  lesions.  The  lesion  is  best  seen  (Fig.  428)  in  the  lymph- 
glands  where,  in  different  nodules,  it  may  be  followed  through  the  changes 
which  it  undergoes  in  the  course  of  its  development.  In  the  smaller  nodes 
the  beginning  of  the  process,  as  Dr.  Reed  pointed  out,  consists  in  a  prolifera- 
tion of  the  lymphoid  cells,  which  is  soon  followed  by  the  appearance  of  a 
coherent  tissue  formed  of  larger  and  paler  cells  with  elongated  vesicular 
and  rather  palely  staining  nucleus.  These  resemble  the  reticulum  cells 
and  have  been  called  endothelioid  cells.  They  lie  in  no  particular  order 


HODGKIN'S  DISEASE  OR  LYMPHOGRANULOMATOSIS 


855 


but  they,  together  with  the  lymphoid  cells  and  others  to  be  described, 
soon  spread  so  as  to  replace  the  normal  tissue  of  the  whole  gland,  obliter- 
ating the  distinction  between  lymph-cords  and  sinuses.  Among  these  cells 
there  are  found  much  larger  ones  which  constitute  the  most  characteristic 
feature  of  the  lesion.  These  are  really  quite  large  cells,  and  while  they  vary 
greatly,  are  many  times  the  size  of  the  lymphocytes.  Their  protoplasm  is 
clear  except  for  scattered,  irregular  stainable  shreds,  and  their  outline  is 
rather  ragged.  They  contain  one  or  two  or  several  large  nuclei  which  are 
rounded  or  indented  or  lobed  and  usually  lie  close  together.  These  nuclei 


Fig  428A. — Hodgkin's  disease;  early  stage. 

are  very  sharply  outlined  with  a  deeply  staining  chromatin  membrane 
within  which  the  nuclear  substance  is  relatively  sparsely  granular.  In 
each  nucleus  there  is  a  large  nucleolus,  sometimes  two,  and  these  nucleoli 
stand  out  very  clearly  with  a  deep  stain.  Besides  the  lymphoid,  epithelioid 
(or  endothelioid)  cells  and  these  large  cells  there  are  usually  found  many 
eosinophile  leucocytes.  Dr.  Reed  made  much  of  their  presence,  but  later 
agreed  that  they  might  be  absent  without  lessening  the  certainty  with 
which  one  might  recognize  the  tissue.  Occasionally,  but  in  my  experience 
rarely,  there  are  found  giant-cells  of  another  type  with  many  rather  small 
nuclei  arranged  in  a  ring  or  horseshoe.  These  are  much  closer  to  the  sort 


856 


TEXT-BOOK   OF   PATHOLOGY 


found  in  foreign  body  giant-cells  or  even  to  those  of  the  tubercle.  The 
reticulum,  in  the  meshes  of  which  these  cells  lie,  is  of  extreme  delicacy  and 
the  whole  mass  thus  forms  a  soft,  rather  translucent  grayish  tissue,  which  is 


•jVrf*  <•<  ~-+-  T-5»rfr:->    ,;     .  --•-     .    .jCT^f     3 

Fig.  429.— Hodgkin's  disease.     Partly  scarred  mass  in  which  there  are  still  areas  of  the 
characteristic  tissue.    The  large  nodule  has  undergone  partial  hyaline  change. 


Fig.  430.-Hodgkin's  disease.    Multiple  irregular  nodules  of  specific  tissue  in  the  spleen. 


HODGKIN'S  DISEASE  OR  LYMPHOGRANULOMATOSIS  857 

quite  elastic  and  in  appearance  quite  homogeneous  (Fig.  428A).  This  cel- 
lular condition  is  found  in  the  earlier  stages,  but  after  a  time  there  appears  a 
progressive  scar  formation  throughout  the  gland  coincident  with  the  dis- 
appearance of  the  cells.  Every  step  in  the  development  of  this  change  can 
be  followed  until  finally  there  is  left  a  dense  mass  of  fibrous  tissue  in  which, 
bere  and  there,  are  to  be  found  pockets  or  nests  of  such  cells  as  have  been 
described  (Fig.  429).  It  should  be  noted  that  this  change  in  the  gland  is 
one  which  even  in  the  earlier  stages  involves  the  whole  gland  and  obliterates 
its  architecture  by  replacing  the  lymph-cords  and  sinuses  with  a  uniform 
cellular  tissue.  In  the  neighborhood  of  such  glands  tiny  new  glandular 
clumps  of  lymphoid  tissue  are  formed  by  a  regenerative  process,  but  these 
are  no  sooner  developed  than  they  are  transformed  into  the  same  new  tissue. 
The  glands  first  affected  are  usually  those  at  the  root  of  the  neck  just  above 
the  clavicle,  where  they  form  a  nodular  mass  almost  like  a  sort  of  collar. 
Thence  those  higher  in  the  neck  are  quickly  involved ;  axillary  and  inguinal 
glands  are  only  less  frequently  concerned.  Sometimes  they  are  extirpated 
at  operation,  and  it  is  then  found  that  in  the  early  stages  they  are  oval  or 
round,  discrete  nodes  which,  unlike  tuberculous  glands  which  adhere  and 
tend  to  bind  themselves  together  in  a  solid  mass,  can  be  easily  pulled  apart. 
The  smooth  glands  on  section  show  the  grayish  gelatinous  elastic  tissue 
described,  but  in  the  somewhat  later  stage  one  very  frequently  finds  in 
them  dry,  opaque,  firm,  yellowish-white  areas  of  necrotic  tissue  with  occa- 
sional hemorrhages.  The  old  cases  still  show  the  glands  in  packets,  loosely 
bound  together,  but  as  time  passes  there  is  more  tendency  to  adhesion. 
The  capsule  and  adjacent  tissue  may  be  especially  thickly  infiltrated  with 
eosinophiles  in  these  advanced  cases.  In  the  interior  of  the  body  the 
bronchial,  peritracheal,  and  mediastinal  glands  are  extensively  involved  and 
form  such  masses  as  to  compress  the  trachea  or  impede  the  heart-beat.  I 
saw  one  case  in  a  woman  in  which  huge  masses  existed  in  the  place  of  the 
bronchial  glands  at  the  bifurcation  of  the  trachea.  From  these  the  tissue 
extended  into  the  lungs  and  there  were  numerous  large  discrete  nodules 
scattered  in  the  lung  tissue.  In  another,  a  negro  boy,  one  lung  was  con- 
verted into  a  solid  gray  translucent  mass  closely  bound  by  the  much 
thickened  pleura  and  showing  no  air-containing  lung  tissue,  but  only 
patches  of  collapsed  alveoli  in  which  the  epithelial  cells  were  loaded  with 
fat.  All  the  gray  tissue  was  of  the  character  just  described  and  though 
already  rather  fibrous,  showed  very  distinctly  all  the  types  of  cells.  In  the 
abdomen,  the  retroperitoneal  glands  and  perhaps  more  especially  the  peri- 
pancreatic  and  periportal  glands  are  likely  to  be  involved.  The  periportal 
glands  may  be  large  enough  to  compress  and  obstruct  the  common  bile- 
duct  and  produce  jaundice.  In  the  liver  Dr.  Reed  describes  the  wide- 
spread occurrence  of  perivascular  and  interlobular  accumulations  of  the 
typical  tissue,  with  its  specific  large  cells,  in  strands  and  small  nodules. 
This  seems  to  be  rather  infrequent.  On  the  other  hand  the  spleen  is 
pretty  regularly  involved,  sometimes  with  mere  swelling  and  with  diffuse 
infiltration  of  the  pulp;  at  other  times,  as  shown  in  Fig.  430,  with 


£58  TEXT-BOOK   OF    PATHOLOGY 

great  enlargement  and  with  numerous  gray  nodules  composed  of  the  char- 
acteristic tissue  and  pretty  sharply  marked  off  from  the  deep  red  pulp. 
Occasionally  such  foci  are  found  in  the  bone-marrow,  which  otherwise 
shows  no  change  except  the  hyperplasia  due  to  secondary  anaemia. 

Longcope  describes  the  invasion  of  the  Hodgkin's  tissue  through  the 
walls  of  the  blood-vessels  so  as  to  penetrate  the  intima.  There  is,  however, 
no  leuksemic  change  in  the  blood  from  such  invasion;  instead  there  is  a 
decrease  in  the  red  cells  and  usually  a  moderate  increase  in  the  leucocytes 
without  much  disturbance  of  their  relative  numbers.  On  the  whole  we  find 
in  this  disease  an  affection  principally  of  the  lymph-glands,  which  become 
greatly  enlarged  by  the  development  in  them  of  a  peculiar  tissue  which 
rather  rapidly  takes  the  place  of  the  original  structure.  Cellular  and  soft 
at  first,  this  tissue  in  the  course  of  time  loses  most  of  its  cells  and  becomes 
scarred  and  hard.  Hence  the  recognition  of  soft  and  hard  forms  of  lymph- 
gland  involvement.  The  growth  is  not  limited  to  the  lymph-glands  but 
may  extend  into  the  adjacent  tissues,  such  as  the  lung  and  pleura,  or  ap- 
pear separately  as  a  sort  of  metastasis  in  the  spleen  beginning  perhaps 
in  the  Malpighian  bodies  and  extending  to  the  pulp, 

It  is  evident  that  this  is  not  a  hyperplasia  of  the  essential  lymphoid  cells 
of  the  gland,  nor  is  it  anything  like  the  myeloid  hyperplasias  described 
above.  It  has  some  of  the  characters  of  a  tumor  growth,  but  by  far  the 
greater  weight  of  evidence  is  in  favor  of  its  being  an  infectious  process 
involving  simultaneously  much  of  the  lymphatic  gland  system.  As  to  the 
portal  of  entry  of  the  infectious  agent  nothing  can  be  said.  The  tonsils 
are  most  often  unaffected. 

Nor  can  anything  definite  be  said  as  to  the  nature  of  the  causative  agent. 
Sternberg  maintained  for  a  time  that  this  is  a  peculiar  form  of  tuberculosis, 
but  all  efforts  to  demonstrate  tubercle  bacilli  or  to  infect  guinea-pigs  with 
the  tissue  were  in  vain,  unless,  of  course,  as  was  true  in  Dr.  Reed's  first  case, 
there  was  a  coincident  infection  with  tuberculosis,  and  tuberculous  lesions 
and  those  of  Hodgkin's  disease  lay  side  by  side.  Afterward  Sternberg  and 
others  thought  it  due  to  a  weakened  tubercle  bacillus  but  this  seems  un- 
likely in  view  of  the  case  just  cited  and  also  because  a  weakened  tubercle 
bacillus  ought  to  produce  injuries  less  destructive  than  those  caused  by  a 
virulent  one  and  not  necessarily  fatal.  Hodgkin's  disease  produces  lesions 
quite  unlike  those  of  tuberculosis  but  is  always  fatal.  Frsenkel  and  Much 
have  described  certain  granular  Gram-positive  rodlets  which  they  find  fre- 
quently and  consider  that  they  have  found  the  cause  of  the  disease.  On  the 
other  hand,  Bunting  and  Yates  have  found  a  pleomorphic  diphtheroid 
bacillus  which  they  think  is  the  cause.  It  is  too  early  to  decide  as  to  the 
merits  of  these  different  organisms,  but  the  impression  is  strong  that 
Hodgkin's  disease  is  an  infectious  process. 


HODGKIN'S  DISEASE  OR  LYMPHOGRANULOMATOSIS  859 

LITERATURE 
Myeloid  Leukaemia — Nsegeli:  Leukamie,  Wien,  1913. 

Sternberg:  Wien.  kl.  Woch.,  1911,  xxiv,  1623. 

Herxheimer:  Munch,  med.  Woch.,  1913,  Ix,  2506. 

Burckhardt:  Frankf.  Ztsch.  f.  Path.,  1911,  vi,  107. 

Sternberg:  Ziegler's  Beitr.,  1915,  Ixi,  89. 
Myeloid  CMoroma.— Meixner:  Wien.  kl.  Woch.,  1907,  xx,  593. 

Sternberg:  Ziegler's  Beitr.,  1904,  xxxvii,  437. 

Roman:  Ibid.,  1913,  Iv,  61.     (Lit.) 
Myeloid  Myeloma. — Shennan:  Edinb.  Med.  Jour.,  1913,  x,  321. 

MacCallum:  Jour.  Exp.  Med.,  1901,  vi,  53. 

Boggs  and  Guthrie:  Johns  Hopkins  Hosp.  Bull.,  1912,  xxiii,  353; 

1913,  xxiv,  368. 

Hodgkin's  Disease. — Sternberg:  Ctbl.  f.  d.  Grenz.  d.  Med.  u.  Chir.,  1899,  ii,  641. 

Ztsch.  f.  Heilk.,  1898,  xix,  21. 
Reed:  Johns  Hopkins  Hosp.  Reports,  1902,  x,  133. 
Longcope:  Bull.  Ayer  Clin.  Labty.,  1903,  i,  4. 
K.  Ziegler:  Hodgkin'sche  Krankheit,  Jena,  1911. 
Bunting  and  Yates:  Jour.  Amer.  Med.  Assoc.,  1913,  Ixi,   1803; 

1914,  Ixii,  516. 

Discussion  to  Sternberg:  Verh.  d.  D.  Path.  Gesellsch.,  1912,  xv,  22. 


CHAPTER  XLIII 

DISEASES  DUE  TO  INJURIES  OF  THE   ORGANS  OF  INTERNAL 

SECRETION 

Pancreas.  Diabetes  mellitus.  General  character  of  process.  Pathological  anatomy. 
Nature  of  disturbance  of  carbohydrate  metabolism.  Relation  of  other  organs.  Diabetic 
acidosis.  Resume:  Thyroid:  anatomy  and  physiology.  Myxcedema,  effects  of  extracts. 
Cretinism,  goitre,  exophthalmic  goitre,  general  symptoms,  pathological  nature  of  disease. 

IN  considering  the  diseases  which  depend  upon  disturbance  of  the  activities 
of  the  organs  of  internal  secretion  we  must  usually  speak  of  a  disease  in 
which  one  of  these  organs  is  most  prominently  affected,  because  it  is  known 
that  they  seem  to  cooperate  in  such  a  way  that  the  disabling  of  one  disturbs 
the  others. 

Diabetes  mellitus  is  an  example  of  this,  for  while  we  find  the  pancreas 
most  prominently  concerned,  we  are  not  yet  sure  of  the  part  played  by 
adrenal,  thyroid,  hypophysis,  etc.  Nor  are  we  sure  in  the  case  of  exoph- 
thalmic goitre  whether  thyroid  or  thymus  or  some  other  organ  is  chiefly 
responsible  for  the  disease. 

. 

THE  PANCREAS 
DIABETES  MELLITUS 

Diabetes  mellitus  is  a  disease  occurring  at  almost  all  ages  and  usually 
more  severe  and  quickly  fatal  in  young  persons.  It  is  peculiar  in  that 
the  carbohydrate  metabolism  is  deranged  in  such  a  way  that  sugar  ab- 
sorbed from  the  intestine  is  no  longer  stored  in  reserve  in  the  form  of  gly- 
cogen  in  the  liver  and  body  muscles,  but  circulates  in  the  blood  and  is 
excreted  in  the  urine.  Since  sugar  ordinarily  forms  the  great  source  of 
energy  for  the  muscles  and  is  now  scarcely  used  by  them,  great  changes  in 
the  general  metabolism  arise.  Protein  substances,  even  including  those  of 
the  tissues,  are  consumed  in  an  unaccustomed  way  to  develop  the  necessary 
energy  and  a  part  split  off  from  them  in  the  form  of  sugar  becomes  useless 
because  of  its  carbohydrate  nature  and  is  excreted  with  the  rest  in  the 
urine.*  In  severe  cases  in  spite  of  enormous  quantities  of  food  consumed 
usually  with  great  amounts  of  water  (polyphagia,  polydipsia)  the  protein 
becomes  inadequate  to  supply  the  energy  demands  and  the  fats  are  at- 
tacked. Being  incompletely  oxidized,  these  give  rise  to  intermediary  prod- 
ucts, /3-oxy butyric  acid,  aceto-acetic  acid,  and  acetone,  which  are  excreted 

*  That  this  is  only  partly  true  is  shown  by  experiments  with  depancreatized  animals 
m  which  the  high  sugar  content  of  the  blood  is  greatly  decreased  by  muscular  work. 

860 


DIABETES   MELLITUS  861 

in  part,  but  which  also  act  as  poisons,  producing  the  diabetic  coma  that  so 
commonly  leads  to  death.  The  excretion  of  large  quantities  of  urine  seems 
dependent  upon  the  increased  intake  of  water.  Peripheral  neuritis  and 
various  trophic  disturbances,  sometimes  with  gangrene  of  the  extremities, 
are  met  with,  and  the  patients  show  such  an  extraordinarily  lowered 
resistance  to  bacterial  infection  that  rapidly  progressing  tuberculosis 
or  generalized  and  local  infections  of  other  sorts  may  become  the  actual 
cause  of  death. 

Pathological  Anatomy. — The  nature  of  this  process  is  not  made  clear 
by  anatomical  study  at  autopsy,  for  in  most  cases  no  gross  changes  are 
found  in  any  of  the  organs  which  seem  capable  of  explaining  the  complete 
upset  of  the  general  metabolism.  Study  of  the  blood  reveals  an  increased 
amount  of  blood  sugar.  The  liver  is  devoid  of  glycogen,  or  nearly  so. 
That  usually  found  in  globules  or  granules  in  the  protoplasm  of  the  liver 
cells  is  gone,  and  the  nuclei  of  the  cells,  which  are  swollen,  now  contain 
whatever  glycogen  remains  in  the  organ.  The  muscles  have  also  lost  their 
reserve  of  glycogen,  and  this  is  true  of  all  the  tissues  except  the  heart 
muscle,  the  leucocytes,  and  the  renal  epithelium,  particularly,  as  pointed 
out  by  Baehr,  that  in  the  terminal  part  of  the  first  convoluted  tubules. 
Since  the  time  of  Claude  Bernard  who  produced  glycosuria  and  hyper- 
glycsemia  by  injuries  to  the  brain  (piqure)  it  has  been  known  that  this 
disease  is  in  some  way  associated  with  disturbances  of  the  central  nervous 
system,  and  indeed,  various  lesions  of  the  brain  and  spinal  cord  have  been 
found  in  cases  dying  after  prolonged  glycosuria.  But  they  are  very  variable 
lesions  and  although  they  seem  to  cause  glycosuria,  they  do  so  by  no  means 
constantly.  It  is  quite  possible  that  their  effects  are  due  to  changes  in  the 
hypophysis.  On  the  other  hand,  most  cases  of  outspoken  diabetes  present 
no  recognizable  alterations  of  the  nervous  system. 

Mering  and  Minkowski  showed  that  extirpation  of  the  pancreas  is 
followed  regularly  by  all  the  phenomena  of  diabetes,  and  this  led  to  the 
prevailing  view  of  the  predominant  importance  of  the  pancreas  in  this 
disease.  That  it  was  really  the  loss  of  the  pancreas  that  produced  these 
results  and  not  injury  to  the  intestine  or  to  the  nerves  has  been  proven 
by  the  most  severe  tests.  So  long  as  a  part  of  the  pancreas  remains 
well  supplied  with  blood,  even  separated  from  all  its  original  connections 
with  the  intestine,  no  diabetes  appears,  but  as  soon  as  that  fragment  is 
removed  from  the  circulation,  even,  in  suitable  experiments,  by  a  single 
ligature  placed  on  its  blood-vessels,  hyperglycaemia  and  glycosuria  appear 
at  once. 

Lesions  may,  therefore,  be  sought  in  the  pancreas  in  cases  of  diabetes. 
It  must  be  said  that  while  various  changes  are  found  it  usually  requires  a 
certain  complaisance  to  ascribe  the  extreme  diabetic  symptoms  to  them 
because  they  are  practically  never  destructive  enough  to  be  compared  with 
the, extirpation  of  the  gland.  Nevertheless,  as  we  shall  see,  there  are  other 
things  which  enhance  the  effect  of  a  partial  destruction  of  the  gland. 


862 


TEXT-BOOK    OF    PATHOLOGY 


Further,  it  may  well  be  that  the  destruction  of  an  inconspicuous  constituent 
of  the  gland  will  be  followed  by  results  out  of  proportion  to  the  change  in 
its  gross  appearance.  It  is  well  known  that  while  the  acinar  parts  of  the 
pancreas  secrete  the  pancreatic  juice  into  the  intestine  by  way  of  the  duct, 
the  islands  of  Langerhans  have  no  direct  connection  with  them  or  with  the 
ducts,  but  are  isolated  groups  of  cells  with  very  rich  blood-supply  scattered 
through  the  organ.  The  cells  do  not  resemble  those  lining  the  acini  in 


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Fig.  431. — Hyaline  island  of  Langerhans  from  a  case  of  diabetes. 

form  or  arrangement.     Their  protoplasmic  granules  are  quite  different  and 
much  finer  and  the  cells  are  connected  in  an  irregular  network. 

By  special  stains  one  may  even  recognize  two  kinds  of  cells  in  these  islands 
distinguished  by  their  different  types  of  granules.  The  names  of  Opie, 
Schaefer,  and  Ssobolew  are  connected  with  the  idea  that  these  islands  are 
responsible  for  maintaining  at  least  one  part  of  the  chain  of  events  in  the 
metabolism  of  carbohydrates,  and  that  they  may  be  regarded  as  the 
structures  in  the  pancreas  which  produce  an  internal  secretion  which  is 
liberated  into  the  blood.  Opie  described  a  case  of  severe  diabetes  in  which 


DIABETES   MELLITUS  863 

practically  all  of  the  islands  of  Langerhans  were  converted  into  hyaline, 
inert  masses  in  which  living  cells  could  no  longer  be  seen  (Fig.  431).  The 
rest  of  the  pancreas  was  normal,  and  naturally  such  an  inconspicuous  lesion 
produced  no  change  in  the  gross  appearance.  Were  this  a  constant  finding 
there  would  be  little  difficulty  in  establishing  this  plausible  theory  of  the 
relation  of  the  islands  to  diabetes,  but  there  are  many  cases  of  diabetes  in 
which  no  such  universal  destruction  of  the  islands  is  found.  Instead,  one 
finds  very  often  a  fine  scarring  of  the  organ  analogous  to  cirrhosis  of  the 
liver  or  sometimes  no  recognizable  change  at  all.  Hence  there  are  many 
who  refuse  to  believe  in  the  specific  relation  of  the  islands  of  Langerhans  to 
diabetes  and  think  rather  that  the  whole  glandular  substance  of  the  pan- 


.  ^ 


t> 


c 


V 


Fig.  432. — Pancreas  of  guinea-pig  one  year  after  ligation  of  the  ducts.     The  islands  of 
Langerhans  alone  remain,  embedded  in  fat. 

creas  is  concerned.  Nevertheless  Cecil,  in  studying  a  large  number  of 
cases  of  diabetes,  found  pancreatic  lesions  in  more  than  87  per  cent,  and 
showed  that  in  these  the  islands  of  Langerhans  were  always  affected;  in 
about  12  per  cent,  the  islands  alone  were  injured. 

Certain  experimental  studies  furnish,  it  seems,  the  only  unassailable  evi- 
dence in  this  connection.  The  ligature  of  the  pancreatic  ducts  results  in 
atrophy  of  the  acini,  but  since  the  islands  of  Langerhans  have  no  connec- 
tion with  these  they  do  not  suffer  and  no  glycosuria  results.  In  one  type 
of  experiment,  half  of  the  pancreas  was  thus  ligated  off,  and  the  animal 
survived  perfectly  well.  After  a  year  such  an  animal  (dog  or  guinea-pig) 
showed  the  complete  reduction  of  the  ligated  part  to  a  thin,  transparent 


864  TEXT-BOOK   OF    PATHOLOGY 

film  in  the  mesentery;  extirpation  of  the  remaining  intact  half  of  the  pan- 
creas was  followed  in  such  an  experiment  by  transient  glycosuria,  but  after 
one  day  of  this  the  animal  showed  no  symptoms  whatever  and  could 
assimilate  large  amounts  of  glucose  or  starch.  After  a  month,  the  trans- 
parent film  which  represented  the  other  half  of  the  pancreas  was  extirpated, 
and  then  the  animal  was  plunged  into  the  severest  diabetes.  This  film 
contained  only  islands  of  Langerhans,  as  was  proved  in  the  case  of  the 
guinea-pig  at  least  by  the  special  stain  of  Bensley  (MacCallum:  Johns 
Hopkins  Hosp.  Bull,  1909,  xx,  222;  Kirkbride:  J.  Exp.  Med.,  1912,  xv, 
101)  (Figs.  432, 433). 
Other  investigators  have  sometimes  found  destructive  changes  in  the 

' 


Fig.  433. — Island  of  Langerhans  enlarged  from  Fig.  432.     The  sharp  differential  stain- 
ing of  the  granules  shows  that  the  cells  are  intact. 

islands  after  such  obstruction  of  the  ducts,  but  it  seems  that  the  weight 
of  evidence  is  at  present  in  favor  of  the  belief  that  the  islands  are  the 
specific  organs  of  internal  secretion. 

It  is  true  that  in  many  cases  of  diabetes  it  is  difficult  if  not  impossible 
to  demonstrate  any  lesion  in  the  pancreas,  and  then  it  may  be  necessary  to 
assume  that  some  extra-pancreatic  cause  has  brought  about  the  disease, 
but  in  such  studies  as  that  of  Cecil,  changes  in  the  islands  are  found  in  an 
overwhelming  proportion  of  the  cases. 

Thus,  while  it  is  not  invariably  possible  to  demonstrate  the  existence  of 
lesions  of  the  pancreas  in  cases  of  diabetes,  they  are  usually  found;  on  the 
other  hand,  the  whole  symptom-complex  can  be  produced  by  extirpation 
of  the  organ  and  not  in  any  other  way,  although  transient  glycosuria  may 


DIABETES   MELLITUS  865 

have  many  other  causes.     The  role  of  the  pancreas  in  diabetes  must  there- 
fore be  regarded  as  very  important. 

Nature  of  Disturbance  of  Carbohydrate  Metabolism.— Experimental 
and  physiological  studies  have  thrown  more  light  on  the  nature  of  the 
disease  than  has  anatomical  investigation. 

Carbohydrates  are  transported  in  the  body  to  the  tissues,  which  need  them  as  energy 
producers,  in  the  form  of  grape-sugar  or  dextrose.  Only  monosaccharids,  such  as  dex- 
trose, maltose,  and  levulose,  can  be  consumed  by  these  tissues;  others,  such  as  cane- 
sugar,  if  injected  into  the  blood  are  excreted  unchanged.  Therefore  starch  and  allied 
substances  and  cane-sugar  are  hydrolyzed  by  the  action  of  ferments  in  the  intestinal 
tract,  beginning  with  the  ptyalin  of  the  saliva  and  ending  with  the  diastase  of  the 
pancreatic  secretion,  into  one  of  these  simpler  sugars.  Starch  acted  upon  by  diastase 
passes  through  dextrine  to  maltose,  which  is  converted  into  dextrose  by  another  ferment, 
maltase.  Arrived  by  way  of  the  portal  vein  in  the  liver,  the  dextrose  is  polymerized, 
by  the  action  of  the  liver-cells,  into  glycogen.  Doubtless  the  liver-cells,  like  the  muscle 
cells  and  others  capable  of  elaborating  and  storing  up  glycogen  from  dextrose,  do  so 
by  the  aid  of  a  ferment,  but  although  this  may  perhaps  be  a  diastase  reversing  its  action, 
the  actual  ferment  has  not  been  demonstrated.  As  far  as  experimental  study  goes  it 
seems  that  only  living  cells  are  able  to  bring  about  this  change. 

The  glycogen  is  set  free  from  the  liver  and  poured  into  the  blood  through  the  action 
of  a  diastatic  ferment,  glycogenase,  which  apparently  occurs  in  all  the  organs  and  is 
able  to  convert  glycogen  into  dextrose  through  several  steps,  in  the  last  of  which  maltose 
becomes  dextrose  through  the  agency  of  the  ubiquitous  maltase. 

Liberated  in  this  way,  the  dextrose  is  used  by  the  muscles  as  a  source  of  energy, 
though  the  steps  of  this  process  are  yet  shrouded  in  mystery.  In  the  end  it  is  an  oxida- 
tion, although  the  sugar  may  at  first  be  decomposed  into  various  intermediary  sub- 
stances. Taylor  suggests  glyoxal,  lactic  acid,  and  alcohol,  as  the  successive  steps,  but 
this  is  not  established.  Much  ingenuity  and  labor  has  been  spent  in  the  attempt  to 
elucidate  this  process  of  "glycolysis,"  and  the  theory  of  O.  Cohnheim  is  especially 
well  known  although  not  now  generally  accepted.  He  seemed  to  prove  that  muscle 
juice  could  cause  glucose  to  disappear  only  when  activated  by  pancreas  extract,  but  it 
has  been  shown  that  this  disappearance  is  not  really  oxidation  of  the  sugar  but  only 
the  assumption  of  another  form  in  which  it  will  no  longer  reduce  copper  salts. 

But  if  we  do  not  know  the  steps  in  the  process,  it  is  f  airly  clear  that  sugar  is  finally 
oxidized  in  the  working  muscles  to  carbon  dioxide  and  water,  and  we  can  recognize 
the  effect  of  this  combustion  in  the  amount  of  carbon  dioxide  exhaled  as  compared 
with  the  amount  of  oxygen  consumed  in  the  respired  air. 

It  is  well  known  that  this  "respiratory  quotient"  gives  some  idea  of  the  character 

of  the  materials  undergoing  combustion,  for  the  oxidation  of  carbohydrate  results  in 

OO 
the  proportion   -^T  =  1,  while  the  combustion  of  proteins  and  fats  gives  a  lower  figure. 

Upon  extirpation  of  the  pancreas  this  whole  chain  of  events  is  at  once 
disarranged.  Probably  the  sugars  are  sufficiently  well  prepared  in  the 
intestine  and  absorbed,  although  the  amylolytic  ferment  of  the  pancreas  is 
no  longer  furnished  there. 

But  when  the  sugar  reaches  the  liver,  it  is  not  stored  up  as  glycogen. 
Either  the  loss  of  the  pancreas  makes  it  impossible  for  the  liver-cells  to 
form  and  store  glycogen  from  the  sugar  presented,  or  it  allows  the  diastatic 
ferment,  the  glycogenase,  to  run  riot,  decomposing  at  once  all  the  glycogen 
already  lodged  in  the  liver  and  forestalling  the  formation  of  any  more. 

56 


866  TEXT-BOOK    OF    PATHOLOGY 

Since,  after  the  complete  destruction  of  the  pancreas,  the  glycogenase  is  so 
active,  it  seems  necessary  to  conclude  that  the  internal  secretion  of  the 
pancreas  and  the  glycogenase  are  very  different  things. 

Set  free  from  the  liver,  the  dextrose  circulates  in  excess  (hyperglycsemia), 
and  much  is  excreted  by  the  kidneys  (glycosuria),  but  none  or  very  little  is 
oxidized  in  the  muscles.  This  is  shown  by  the  lack  of  any  heightening  of 
the  respiratory  quotient  when  sugar  is  fed  to  such  a  diabetic,  and  also  by  the 
fact  that  the  amount  fed  reappears  almost  quantitatively  in  the  urine. 

This  would  suggest  that  the  tissues  had  lost  their  power  to  consume 
dextrose  for  the  liberation  of  energy,  and  indeed  this  is  a  view  long  held  and 
supported  by  much  evidence.  Recent  work  of  Knowlton  and  Starling, 
McLeod,  Ltithje,  and  others  shows,  however,  that  the  tissues  of  depan- 
creatized  animals  if  perfused  with  Locke's  solution  containing  dextrose  are 
quite  as  able  to  consume  the  sugar  as  those  of  normal  animals.  The  original 
experiment  of  Starling  and  Knowlton  with  perfusion  of  normal  and  diabetic 
hearts  seemed  to  show  that  the  diabetic  heart  consumed  less  sugar  than  the 
normal.  This,  however,  was  corrected  later,  since  it  proved  to  be  due  to 
the  increased  store  of  glycogen  in  the  diabetic  heart,  which  was  used  instead 
of  the  sugar  of  the  perfusion  fluid.  Still  it  may  be  that  in  the  diabetic  it  is 
the  blood-sugar  rather  than  the  tissue  which  is  at  fault,  so  that  glycolysis 
is  absent  because  the  sugar  is  in  a  combined  form  which  is  inaccessible. 

We  are  left  then  with  the  problem  as  to  whether  the  hyperglycsemia 
and  glycosuria  arise  because  there  is  an  overliberation  of  sugar  into  the 
blood  or  because  the  tissues  are  unable  to  consume  it. 

Hedon  states  that  the  introduction  of  the  blood  of  the  pancreatic  vein 
of  a  normal  dog  into  the  portal  vein  of  a  depancreatized  dog  will  reduce 
very  greatly  the  amount  of  sugar  in  the  urine  and  also  in  the  blood,  as  though 
a  necessary  ferment  were  secreted  by  the  pancreas  into  the  blood. 

If  this  be  true,  it  still  remains  to  determine  whether  the  ferment  forms 
glycogen,  prevents  the  dissolution  of  glycogen  into  sugar,  or  causes  the 
more  distant  glycolysis.  The  statement  that  it  has  no  effect  except  when 
injected  into  a  branch  of  the  portal  vein  so  as  to  reach  the  liver  directly 
suggests  that  its  influence  is  in  connection  with  the  two  earlier  proc- 
esses. 

Admont  Clark  has  furnished  definite  evidence  in  this  connection  by 
his  skilful  perfusion  experiments,  in  which  Locke's  solution  containing 
known  amounts  of  sugar  and  kept  free  from  bacteria  was  passed  through 
the  pancreas  alone,  through  the  beating  heart  alone,  and  through  pancreas 
and  heart  in  series.  The  pancreas  alone  causes  no  disappearance  of  the 
sugar,  very  little  is  lost  from  the  perfusate  which  passes  through  the  heart 
alone,  but  when  the  fluid  is  passed  first  through  the  pancreas  and  then 
through  the  beating  heart  there  is  a  great  consumption  of  sugar.  A  sugar- 
free  solution  which  has  passed  through  the  pancreas  alone  contains  some- 
thing of  ferment  nature  which,  when  added  to  a  sugar-containing  solution 
used  to  perfuse  the  beating  heart,  enables  the  heart  to  consume  much 


DIABETES    MELLITUS  867 

sugar.  It  is  true  that  the  pancreas  by  itself  can  change  the  optical  rotat- 
ing power  of  dextrose  to  some  extent  when  perfused  through  it,  but  it  is 
most  important  to  have  shown  thus  for  the  first  time  that  the  pancreas 
actually  produces  a  ferment-like  substance  which  is  essential  for  the  proper 
consumption  of  sugar  by  the  muscles. 

Many  observations  tend  to  show  that  other  factors  than  these  fer- 
ments are  concerned  in  the  control  of  the  carbohydrate  metabolism, 
for  hyperglycsemia  and  glycosuria  can  be  induced  in  a  variety  of 
ways.  The  whole  mechanism  of  carbohydrate  control  seems  to  be,  to 
some  extent  at  least,  under  the  influence  of  the  nervous  system, 
especially  the  sympathetic  system.  Injury  to  the  brain  and  especially 
the  so-called  piqure  of  Claude  Bernard  produces  glycosuria,  usually  at- 
tended, however,  by  symptoms  of  asphyxia  and  circulatory  disturb- 
ances which  in  themselves  may  have  similar  effects.  Stimulation  of  the 
splanchnic  nerves  causes  glycosuria  without  the  other  phenomena,  but 
fails-  to  do  so  when  the  adrenal  glands  are  extirpated.  From  various 
experiments  it  seems  that  this  sympathetic  innervation  of  both  adrenals 
comes  from  the  left  splanchnic.  Massage  of  the  adrenals  or  the  injection 
of  adrenaline  causes  glycosuria  without  stimulation  of  the  nerves,  and 
stimulation  of  the  hepatic  sympathetic  plexus  also  does  so  as  long  as  the 
adrenals  are  present,  but  not  when  they  are  extirpated  (Nishi,  McLeod). 

It  seems,  therefore,  that  the  secretion  of  the  adrenal  is  a  necessary  part  of 
the  mechanism  through  which  the  impulses  from  the  sympathetic  passing 
to  the  liver  promote  the  setting  free  of  sugar.  We  may  ask  then  whether 
the  pancreas  opposes  the  action  of  the  sympathetics,  since  in  its  absence 
the  sugar  is  quickly  set  free  and  still  more  quickly  if  adrenaline  be  injected. 

Interesting  relations  exist  between  the  secretions  of  other  related  organs 
and  this  condition  of  hyperglycaemia  and  glycosuria,  for  in  the  absence  of 
the  thyroid  it  becomes  difficult  to  produce  it  in  any  way,  while  it  may 
appear  spontaneously  when  an  excess  of  the  secretion  of  thyroid  or  hypophy- 
sis is  thrown  into  the  circulation.  In  slighter  degrees  such  modification  of 
the  sugar  metabolism  may  be  tested  for  by  determining  the  sugar  tolerance, 
that  is,  the  amount  of  sugar  which  may  be  injected  without  producing 
glycosuria,  or  by  the  respiratory  exchange.  These  relations  and  others 
have  been  much  discussed  by  Eppinger,  Falta,  and  Riidinger,  who  have 
constructed  a  sort  of  formula  which  expresses  them,  but  which  ascribes  all 
the  effects  to  influences  exercised  upon  one  organ  by  another  rather  than  to 
the  chemical  antagonisms  of  their  secretions. 

Glycosuria  may  also  be  produced  by  caffeine,  strychnine,  sensory  stimuli, 
and  asphyxia  (which  in  its  turn  maybe  brought  about  by  various  narcotics, 
ether,  chloroform,  morphine,  etc.),  and  by  curare  (Pollak).  In  other  cases 
(renal  poisons  or  phloridzin  poisoning)  it  seems  that  there  is  no  hyper- 
glycsemia and  that  glycosuria  arises  as  a  result  of  renal  changes.  For 
information  concerning  the  complex  effects  of  phloridzin  poisoning,  Lusk's 
paper  may  be  consulted. 


868  TEXT-BOOK    OF    PATHOLOGY 

It  must  not  be  inferred  from  what  has  been  said  that  the  carbohydrates 
alone  are  disturbed  in  diabetes  nor  that  sugar  is  produced  from  carbohy- 
drates only.  Indeed,  it  has  been  shown  that  proteins  are  split  up  in  such 
a  way  in  the  liver  as  to  liberate  certain  molecules  of  sugar,  and  further  it 
has  been  possible  to  determine  that  certain  of  the  amino-acids  which  go  to 
build  up  these  proteins  are  far  more  capable  than  others  of  liberating  sugar. 
Consequently  some  forms  of  meat  (chicken)  are  found  to  furnish  more 
sugar  in  a  diabetic  organism  than  others  (beef)  (Janney).  Many  other  sub- 
stances, such  as  glycerin,  glycolaldehyde,  glyceric  acid,  dioxyaceton,  have 
been  found  to  produce  sugar  in  the  perfused  liver  (Emden,  Barrenschein) . 

In  pancreatic  diabetes  when  carbohydrates  are  quite  withdrawn  from 
the  food  sugar  may  still  be  excreted,  and  the  amount  of  this  sugar  bears  a 
constant  relation  to  the  amount  of  nitrogen  excreted.  This  D  :N  ratio  is 
thought  to  represent  the  relation  between  the  amount  of  sugar  liberated 
from  the  protein  of  the  food  or  of  the  wasting  tissues  and  the  nitrogen  of 
that  protein.  It  is  evident  that  this  indicates  at  least  a  considerable  waste 
in  the  proteins,  inasmuch  as  the  carbohydrate  portion  is  excreted  as  such. 

Although  certain  authors,  Porges  and  Salomon,  V.  Noorden,  Raubit- 
schek,  and  others,  claim  a  formation  of  sugar  from  fats,  the  weight  of 
evidence  does  not  seem  to  favor  this  idea.  Lipaemia  during  diabetes 
is  common,  fat  streaming  in  visible  form  in  the  blood  in  such  a  way  as 
to  make  the  serum  milky,  and  accumulating  in  large  cells  in  the  spleen. 
The  origin  of  this  fat  is  not  clearly  known,  but  at  first  there  is  a  great  in- 
crease in  lecithin,  and  throughout  a  still  greater  increase  in  cholesterol. 

In  the  absence  of  carbohydrate  utilization  there  occurs  a  peculiar  im-« 
perfect  consumption  of  fats  which  is  analogous  to  that  seen  in  the  course  of 
starvation,  where  for  another  reason  no  carbohydrate  is  supplied  for  energy 
production  to  the  tissues.  For  some  reason  the  oxidation  of  carbohydrates 
renders  easier  the  complete  combustion  of  fats,  and  in  their  absence  this 
is  imperfect,  oxidation  of  the  fatty  acids,  at  any  rate  those  with  an  even 
number  of  carbon  atoms,  takes  place  by  the  oxidation  of  the  third  carbon 
atom  (that  is,  in  the  0  position)  and  the  splitting  off  of  the  terminal  carbon 
atoms.  In  this  way  /3-oxybutyric  acid  can  be  formed  from  all  of  these 
fatty  acids,  including  palmitic,  stearic,  and  oleic  (Knoop).  But  for  some 
time  the  /3-oxybutyric  acid  does  not  appear  in  the  urine,  but,  instead, 
diacetic  acid  and  acetone,  which  are  successive  oxidation  products  derived 
from  it.  Their  formula  are  as  follows: 

0-oxybutyric  acid CH3— CH  OH— CH2— CO  OH 

Diacetic  acid CH3— CO— CH2— CO  OH 

Acetone CH3 — CO— CH3 

These  are  the  so-called  acetone  bodies,  which  tend  to  appear  more  readily 
in  herbivorous  and  omnivorous  animals  than  in  the  purely  carnivorous. 
Diacetic  acid  and  acetone  rarely  occur  in  any  great  amount  in  the  urine. 


DIABETES   MELLITUS  869 

but  the  ,3-oxybutyric  acid  may  reach  50  to  100  grams  a  day,  or  more. 
With  such  disordered  fat  combustion,  toxic  phenomena  appear  which  are 
known  as  the  symptoms  of  acidosis  or  acid  intoxication.  They  are  quite 
similar  to  those  produced  by  the  feeding  of  inorganic  acids  to  rabbits  or 
other  herbivorous  animals,  and  consist  in  a  peculiar  violent  deep  respiration 
or  air  hunger,  and  coma.  These  symptoms  may  be  much  relieved  by  the 
introduction  of  large  quantities  of  an  alkali,  such  as  sodium  bicarbonate. 
During  the  gasping  for  breath  the  blood  is  bright  red  and  contains  very 
little  carbon  dioxide;  instead  the  tissues  are  loaded  with  carbon  dioxide 
which  the  blood  is~unable  to  remove,  presumably  because  the  acid  injected 
has  combined  with  the  sodium  of  the  blood  so  that  it  is  no  longer  able  to 
aid  in  the  transport  of  the  carbon  dioxide  to  the  lungs.  Ordinarily  (Wells) 
it  passes  to  the  lungs  as  bicarbonate,  where  it  is  decomposed  into  the  car- 
bonate, liberating  CO2,  and  returns  to  the  tissues  for  more.  Exactly  the 
same  preemption  of  the  alkali  of  the  blood  results  from  the  presence  of  the 
organic  acids  that  arise  from  the  decomposition  of  the  fatty  acids,  and  the 
diabetic  dies  in  coma  largely  as  a  result  of  this  kind  of  asphyxia,  unless 
the  alkali  is  supplied  rapidly  from  the  outside.  In  carnivorous  animals 
ammonia  is  far  more  ready  to  supply  the  alkali  than  in  the  herbivorous 
ones  because,  from  the  character  of  their  food,  ammonia  is  more  abundantly 
produced.  It  seems  probable  from  these  statements  that  the  great  amount 
of  fat  taken  in  the  food  by  some  diabetics  may  afford  material  for  the  in- 
tensification of  this  production  of  poisonous  acids,  and  Allen  has  em- 
phasized this  in  his  Harvey  lecture. 

Much  attention  has  been  devoted  by  investigators  in  recent  years  to 
the  quantitative  study  of  the  acid  base  equilibrium  in  diabetes  and  particu- 
larly to  the  effect  of  the  administration  of  large  doses  of  sodium  carbonate. 
It  is  found  that  this  has  the  effect  not  only  of  neutralizing  some  of  the 
free  acid  produced  by  the  decomposition  of  the  fat,  but  also  of  decreasing 
the  hyperglycsemia  and  glycosuria.  On  the  contrary,  the  administration 
of  acid  rather  increases  glycosuria.  No  complete  understanding  of  these 
effects  seems  to  have  been  reached. 

Allen's  work  on  the  treatment  of  diabetes  by  prolonged  starvation,  with 
the  idea  of  relieving  the  strain  on  the  islands  of  Langerhans,  need  not  be 
discussed  here.  It  is  based  on  changes  in  the  islands  in  animals  whose 
pancreas  has  been  reduced  to  a  point  at  which  they  are  just  able  to 
maintain  carbohydrate  equilibrium. 

Bensley  and  Lane  have  discovered  that  in  the  islands  of  Langerhans 
some  of  the  cells  have  a  type  of  granule  which  they  designate  A,  the  rest, 
another  type,  B.  Homans,  in  studying  the  condition  of  islands  in 
portions  of  pancreas  left  after  extirpation  of  the  rest  to  what  must  have 
been  an  overstrain,  finds  that  the  evidences  of  their  inadequate  function 
shown  by  glycosuria  are  parallel  with  loss  of  B  granules  in  the  swollen 
islands. 


870  TEXT-BOOK    OF    PATHOLOGY 

Resume. — The  loss  of  the  function  of  the  pancreas  thus  precipitates  a 
condition  in  which  carbohydrates  are  not  normally  utilized.  They  are 
absorbed,  but  neither  stored  in  the  form  of  glycogen  nor  readily  dissociated 
in  the  tissues  to  supply  energy.  Proteins  supply  whatever  is  possible  of 
the  needed  energy,  but  they  too  liberate  from  certain  of  their  amino-acid 
fractions  the  material  for  sugar,  which  promptly  becomes  useless  and 
circulates  until  it  is  excreted.  Fats  aid  in  furnishing  energy  to  the  tissues, 
but  they  too  are  imperfectly  used  and  become  dissociated  in  the  process  of 
oxidation  to  liberate  the  series  of  acetone  bodies  of  which  /3-oxybutyric 
acid  is  the  most  toxic,  and  this,  evincing  part  at  least  of  its  injurious  action 
in  preempting  the  blood  alkalies,  and  thus  causing  tissue  asphyxia,  brings 
about  the  characteristic  air  hunger  and  coma  in  which  many  of  the  victims 
of  severe  diabetes  die. 

Where  the  pancreas  exerts  its  function,  and  precisely  what  are  its  rela- 
tions with  the  nervous  system  and  the  other  organs  of  internal  secretion,  is 
even  yet  very  obscure. 

LITERATURE 

Cecil,  R.  L. :  Jour.  Exp.  Med.,  1909,  xi,  266. 

Lusk:  Erg.  d.  Physiol.,  1912,  xii,  315;  Science  of  Nutrition,  Phila.,  1909. 
McLeod:  Diabetes,  London,  1913.      Harvey  Lectures,  1913-14,  ix,  174.     Amer.  Jour. 

Physiol.,  1916,  xlii,  193,  460. 

Allen:  Glycosuria  and  Diabetes,  Cambridge,  1913.  Harvey  Lectures,  1916-17,  xii,  42. 
Benedict  and  Joslin:  Metabolism  in  Diabetes,  Trans.  Assoc.  Amer.  Physicians,  1910, 

xxv,  172;  1912,  xxvii,  93. 
Wells:  Chemical  Pathology,  Phila.,  1914. 
Bensley:  Harvey  Lectures,  1914-15,  x,  250. 
Homans:  Proc.  Royal  Soc.  Biol.,  1913,  Ixxxvi,  73.    Jour.  Med.  Research,  1914,  xxx,  49; 

1915,  xxxiii,  1. 

Lane:  Amer.  Jour.  Anat.,  1907,  vii,  409. 
Woodyatt:  Jour.  Biol.  Chem.,  1915,  xx,  129;  1916,  xxiv,  327,  343;  1917,  xxx,  155.     Jour. 

Amer.  Med.  Assoc.,  1916,  Ixvi,  1910.     Tr.  Assoc.  Amer.  Phys.,  1916,  xxxi,  12. 
Murlin  and  others:  Jour.  Biol.  Chem.,  1916,  xxviii,  261,  289. 
Joslin:  Harvey  Lectures,    1914-15,  x,  290.    Johns  Hopkins  Hosp.  Bull.,  1918,  xxxix, 

80. 
Clark,  A.:  Jour.  Exp.  Med.,  1916,  xxiv,  621;  1917,  xxvi,  721. 

DISTURBANCES  OF  THE  FUNCTIONS  OF  THE  THYROID  GLAND 

The  thyroid,  arising  from  a  median  and  two  lateral  rudiments  from  the 
fifth  branchial  arch,  is  composed  finally  of  two  lateral  masses  in  some 
animals,  of  a  fused  organ  in  others,  the  isthmus  of  connection  in  man 
crossing  in  front  of  the  trachea.  The  original  duct  opening  at  the  root  of 
the  tongue  is  interrupted  by  the  growth  of  the  hyoid  bone,  but  occasion- 
ally there  are  remnants  of  glandular  tissue  left  about  the'  foramen  caecum, 
which  represents  its  outlet.  The  alveolar  structure  of  the  mature  gland, 
its  relation  to  blood-vessels,  and  its  colloid  secretion,  and  the  surmises 
about  the  fate  of  that  secretion,  are  discussed  in  all  text-books  of  his- 
tology and  physiology. 


MYXCEDEMA  871 

So,  too,  for  that  matter,  are  most  of  the  dramatic  effects  of  the  loss  of 
its  function  or  its  overactivity,  and  every  one  knows  of  its  iodine  content. 
But  even  so  we  are  very  ignorant  of  most  of  its  relations  to  other  organs, 
and  the  actual  nature  of  its  function  is  still  rather  obscure. 

In  early  infantile  life  the  alveoli  are  small  and  contain  very  little  colloid; 
later  they  show  the  homogeneous  colloid  which  may  at  times  become  inspis- 
sated into  an  almost  solid  mass,  floating  in  the  more  recently  secreted  fluid. 
How  the  colloid  leaves  the  alveoli  and  enters  lymphatics  or  veins  has  not 
been  determined,  although  there  are  many  theories. 

Physiology. — Destruction  of  the  thyroid  gland  in  animals  by  operative 
extirpation  is  not  easy,  because  there  are  practically  always  numerous 
minute  accessory  nodules  of  thyroid  tissue  scattered  in  the  neck,  in  the 
thymus,  and  inside  the  pericardium  (Halsted).  On  this  account  it  is  diffi- 
cult to  produce  experimentally  the  effects  of  the  loss  of  the  gland.  The 
difficulty  is  increased  by  the  fact  that  in  some  animals  (cat,  dog,  etc.) 
the  -parathyroid  glands  are  very  closely  associated  with  the  thyroid,  and  if 
they  be  destroyed  in  the  operation,  the  slowly  developing  effects  of  thyroid- 
ectomy  will  never  really  appear  because  the  animal  dies  quickly  from  the 
loss  of  the  parathyroids. 

It  is  in  very  young  animals  that  careful  removal  of  the  thyroids,  leaving 
some  of  the  parathyroids  intact,  produces  the  most  remarkable  changes, 
changes  which  are  the  counterpart  of  those  observed  in  children  in  whom 
some  disease  has  destroyed  the  thyroid  leaving  the  other  glands  unaffected. 
But  in  adult  human  beings  and  animals  similar,  if  less  extreme,  changes  are 
also  brought  about. 

MYX(EDEMA 

The  child  devoid  of  thyroid  tissue  begins  to  show  symptoms  after  it  has 
ceased  to  nurse,  and  these  consist  essentially  in  the  practical  cessation  of 
growth  and  development.  The  rate  of  metabolism  is  greatly  decreased, 
the  temperature  is  low,  relatively  little  food  is  taken,  and  all  the  functions 
of  the  bodily  organs  are  retarded.  Mentally  the  child  remains  at  the  stage 
at  which  the  destruction  of  the  thyroid  found  it.  Sexually  it  ceases  to 
develop,  and  after  twenty  or  thirty  years  of  life  it  is  still  an  infant  in 
these  respects,  although  the  skin  may  be  wrinkled  and  the  hair  sparse. 
Nothing  expressed  the  situation  better  than  the  phrase  "a  sad  old  child" 
which  some  one  has  used. 

Such  children  may  become  very  obese,  but  they  do  not  grow  in  stature, 
because  the  process  of  bone  formation  is  retarded,  not  merely  at  the  epi- 
physes,  as  in  chondrodystrophy  (q.  v.),  but  throughout,  so  that  a  delicate 
small  skeleton  is  produced  in  which  all  the  cartilaginous  epiphyseal  lines 
and  junctions  remain  as  cartilage  until  very  late  in  life. 

In  one  case  dissected  some  years  ago  a  few  of  the  permanent  teeth  had 
appeared,  crowding  inside  the  milk  teeth,  all  of  which  were  still  present. 
The  sternum  was  in  several  parts  at  fifteen  years  of  age,  and  the  three 


872  TEXT-BOOK    OF    PATHOLOGY 

pelvic  bones  were  still  j  oined  only  by  cartilage  in  the  acetabulum.  The  thy- 
roid was  reduced  to  a  minute  mass  of  distorted  alveoli  about  the  foramen 
csecum,  and  two  extremely  small  cystic  nodules  somewhere  in  the  position 
of  the  lateral  lobes.  These  were  smaller  than  the  parathyroid  glands, 
which  were  perfectly  well  preserved,  and  this  is  a  common  finding.  The 
hypophysis  was  rather  large,  and  gave  the  impression  of  being  in  process  of 
hypertrophy.  j 

Such  a  state  might  well  be  the  end  result  of  a  destructive  infection,  such 
as  is  known  to  occur,  without  actual  abscess  formation,  in  the  thyroid,  or  it 
might  possibly  be  thought  of  as  a  congenital  defect,  but  even  then  it  seems 
more  plausible  to  regard  it  as  the  outcome  of  some  intra-uterine  disease. 
This  girl  was  an  idiot  with  the  intelligence  of  a  young  infant. 

In  adults  the  thyroid  may  be  destroyed  by  operation  or  by  disease,  to  a 
degree  sufficient  to  produce  a  condition  which  closely  resembles  that  seen 
in  children,  in  so  far  as  the  already  attained  development  will  allow.  Any 
further  growth  is  stopped,  and  mental  and  sexual  activity  rapidly  recedes, 
so  that  these  people  quickly  becomes  sexually  impotent  and  mentally 
dulled.  They  grow  sluggish  and  cold,  appetite  fails,  metabolism  is  de- 
creased, the  skin  becomes  dry  and  scaly,  and  in  a  curious  way  thickened 
and  dense.  Heavy  pads  form  in  a  characteristic  way  below  the  clavicles 
and  elsewhere,  and  over  the  face  and  forehead  the  skin  may  feel  as  though 
there  were  a  thick,  pasty  elastic  infiltration  in  its  deeper  layers,  so  that  it 
cannot  be  easily  pinched  up  into  a  fold.  Actually,  there  is  said  to  be  an 
accumulation  of  a  bluish-staining  semifluid  material  there,  which  was 
thought  to  have  a  mucoid  character,  and  hence  the  name  myxocdema,  which 
was  given  long  ago  by  Gull.  The  patients  may  or  may  not  become  very 
fat,  heart-beat  and  respiration  are  slowed,  and  the  carbon  dioxide  output  is 
lowered. 

There  are  all  imaginable  grades  of  this  thyroid  insufficiency,  and  the 
slighter  ones  are  difficult  to  recognize,  but  in  the  more  complete  degrees  the 
effects  are  overwhelming.  In  a  relatively  short  time  if  there  is  no  ther- 
apeutic intervention  the  patient  sinks  into  a  state  of  idiocy  and  physical 
torpor  such  that  one  is  reminded  rather  of  the  life  of  a  vegetable  than  that 
of  a  human  being. 

The  proof  that  all  this  is  due  to  the  loss  of  the  thyroid  lies  in  the  fact  that 
the  daily  long-continued  administration  by  mouth  of  an  extract  of  the  thy- 
roid of  some  animal  will  restore  such  an  inert  being  to  life  and  activity. 
The  child  grows  and  develops  and  brightens  into  a  normal  person.  The 
adult  is  transformed  to  his  old  self,  the  whole  machinery  quickens  its  rate, 
the  skin  becomes  thin  and  moist,  and  the  hair  grows.  The  face  loses  its 
dull,  bloated  appearance,  and  the  tongue  its  thickness  and  sluggishness, 
and  words  and  ideas  come  back.  It  is  as  though  the  regulator  of  an  engine 
were  reset  at  the  normal  point.  The  same  effect  has  sometimes  been 
attained  by  the  transplantation  of  thyroid  tissue  into  the  patient,  or  has 
appeared  gradually  with  the  increase  in  size  through  compensatory  hyper- 


CRETINISM  873 

trophy,  of  some  fragment  or  accessory  nodule  left  intact,  or  even  with  the 
growth  of  a  metastasis  from  a  malignant  tumor  of  the  thyroid,  through  the 
surgical  extirpation  of  which  the  myxcedema  arose. 

In  these  persons,  as  in  animals,  it  is  found,  by  studying  the  metabolism, 
that  the  output  of  nitrogen  in  the  urine  is  greatly  decreased,  that  the  intake 
of  oxygen  and  the  discharge  of  carbon  dioxide  are  similarly  on  a  lower  level. 

Unless  the  appetite  is  greatly  decreased,  there  is  apt  to  be  a  gradual  in- 
crease in  weight  under  these  circumstances,  and  most  of  this  is  in  the  form 
of  fat.  Since  the  oxidation  is  thus  decreased  in  the  restricted  metabolism 
of  the  muscles  and  other  organs,  the  production  of  heat  is  diminished, 
and  this  may  reach  the  point  where  the  regulatory  mechanism  is  unable  to 
maintain  the  normal  standard  of  bodily  temperature,  so  that  it  falls  even 
several  degrees. 

Carbohydrate  metabolism  is  affected  in  such  a  way  that  it  becomes 
practically  impossible  to  produce  an  alimentary  glycosuria,  that  is,  to 
cause  the  elimination  of  sugar  in  the  urine  by  feeding  it  in  excessive  amounts. 
Even  those  drugs  and  nervous  disturbances  which  ordinarily  produce 
glycosuria  fail  to  do  so,  or  succeed  only  when  pushed  to  extremes.  Adrena- 
line, which  in  relatively  small  doses  produces  hyperglycsemia  and  glycosuria, 
fails  to  do  this  in  the  absence  of  the  thyroid,  or  does  so  only  when  given  in 
far  larger  doses.  Even  the  glycosuria  of  depancreatized  animals  is  greatly 
modified  by  the  loss  of  the  thyroid,  although  not  entirely  abolished.  It  is 
difficult  to  give  a  satisfactory  explanation  of  this.  Falta,  Riidinger,  and 
Eppinger  regard  it  as  the  effect  of  the  loss  of  the  promoting  influence  of  the 
thyroid  upon  the  chromaffin  system,  and  at  the  same  time  the  loss  of  the 
normal  antagonistic  effect  of  the  thyroid  upon  the  pancreas.  It  seems  more 
simple,  though,  to  think  of  the  thyroid  secretion  as  something  which  plays  a 
role  in  the  final  processes  of  oxidation  of  the  sugar,  acting  in  a  sense  as  an 
antienzyme.  Here,  however,  we  tread  on  uncertain  ground,  not  yet  sup- 
ported by  enough  experimental  results. 

CRETINISM 

In  certain  districts,  especially  in  the  high  valleys  of  the  Alpine  region,  and 
in  similar  mountainous  parts  of  other  countries,  a  considerable  proportion 
of  the  inhabitants  are  defective  in  a  way  very  like  that  of  the  sporadic  or 
scattered  cases  of  myxcedema. 

Unlike  the  myxcedema  cases  which  occur  anywhere  and  everywhere, 
regardless  of  environment  or  hereditary  taint,  these  people,  known  as 
cretins,  are  found  in  regions  where  the  condition  seems  to  be  endemic  or 
inherent  in  the  environment,  and  we  can  usually  trace  in  their  parents  or 
ancestors  some  similar  thyroid  defect. 

In  the  cases  of  myxcedema  one  may  often  determine  the  cause  of  the 
destruction  of  the  gland,  and  find  minute  remnants  of  it  at  autopsy.  In 
the  cretins  there  is  commonly  a  great  enlargement  of  the  thyroid,  which 
none  the  less  seems  to  be  deficient  in  its  function.  Every  grade  of  severity 


874  TEXT-BOOK    OF    PATHOLOGY 

in  the  physical  and  psychical  disturbance  is  found  here  also.  Some  cretins 
are  able  to  earn  a  living  and  procreate  children,  others  are  stunted  idiots. 
Thyroid  treatment  seems  far  less  brilliant  in  its  results  with  them  than  with 
the  cases  of  myxcedema,  but  still  accomplishes  something. 

The  nature  of  this  process  has  been  earnestly  studied,  since  it  affects 
thousands  in  France,  Italy,  Switzerland,  and  Austria,  but  as  yet  without 
any  clear  result. 

Bircher  thought  it  occurred  in  people  who  live  in  a  country  formed  by 
strata  which  had  once  been  submerged  under  the  ocean,  and  not  in  those 
living  on  strata  formed  under  fresh  water  or  on  volcanic  formations.  The 
introduction  of  a  new  water  supply  from  a  district  of  different  character  into 
one  of  these  foci  (Aarau)  seemed  to  bring  with  it  a  great  decrease  in  the 
number  of  new  cases  and  improvement  in  the  old. 

Bacteria  have  been  sought  in  the  drinking-water  and  found,  together  with 
many  other  forms  of  life,  but  it  could  not  be  proved  that  they  bore  any 
relation  to  the  disease.  Still  the  goitre  could  be  produced,  even  in  animals, 
by  giving  them  the  water  from  wells  and  springs  in  the  affected  districts, 
and  so  firmly  fixed  is  the  idea  of  this  connection,  that  some  of  these  springs 
are  called  "  Kropf brunnen, "  or  goitre  springs.  But  animals  fed  on  im- 
ported food  and  water  and  kept  in  the  district  also  acquire  goitres.  The 
water  will  produce  goitre  in  animals  kept  in  another  country;  the  agency, 
whatever  it  is,  will  not  pass  through  a  dialyzing  membrane,  and  therefore 
it  must  be  of  colloid  character,  but  it  will  withstand  temperatures  up  to 
75°  to  80°  C.  Wherefore  it  is  agreed  that  it  cannot  be  a  living  thing,  and 
the  problem  is  still  to  be  solved.  Nevertheless  there  are  those  who  main- 
tain stoutly  that  it  is  an  infection  (McCarrison) 

GOITRE 

Something  has  been  said  of  goitre,  which  is  the  term  long  used  in  general  to 
indicate  an  enlargement  of  the  thyroid  gland.  It  is  not  only  in  cretins  that 
such  enlargement  occurs.  There  are  various  forms,  and  while  one  gains  the 
impression  that  they  are  more  frequently  found  in  certain  districts,  such  as 
the  shores  of  the  Great  Lakes  in  this  country,  they  do  appear  elsewhere  in 
people  and  animals  which  have  not  been  exposed  to  any  recognizable 
peculiarity  of  environment.  What  it  is  in  these  goitre  districts  which  pro- 
duces goitre  without  especial  signs  of  thyroid  deficiency  is  as  obscure  as 
in  the  case  of  the  cretins.  Perhaps  it  is  the  same  influence,  since  in  the 
Alpine  regions  there  are  many  persons  afflicted  with  goitre  who  are  not 
cretins.  About  Kingston,  in  Ontario,  and  about  Cleveland  it  is  especially 
common,  and  Marine  states  that  80  per  cent,  or  more  of  the  stray  dogs  near 
Cleveland  have  enlarged  thyroids.  Possibly,  as  he  thinks,  it  may  be  due 
to  a  lack  of  assimilation  of  iodine  from  the  food,  since  iodine  has  long  been 
known  as  a  remedy  in  this  disease  which  is  more  or  less  efficient  in  diminish- 
ing the  size  of  the  gland. 

There  are  many  variations  in  the  anatomical  character  of  these  enlarge- 


GOITRE 


875 


ments,  many  combinations  and  progressive  alterations,  but  there  seem  to 
be  two  essentially  different  forms  which  constitute  the  basis  for  all  these 
variations. 

In  one  of  these,  the  so-called  colloid  or  gelatinous  goitre,  the  gland  is  fairly 
uniformly  enlarged,  because  every  alveolus  is  increased  in  size  and  dis- 
tended with  colloid,  even  to  such  a  degree  that  the  lining  epithelium  is 
flattened  to  a  scale-like  form.  Such  a  goitre,  on  section,  is  rather  soft  and 
translucent,  like  amber,  and  uniform  in  appearance  throughout,  although 
there  are  often  haemorrhages  or  necroses,  or  the  scars  which  result  from 
these.  The  alveoli  filled  with  clear 
colloid  are  often  so  large  that  they  are 
visible  to  the  naked  eye. 

The  other  form,  frequently  combined 
with  this,  but  also  occurring  alone, 
seems  to  begin  in  young  persons  about 
the  time  of  puberty,  and  to  progress 
very  slowly.  It  is  not  a  diffuse  en- 
largement, but  is  produced  by  the 
presence  of  one  or  many  circumscribed 
nodules  made  up  of  a  tissue  different 
in  appearance  from  the  surrounding 
thyroid,  which  becomes  greatly  com- 
pressed by  the  sharply  outlined  nod- 
ules. In  their  fresher  state  these  nod- 
ules are  elastic,  and  on  section  show  a 
smooth  swelling,  finely  granular,  or 
velvety  surface,  which  is  grayish  white 
or  flecked  with  small  diffuse  hemor- 
rhages (Fig.  434).  Microscopically,  it 
is  seen  to  be  made  up  of  many  small 
round  alveoli  lined  with  rather  high 
cubical  epithelium,  inclosing  a  small 
lumen  which  usually  contains  little  or 
no  colloid  (Fig.  435) .  The  alveoli  are 

not,  as  a  rule,  closely  packed  together,  but  are  separated  by  an  abundant, 
rather  cedematous  looking  stroma,  rich  in  blood-vessels,  from  which  inter- 
alveolar  hemorrhages  are  often  seen  to  have  arisen.  In  some  cases  the 
alveoli  are  larger  and  more  irregular  in  form  and  filled  with  colloid.  Indeed 
one  occasionally  finds  nodules  of  almost  the  character  of  the  colloid  goitre. 
After  they  have  existed  for  a  time  necroses  arise  in  the  central  portion  and 
appear  as  opaque  yellow  areas.  They  may  become  calcified,  or  they 
soften  so  that  the  nodule  becomes  a  cyst,  with  turbid  and  blood-stained 
liquid  contents,  which  in  time  may  become,  in  turn,  a  clear  yellow  fluid. 
The  rind  of  the  nodule  persists,  often  with  extensive  calcification,  and  is 


Fig.  434. — Large  adenoma  of  thy- 
roid. The  nodule  is  sharply  outlined 
and  surrounded  by  compressed  thyroid 
tissue.  Necroses,  haemorrhages,  and 
areas  of  calcification  in  its  substance. 


876 


TEXT-BOOK   OF    PATHOLOGY 


deeply  pigmented  with  hsemosiderin  from  the  blood  which  was  extravasated 
in  the  interior. 
These  seem  to  be  tumor-like  growths  or  adenomata.     It  is  true  that 


!f 


W& 

:^#'"t  ' 


p^fO] 

OP3^5 


>vi^ri-^^^!£vH  ^v^s?  n^^n  -;i 

NSrf^SNSXs^i 

j2x~^-K-:t^  *     „,. .  yt  -^;<f.--.-      *  '^I:X/-5s&v'''% 
^^^:®^-^----;^,:l.- 

^^^^^^^^^ 

^"-i  -.~::;:vv-'>-^svM  ""^^  ;•: ;.,--*v 

:'-\-^:--e^:v,:  '   '-•••' ^^-^-:-^ 


Fig.  435. — Circumscribed  adenomatous  nodule  of  the  thyroid.  The  surrounding 
tissue  is  somewhat  compressed.  The  alveoli  of  the  nodule  are  small  and  round,  and  are 
embedded  in  abundant  stroma. 


their  structure  bears  a  faint  resemblance  to  that  of  the  foetal  thyroid  in  the 
lack  of  colloid,  but  I  do  not  think  it  justifiable  to  call  them,  as  Wolfler  does, 
foetal  adenomata,  since  there  is  no  evidence  whatever  that  there  is  any- 


GOITRE  877 

thing  foetal  about  them.  Instead,  the  condition  might  be  called  adenoma- 
tons  or  nodular  goitre. 

Both  of  these  forms,  or  combinations  of  them,  even  when  considerable 
scarring  has  taken  place,  seem  to  be  compatible  with  practically  normal 
life,  without  any  evidences  of  deficiency  or  excess  of  thyroid  function. 

If  anything,  it  would  seem  that  the  error  would  be  on  the  side  of  defi- 
ciency, since  the  colloid  is  found  on  analysis  to  be  relatively  poor  in  iodine 
(which  may  perhaps  be  taken  as  an  indication  of  the  efficiency  of  the  gland), 
but  the  quantity  of  colloid  is  so  increased  in  the  first  form  that  the  total 
amount  of  iodine  may  exceed  the  normal.  It  leads  one  to  the  idea  that  the 
enlargement  may  be  a  compensatory  phenomenon,  an  attempt  to  make  up 
in  bulk  what  is  deficient  in  quality  of  the  colloid. 

It  has  long  been  recognized  that  there  is  some  connection  between  iodine  and  the 
thyroid;  poultices  of  burnt  seaweed  which  contains  iodine  were  long  ago  applied  with 
effect. in  the  attempt  to  reduce  the  size  of  goitres,  and  in  a  similar  way  iodine  has  been 
painted  on  the  skin  over  them.  Baumann  isolated  an  iodine-containing  protein  ma- 
terial which  he  regarded  as  a  characteristic  constituent  of  the  thyroid,  while  Oswald 
later  determined  that  this  substance  is  a  globulin,  and  named  it  thyreoglobulin.  Its 
iodine  content  varies  in  different  glands,  and  indeed  may  be  changed  at  will  by  the  ad- 
ministration of  iodine,  much  as  the  iodine  content  of  other  organs  is  affected,  but  in  a 
far  more  striking  degree.  The  lipoid  contents  of  the  gland,  while  showing  a  certain 
avidity  for  iodine,  seems  to  play  no  important  part  in  the  actual  iodine  interchange  of  the 
gland  (Howe).  Kendall  claims  to  have  isolated  in  a  substance  with  an  oxyindol  nucleus 
the  active  principle  of  the  thyroid,  and  has  even  synthesized  it  (Tr.  Assoc.  Amer. 
Phys.,  1918,  xxxiii,  324). 

Marine  has  shown  that  the  iodine  content  of  the  thyroid  is  in  inverse  proportion  to  the 
activity  of  its  efforts  at  hyperplasia.  This  hyperplasia  involves  the  new  formation  of  epi- 
thelium, which  is  thrown  up  into  folds,  and  usually  the  diminution  or  disppearance  of  the 
colloid.  The  administration  of  iodine  has  the  remarkable  effect  of  checking  the  hyper- 
plastic  epithelial  growth  and  restoring  the  gland  to  its  colloid-filled  state.  When  the  hy- 
perplasia is  already  advanced,  the  nearest  approach  to  the  normal  gland  attained  by  giving 
iodine  is  seen  in  an  organ  whose  alveoli  are  rather  overstretched  with  colloid.  Marine 
therefore  looks  upon  such  epithelial  hyperplasia  as  a  normal  effort  to  compensate  for  an 
insufficiency  due  to  inability  to  absorb  or  assimilate  sufficient  iodine.  Probably  the  long- 
recognized  reduction  in  the  bulk  of  colloid  goitres  upon  the  application  of  iodine  may  be 
due  to  the  concentration  of  the  iodine  content  of  the  dilute  colloid,  and  a  consequent  re- 
duction in  its  amount. 

Although  the  functional  activity  of  such  enlarged  and  distorted  thyroid 
glands  may  not  be  strikingly  disturbed,  the  mechanical  effects  upon 
the  neighboring  organs  are  often  serious.  The  goitre  may  be  so  large  as  to 
be  very  unsightly,  and  impede  the  movements  of  the  head,  but  more  impor- 
tant than  this  are  the  results  of  pressure  upon  the  trachea,  the  oesophagus, 
and  the  circulatory  organs. 

Lateral  pressure  upon  the  trachea  frequently  reduces  its  calibre  to  a 
narrow  slit,  with  distortion  and  softening  of  the  cartilages,  so  that  extreme 
dyspnoea,  emphysema  of  the  lungs,  etc.,  may  ensue.  Dysphagia  from 
compression  of  the  oesophagus  is  far  less  common,  but  the  circulation  is 


878  TEXT-BOOK    OF    PATHOLOGY 

sometimes  embarrassed,  so  that  palpitations  and  tachycardia  and  finally 
cardiac  hypertrophy  are  brought  about. 

Minnich,  who  has  made  a  study  of  such  goitre  hearts,  points  out  the 
mechanical  strain  offered  in  the  lesser  circulation  by  the  effects  of  dysp- 
noea, but  thinks  that  even  more  frequently  the  circulation  is  disturbed  by 
alterations  in  the  secretions  of  the  thyroid,  which  affect  the  nervous 
regulators  of  the  heart,  diminishing  especially  the  action  of  the  depressor 
and  allowing  the  heart  to  be  overworked. 

An  interesting  if  rare  form  of  enlargement  of  the  thyroid  is  the  so-called 
plunging  goitre,  which  hangs  down  behind  the  sternum  and  moves  up  and 
down,  in  and  out  of  the  thorax,  with  respirations. 

EXOPHTHALMIC  GOITRE 

Most  interesting  of  all  the  diseases  which  affect  the  thyroid  is  this  so-called 
Graves'  or  Basedow's  disease,  in  which,  at  least,  there  are  active  symptoms 


Fig.  436. — Exophthalmic  goitre.     The  patient  shows  a  goitre  of  moderate  size;  great 
exophthalmos,  smooth  forehead,  and  abnormal  expression. 

in  place  of  the  sluggish  effects  met  with  in  the  diseases  following  upon 
deficiencies  in  the  thyroid  glands.  But  here  the  nature  of  the  relation  of 
the  symptoms  to  the  thyroid  is  not  so  clear,  although  it  is  commonly  looked 
upon  as  the  effect  of  overactivity  of  the  gland. 

The  disease  is  common,  occurring  sporadically  everywhere  without 
recognizable  relation  to  any  particular  district,  and  much  more  frequently 
in  women  than  in  men.  Extremes  of  age  have  been  reported,  but  it  is 
essentially  an  affection  of  young  and  middle-aged  adults.  It  begins  with- 
out any  very  obvious  causes,  after  recovery  from  some  infection  or  often 


EXOPHTHALMIC    GOITRE 


879 


after  some  violent  emotional  disturbance  or  fright,  sometimes  appearing 
suddenly  in  its  full  intensity,  more  frequently  developing  gradually.  The 
more  prominent  disturbances  of  function  are  briefly  as  follows:  there  are 
nervousness  and  irritability,  the  patient  being  agitated  and  perturbed  by 
occurrences  which  would  produce  little  impression  on  a  normal  person; 
the  skin  is  flushed  and  moist,  and  the  patient  feels  hot;  the  heart  beats 
very  rapidly  and  forcibly,  and  the  peripheral  vessels  are  distended  and 
thump.  There  is  tremor;  the  eyes  protrude  abnormally,  so  that  the 
eyelids  may  fail  to  cover  them  properly;  there  are  disturbances  in  the 
motility  of  the  eyelids  and  of  the  forehead  (Fig.  436).  There  is  often, 
though  not  always,  enlargement  of  the  thyroid,  and  finally,  in  spite  of  the 
good  appetite,  the  patient  wastes  away.  Nitrogenous  metabolism  is 
increased,  as  judged  by  the  excretion  of  nitrogen  in  the  urine;  the  calor- 


Fig.  437. — Exophthalmic  goitre.     Gross  external  appearance  of  the  thyroid. 


imeter  shows  an  increased  dissipation  of  energy.  The  tolerance  for  sugar  is 
lowered,  and  glycosuria  is  readily  brought  about  or  occurs  spontaneously, 
since  the  storage  of  carbohydrate  is  so  unstable. 

Such  patients  are  more  or  less  incapacitated,  but  some  of  them  go  on  for 
years  and  die  of  an  intercurrent  affection.  Others  develop  symptoms  of 
such  intensity  that  they  die  from  the  disease  itself,  often  with  mental 
derangement,  with  cardiac  dilatation,  with  excessive  vomiting,  or  with 
exhaustion  from  any  of  these. 

At  autopsy  fairly  constant  changes  are  found  in  the  thyroid,  in  the 
thymus,  and  in  the  lymphoid  structures.  The  heart  is  frequently  hyper- 
trophied,  but  there  are  no  very  obvious  changes  in  the  other  organs.  The 
brain,  in  spite  of  most  diligent  search,  has  shown  nothing  constant. 


880 


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The  Thyroid. — Many  descriptions  of  the  thyroid  alterations  have  been 
given  and  many  subdivisions  made,  but  it  is  doubtful  whether  these  classi- 
fications have  any  great  significance.  Many  stages  or  degrees  of  altera- 
tion are  found  in  the  gland,  and  these  must  be  studied  in  detailed  reports 
on  this  subject  (A.  Kocher,  etc.).  There  is  not  always  a  great  enlarge- 
ment of  the  gland,  and  sometimes  it  cannot  be  palpated.  When  the  thy- 
roid is  exposed  at  operation,  it  is  found  to  be  very  richly  supplied  with 
blood,  and  over  the  surface  course  huge  distended  veins  whose  walls  tear 


.'N 


Fig.  438. — Exophthalmic  goitre.     Alveoli  are  irregular  in  form,  lined  with  columnar 
epithelium,  and  almost  devoid  of  colloid.    The  stroma  is  increased  in  quantity. 

readily,  so  that  the  risk  of  haemorrhage  is  great  in  these  operations.  After 
removal,  when  the  blood  runs  out,  the  gland  appears  pale,  dense,  and 
hard,  and  on  section  its  cut  surface  is  both  finely  and  coarsely  lobulated, 
opaque,  and  of  a  pale,  grayish-pink  color  (Fig.  437).  Little  or  no  colloid 
can  be  found.  On  the  other  hand,  there  are  some  cases  in  which  colloid 
is  abundant,  so  that  the  characteristic  gross  appearance  of  opacity  is  not 
produced. 

Microscopically,  there  is  found  in  the  most  typical  cases  an  alteration  of 
the  gland  (Fig.  438)  which  closely  resembles  that  recognized  as  a  com- 


EXOPHTHALMIC    GOITRE  881 

pensatory  hyperplasia  in  the  remnant  of  the  thyroid  of  a  normal  animal, 
some  time  after  a  large  part  of  the  gland  has  been  extirpated.  The  alveoli 
are  no  longer  uniform  in  size  or  shape,  and  contain  little  or  no  colloid. 
What  they  do  contain  is  no  longer  homogeneous  or  refractive,  but  granular 
or  shreddy,  like  a  thin,  coagulated  fluid.  The  epithelium,  instead  of  being 
flattened  or  low  cubical,  is  high  and  often  distinctly  columnar,  and  is  so 
increased  in  amount  that  it  is  thrown  up  into  folds,  giving  to  the  alveolus 
an  irregular  outline,  with  papillary  ingrowths  encroaching  greatly  upon 
the  cavity.  Commonly  many  very  small  alveoli  are  associated  with  each 
larger  one,  and  one  sometimes  receives  the  impression  that  many  of  these 
are  merely  cross-sections  of  the  bays  which  project  from  the  larger  ones. 
The  stroma  is  frequently  but  not  always  fortified  by  scar  tissue,  sometimes 
to  such  an  extent  as  to  suggest  a  cirrhotic  condition.  Definite  lymphoid 
nodules  are  often  found  scattered  through  the  gland,  an  appearance  which, 
while  fairly  characteristic  of  this  disease,  is  rarely  if  ever  seen  in  the  normal 
thyroid. 

These  changes  may  sometimes  be  recognized  as  beginning  in  patches 
scattered  through  the  normal  gland  or  in  adenomatous  nodules,  but  in 
most  cases  they  appear  gradually  and  diffusely  throughout  the  organ. 
They  are  constantly  found,  in  some  stage  of  development,  although  in 
any  large  series  one  finds  several  cases  in  which,  although  the  symptoms 
are  definite  and  intense,  the  alveoli  of  the  thyroid  are  still  large  and  fairly 
uniform  in  outline  and  filled  with  colloid.  The  various  modifications  of 
this  anatomical  picture  which  involve  reduplication  of  the  epithelial 
lining,  distortion  and  irregularity  in  the  form  of  the  cells,  desquamation 
of  the  epithelium,  etc.,  must  be  read  in  such  papers  as  that  of  Kocher. 

The  thymus,  which  is  ordinarily  atrophied  in  adult  life  except  for  micro- 
scopical remnants,  is  found  to  be  greatly  enlarged.  This  has  been  con- 
stant in  the  autopsies  which  I  have  seen,  and  in  some  cases  it  has  presented 
itself  as  an  organ  almost  the  size  of  one's  hand.  HassaFs  bodies  persist, 
and  the  small  cells  are  in  such  excess  that  the  ordinary  distinction  between 
medulla  and  cortex  is  obscured.  Dr.  Halsted  discusses  its  importance  in 
connection  with  the  symptoms  and  the  favorable  effect  of  its  extirpation. 

The  lymph-glands,  especially  in  the  neck,  are  often  markedly  enlarged. 
In  some  cases  this  increase  in  the  bulk  of  the  lymphoid  tissue  occurs 
throughout  the  body,  even  the  solitary  nodules  in  the  intestine  projecting 
as  gray  prominences.  Together  with  this,  which  corresponds  with  the 
finding  of  new  lymph-nodes  in  the  substance  of  the  thyroid,  there  is  a  dis- 
tinct lymphocytosis  (Kocher),  which  is  reduced  to  normal  when  the  thy- 
mus is  removed  (Capelle  and  Bayer). 

Conceptions  of  Nature  and  Cause  of  the  Disease. — In  spite  of  all  investi- 
gation, the  nature  of  this  disease  is  still  in  doubt.  Since  the  statements  of 
Mobius  it  has  been  most  commonly  thought  of  as  the  effect  of  hypersecre- 
tion  or  perhaps  an  altered  secretion  on  the  part  of  the  thyroid,  without  any 
further  curiosity  being  shown  as  to  what  might  cause  this  altered  activity 

57 


TEXT-BOOK   OF    PATHOLOGY 

of  the  thyroid.  The  main  support  for  this  lies  in  the  recognition  (by  the 
acetonitrile  method  of  Hunt)  of  excess  of  thyroid  secretion  in  the  circulating 
blood,  in  the  increased  nitrogenous  metabolism  during  the  disease,  in  the 
harmful  effects  of  thyroid  extract,  and  in  the  peculiar  hypertrophic  changes 
in  the  thyroid  itself.  The  lack  of  colloid  there  is  ascribed  to  the  rapidity 
of  its  removal  by  the  passing  blood.  Further,  the  view  is  supported  by  the 
beneficial  effects  of  removing  part  of  the  thyroid  or  of  ligating  the  thyroid 
arteries. 

Opposed  to  this  view  are  the  following  facts :  the  thyroid  gland  and  the 
colloid  contain  less  iodine  than  the  normal  gland;  after  extensive  operative 
extirpation,  or  even  in  the  natural  course  of  the  disease,  symptoms  of 
myxcedema  which  surely  indicate  insufficiency,  may  arise,  while  the  symp- 
toms of  exophthalmic  goitre  are  still  present  and  intense.  Nor  do  the 
symptoms  of  exophthalmic  goitre  disappear  with  any  precision  upon  the 
removal  of  hah"  or  more  of  the  gland,  as  they  should  if  they  were  merely 
the  result  of  an  excessive  secretion.  What  actually  happens  is  that 
the  recognized  influence  of  the  thyroid  in  promoting  nitrogenous  katabol- 
ism  is  halted  by  the  loss  of  the  gland,  and  for  a  time  the  patient,  in  spite  of 
her  other  symptoms,  gains  weight.  Nevertheless,  with  the  compensatory 
growth  of  the  thyroid  the  weight  sinks  again.  Further,  it  is  impossible 
to  reproduce  exactly  the  whole  symptom  complex  by  administering  an 
excess  of  thyroid  secretion,  although  some  of  the  phenomena  can  thus  be 
brought  about. 

On  the  whole,  it  seems  clear  that  while  the  thyroid  is  profoundly  affected, 
and  through  the  disturbance  of  its  function  does  cause  many  of  the  symp- 
toms, it  is  not  alone  responsible,  but  forms  part  in  a  chain  or  circle  in  which 
notably  the  sympathetic  system  and  probably  the  other  organs  of  internal 
secretion,  perhaps  especially  the  thymus,  are  concerned.  This  is  true,  as 
we  have  seen,  in  most  of  the  diseases  which  involve  these  organs,  and  in 
their  study  we  are  more  and  more  impressed  with  their  close  interrelation. 

Cannon  has  recently  reported  an  ingenious  experiment  which  may  shed 
much  light  on  the  affection,  although  in  itself  it  must  be  regarded  as  a  purely 
artificial  imitation  of  the  disease.  He  anastomosed  the  phrenic  nerve, 
which  sends  an  impulse  with  every  breath  to  the  diaphragm,  with  the 
cervical  sympathetic,  which  gives  sympathetic  fibres  to  the  thyroid. 
After  the  time  necessary  for  the  functional  union  of  the  two  nerves  had 
passed,  he  found  that  the  animals  (cats)  showed  practically  all  the  symp- 
toms of  exophthalmic  goitre,  tachycardia,  diarrhoea,  greatly  increased  appe- 
tite, emaciation,  an  increase  of  150  per  cent,  in  the  nitrogenous  metabolism, 
exophthalmos,  and,  while  in  the  dark,  a  rhythmic  expansion  and  contrac- 
tion of  the  pupil  with  each  breath. 

On  the  basis  of  such  experiments  he  thinks  that  in  exophthalmic  goitre 
there  may  be  a  lowering  of  the  threshold  which  normally  limits  the  passage 
of  sympathetic  stimuli  to  the  organs,  and  that  the  overactivity  of  the  thy- 
roid and  the  consequent  symptoms  are  due  primarily  to  a  disturbance  of 


EXOPHTHALMIC    GOITRE  883 

the  central  nervous  system  and  the  preponderance  of  the  sympathetic 
over  the  autonomic  stimuli.  (For  a  discussion  of  the  relation  of  sympa- 
thetic to  autonomic  nerve  influences  see  Barker,  Trans.  Assoc.  Amer. 
Phys.,  1912,  xxvii,  491.) 

THYROID  LITERATURE 
Halsted:  Jour.  Exp.  Med.,  1912,  xv,  205. 

v.  Eiselsberg:  Krankh.  d.  Schilddriise,  Dtsche.  Chirurgie,  1901,  38. 
Marine:  Arch.  Int.  Med.,  1909,  iv,  440;  1911,  vii,  506. 
Oswald:  Chemische  Beschaffenheit  d.  Schilddriise,  Strassburg,  1900. 
Minnich:  Das  Kropfherz,  Leipzig,  1904. 
Mobius:  Die  Basedow'sche  Krankheit,  Wien,  1906. 
A.  Kocher:  Virch.  Arch.,  1912,  ccviii,  86. 
MacCallum:  Jour.  Am.  Med.  Assoc.,  1905,  xlix,  1158. 

Halsted:  J.  H.  H.  Bull.,  1914,  xxv,  223;  Harvey  Lectures,  1913-1914,  ix,  224. 
Capelle  and  Bayer:  Beitr.  z.  klin.  Chir.,  1913,  Ixxxvi,  509. 


CHAPTER  XLIV 

DISEASES  DUE  TO   INJURIES  OF  THE  ORGANS  OF  INTERNAL 
SECRETION  (Continued) 

The  parathyroid:  Anatomy,  physiology.  Tetany,  hyperexdtability  of  nerves.  Relation  to 
calcium  metabolism,  pathological  anatomy.  Other  types  of  tetany.  Thymus:  Anatomy, 
evolution,  and  involution.  Hyperplasia.  Thymus  in  exophthalmic  goitre,  in  myasthenia 
gravis,  in  status  thymico-lymphaticus;  accidental  involution.  Adrenal:  Anatomy. 
Function  of  medulla,  functions  of  cortex.  Addison's  disease. 

DISTURBANCES  OF  FUNCTION  OF  THE  PARATHYROID  GLANDS 

THE  parathyroid  glands  arising  from  the  walls  of  the  third  and  fourth 
branchial  clefts  come  to  lie  in  man  in  various  situations  along  the  posterior 
edge  of  the  thyroid,  and  are  usually  four  in  number.  They  are  brown 
and  soft,  with  conspicuous  peripheral  veins,  and  are  composed  of  anastomos- 
ing strands  of  cells  many  of  which  have  a  very  clear  protoplasm  in  early 
youth,  while  in  later  life  the  predominant  cells  have  a  slightly  granular 
cytoplasm,  a  few  groups  standing  out  by  reason  of  their  small  dark  nuclei 
and  their  bright  eosinophile  protoplasm.  Differences  in  the  function  of 
these  cells  are  not  understood. 

Experimental  study  has  shown  convincingly  enough  the  complete  inde- 
pendence of  these  organs,  although  there  are  still  writers  who  claim  that 
they  are  merely  undeveloped  portions  of  thyroid  tissue.  That  they  are 
intimately  related  functionally  in  the  community  of  organs  of  internal 
secretion  is,  however,  pretty  certain,  although  it  is  not  yet  possible  to  out- 
line precisely  the  part  that  they  play. 

Physiology. — When  the  parathyroids  are  completely  extirpated,  a  period 
of  twelve  hours  to  several  days  elapses  during  which  there  are  no  symptoms, 
but  then  there  appear  the  evidences  of  the  so-called  tetany,  which  may 
quickly  reach  the  greatest  intensity.  Twitchings  of  various  muscles 
appear,  and  soon  there  is  a  continuous  quivering  or  vibration  of  the  tense 
muscle,  which  can  be  felt  as  a  thrill  interrupted  by  violent  convulsive 
jerks.  The  whole  body  becomes  rigid,  the  jaws  snap,  and  every  muscle 
is  thrown  into  violent  clonic  convulsions.  Smooth  muscle  is  said  to  be 
affected  also,  but  its  participation  is  inconspicuous.  Such  convulsions 
involve  the  most  extreme  labor  on  the  part  of  the  muscles,  and  the  tempe- 
rature rises  to  fever  heat  because  the  dissipation  of  heat  cannot  proceed 
rapidly  enough.  In  the  dog  respiration  becomes  very  rapid,  because  that 
is  its  way  of  dissipating  heat.  Death  may  occur  in  such  a  convulsive 
seizure,  or  the  tetany  may  pass  off  for  a  time  and  recur  until  death  follows 
from  complete  exhaustion.  Sometimes  a  sort  of  continuous  milder  twitch- 

884 


DISTURBANCES    OF   FUNCTION   OF   PARATHYROID    GLANDS       885 

ing  persists  for  a  long  time,  the  animal  rapidly  wastes  and  becomes  infected, 
and  dies  in  a  kind  of  cachexia. 

All  this  depends  upon  the  most  striking  and  constant  feature  of  tetany, 
the  hyperexcitability  of  the  motor  nerves,  with  which  there  appears  to  be 
associated  a  similar  hyperexcitability  of  the  sensory  nerves. 

This  hyperexcitability  is  easily  shown,  in  that  a  muscular  jerk  is  elicited 
by  a  galvanic  shock  applied  over  the  motor  nerve,  so  weak  that  it  would  have 
no  effect  under  normal  conditions.  The  direction  of  the  current  and  the 
character  of  the  shock,  whether  due  to  opening  or  closing  of  the  circuit, 
must  be  considered,  and  the  following  table  will  give  an  average  comparison 
between  the  shocks  necessary  to  produce  a  visible  muscular  contraction  in 
a  normal  and  a  tetanic  animal. 

NORMAL  TETANT 

MlLLIAMPERES  MlLLIAMPERES 

Kathode  closing 0.3  0.05 

Kathode  opening 6.0  0.6 

Anode  closing 1.8  0.8 

Anode  opening 2.0  0.8 

It  will  be  seen  that  the  greatest  and  most  characteristic  change  is  in  the 
reaction  to  the  kathode  opening  shock;  that  is,  where  the  kathode  of  the 
battery  is  put  on  the  nerve  and  the  current  broken.  Practically  all  the 
other  symptoms  seem  to  depend  upon  this  hyperexcitability  of  the  nervous 
system. 

It  was  found  (MacCallum  and  Voegtlin)  that  injection  of  a  salt  of  calcium 
would  abolish  the  hyperexcitability  and  cure  all  symptoms  of  tetany,  even 
to  the  extent  of  keeping  the  animal  alive  and  well  for  months  if  regularly 
administered,  and  it  was  suspected  that  a  lack  of  calcium  in  the  circulating 
fluids  and  tissues  might  explain  the  hyperexcitability  of  the  nerves.  As  a 
fact,  the  blood  and  nerve  tissues  of  animals  in  tetany  contain  a  decreased 
amount  of  calcium.  It  was  shown  (MacCallum)  that  if  an  isolated 
extremity  of  a  normal  animal  be  perfused  with  blood  from  another  in  the 
height  of  tetany,  the  excitability  of  its  nerves  would  be  increased  to  the 
tetany  level,  returning  to  normal  when  again  perfused  with  normal  blood. 
Conversely,  if  one  extremity  of  a  dog  in  tetany  be  perfused  with  normal 
blood,  the  excitability  of  the  nerves  of  that  leg  becomes  normal,  and  that 
leg  ceases  to  twitch,  although  the  excitability  rises  and  the  twitchings  begin 
again  if  the  femoral  vessels  are  reanastomosed  with  their  stumps,  so  that 
the  leg  is  again  flooded  with  its  own  " tetany  blood."  This  blood  is  poor 
in  calcium,  and  it  seems  that  the  hyperexcitability  of  ganglion-cells  of  the 
central  nervous  system  throughout,  as  well  as  the  nerve  endings,  is  pro- 
duced by  this,  for  if  one  remove  calcium  from  the  blood  by  dialysis  (Mac- 
Callum and  Lambert),  and  then  perfuse  an  extremity  with  that  blood, 
exactly  the  same  hyperexcitability  is  produced.  Further  evidence  in 
favor  of  the  conception  of  the  parathyroid  as  an  organ  presiding  in  some 
sense  over  the  calcium  metabolism  is  presented  by  Erdheim,  who  finds 
that  in  chronic  tetany  in  rats,  produced  by  extirpating  almost  all  of  the 


TEXT-BOOK   OF   PATHOLOGY 

numerous  scattered  glands,  calcium  fails  to  be  deposited  in  the  constantly 
growing  teeth,  so  that  they  become  soft  and  break  off.  Fractured  bones 
heal  with  only  a  soft  callus,  and  thus  fail  to  unite  firmly.  Reimplantation 
of  parathyroid  tissue  restores  the  ability  of  the  dentine  to  calcify  and 
harden,  and  reestablishes  the  ossification  process  as  long  as  the  graft  lives. 

The  influence  upon  the  sympathetic  system  is  not  yet  worked  out, 
although  there  are  vague  indications  of  hyperexcitability  of  those  nerves 
after  the  destruction  of  the  glands. 

Metabolism  in  tetany  has  been  studied,  but  with  unsatisfactory  results, 
and  nothing  which  definitely  illuminates  the  situation  has  been  found 
(Cooke,  Greenwald,  etc.). 

Tetany  in  Human  Beings. — In  human  disease  the  parathyroid  plays  a 
part  in  the  various  forms  of  spontaneous  and  post-operative  tetany,  and  also 
possibly  in  certain  diseases  which  exhibit  a  disturbance  in  calcification, 
such  as  osteomalacia  and  rickets,  although  in  these  their  role  is  by  no 
means  assured. 

The  simplest  example  is  undoubtedly  the  post-operative  tetany,  in  which 
the  parathyroids  may  have  been  removed  or  crushed  or  their  circulation  so 
impaired  that  they  are  unable  to  function.  There  may  remain  enough 
uninjured  tissue  to  reestablish  the  function;  if  the  immediate  emergency 
be  tided  over,  as  by  the  administration  of  calcium,  until  it  can  undergo 
some  compensation  from  hypertrophy,  the  smallest  portion  of  intact  gland 
substance  can  maintain  normal  conditions  under  favorable  circumstances. 

It  is  more  difficult  to  understand  those  forms  of  tetany  in  which  there  is 
no  disease  of  the  parathyroids,  but  w^hich  seem  to  arise  because  conditions 
are  produced  in  the  blood  and  tissues,  which  cause  tetany,  in  spite  of  the 
presence  of  normal  glands.  Such  are  perhaps  the  tetany  of  pregnancy  and 
of  lactation,  as  well  as  that  which  occurs  wrhen  the  pylorus  is  obstructed 
and  there  is  stagnation  of  the  stomach-contents,  with  excessive  vomiting. 
There  are  other  forms  which  seem  to  be  due  to  intoxications  of  one  sort  or 
another,  as  with  ergot,  phosphorus,  etc.,  or  simply  occur  in  certain  localities 
or  among  certain  types  of  workmen.  Finally  there  is  the  form  which 
affects  infants,  especially  those  which  are  improperly  or  artificially  fed,  and 
which  some  have  thought  due  to  inadequate  absorption  of  calcium,  others 
to  haemorrhages  in  the  parathyroid  glands  which  may  have  occurred  at 
birth.  On  the  whole,  these  explanations  have  not  yet  been  satisfactorily 
established. 

LITERATURE 

Frankl  Hochwart:  Tetanie  d.  Erwachsenen,  Wien,  1909. 
Escherich:  Tetanie  d.  Kinder,  Wien,  1909. 
Erdheim:  Mitth.  Grenz.  d.  Med.  u.  Chir.,  1906,  xvi,  632. 
MacCallum:  Ibid.,  1913,  xxv,  941. 

MacCallum  and  Voegtlin:  Jour.  Exp.  Med.,  1909,  xi,  118. 
MacCallum  and  Vogel:  Jour.  Exp.  Med.,  1913,  xviii,  618. 
MacCallum  and  Lambert:  Jour.  Exp.  Med.,  1914,  xx,  149. 

MacCallum:  Ergebn.  d.  innere  Medizin,  1913,  xi,  569  (Lit.);  Jour.  Amer.  Med.  Assoc., 
1912,  lix,  319. 


DISEASES  DUE  TO  DISTURBANCES  IN  FUNCTION  OF  THYMUS    887 

DISEASES  DUE  TO  THE  DISTURBANCES  IN  THE  FUNCTION  OF  THE  THYMUS 

The  thymus  arises  in  man  as  a  paired  ventral  outgrowth  from  the  entoderm 
of  the  third  and  fourth  branchial  clefts,  the  main  portion  of  the  gland  being 
derived  from  the  third  cleft. 

Its  original  form  is  that  of  a  flat  pouch.  With  the  gradual  thickening  of 
the  walls  of  the  sac  the  original  lumen  is  obliterated,  but  vestiges  of  the 
original  canal  may  be  found  even  in  the  fully  developed  organ.  In  embryos 
of  30  to  40  mm.  the  rapid  increase  in  size  leads  to  great  convolution  of  the 
surface,  but  although  the  form  of  the  gland  becomes  more  complicated,  the 
parenchyma  maintains  its  continuity.  The  right  and  left  lobes  remain 
separate,  but  there  is  no  formation  of  isolated  lobules. 

Two  types  of  cells  are  distinguishable  in  the  thymus — one,  resembling 
the  lymphocyte,  being  concentrated  in  especial  abundance  in  what  thus 
becomes  the  cortex  of  the  organ,  while  the  other,  recognized  as  epithelial 
in  nature,  occurs  throughout,  but  is  less  masked  in  the  central  or  medullary 
part. 

Long  dispute  has  occurred  as  to  the  nature  of  these  cells  and  their  origin, 
and  the  controversy  is  not  yet  finished.  For  many  years  the  lymphocytic 
nature  of  the  small  cells  was  unquestioned,  but  their  origin  was  attributed 
by  one  school  (His,  Stieda,  etc.)  to  an  early  invasion  of  the  epithelial  ele- 
ments by  wandering  mesenchymal  cells,  by  another  to  a  direct  differentia- 
tion of  the  epithelial  cells  into  lymphocytes  identical  with  those  of  the  blood- 
stream and  lymphatic  tissues  (Beard,  Kolliker,  Prenant,  etc.). 

Stoehr,  in  1906,  declared  that  the  small  thymus  cells  were  neither  genet- 
ically nor  functionally  lymphocytes,  but  true  epithelial  cells,  while  more 
recently  Hammar  and  Maximow  have  demonstrated  an  early  invasion  of 
the  epithelial  cells  by  migrating  lymphocytes  which  accompany  the  in- 
growing blood-vessels. 

Morphologically  and  biologically  the  small  cells  resemble  in  almost 
every  respect  the  lymphocytes. 

The  greater  portion  of  the  medulla  and  the  reticular  framework  of  the 
cortex  are  formed  of  derivatives  of  the  original  epithelial  cells.  They  tend 
to  arrange  themselves  in  concentric  fashion  to  form  the  Hassal  bodies, 
which  are  not  vestigial  structures,  but  are  constantly  being  newly  formed 
from  hypertrophic  epithelial  cell  complexes.  The  protoplasm  of  the  epi- 
thelial cells  has  a  fibrillary  character,  and  gives  rise  in  places  to  intracellular 
fibrils  resembling  neuroglia  fibrils. 

There  is  no  fibrous  reticulum  within  the  substance  of  the  organ,  and  only 
a  delicate  sheath  accompanying  the  blood-vessels.  Opinion  is  divided  as 
to  the  significance  of  the  thymus  as  a  blood-forming  tissue,  aside  from  its 
importance  as  a  site  for  the  production  of  lymphoid  cells. 

The  thymus  is  thus,  if  we  accept  the  prevailing  view  as  to  the  lympho- 
cytic nature  of  the  smaller  thymus  cells,  an  organ  composed  of  two  genet- 
ically distinct  types  of  tissue.  These  two  types  of  cells,  lymphoid  and 
epithelial,  are  intimately  commingled,  and  in  the  normal  gland  there  con- 


888  TEXT-BOOK   OF   PATHOLOGY 

stantly  occurs  a  destruction  of  the  lymphoid  cells  and  phagocytosis  of  the 
degenerating  cells  and  pyknotic  nuclear  fragments,  by  the  larger  epi- 
thelial cells. 

Normal  Evolution  and  Involution. — The  thymus  reaches  its  maximum 
development  coincidentally  with  the  maturation  of  the  sexual  organs,  and 
then  gradually  atrophies.  This  is  the  normal  involution,  but  since  the 
work  of  Waldeyer  it  has  been  known  that  even  in  senescence  there  are 
regularly  found  the  strands  of  thymic  tissue  containing  presumably  func- 
tioning thymic  cells. 

In  early  childhood  cortex  and  medulla  cannot  be  distinguished,  as  the 
lymphoid  cells  are  predominant  throughout.  In  later  childhood  the  differ- 
entiation between  cortex  and  medulla  becomes  more  pronounced,  but 
from  adolescence  on  there  is  a  progressive  reduction  in  the  amount  of  the 
parenchyma,  the  Hassal  bodies  are  brought  together,  and  the  interstitial 
tissue  and  fat  form  a  large  part  of  the  volume  of  the  organ. 

Hammar  gives  a  table  of  normal  weights  at  various  ages,  from  which  the 
following  may  be  extracted : 

GRAMS 

New-born 13.26 

6-10  years 26.1 

11-15  years 37.52 

21-25  years 24.73 

56-65  years , 16.08 

66-75  years 6.0 

Effects  of  Extirpation. — Many  efforts  have  been  made  to  show  the 
nature  of  the  function  of  the  thymus  by  extirpating  the  organ,  but  these 
have  given  variable  and  unsatisfactory  results.  Probably  most,  if  not  all, 
were  really  incomplete  extirpations,  and  while  some  authors  describe  re- 
tardation of  growth  and  rachitic  changes  in  the  bones,  Park,  in  his  recent 
review  of  the  literature  and  description  of  his  own  experiments  upon 
guinea-pigs,  concludes  that  results  such  as  his  own,  which  were  quite 
negative,  are  most  trustworthy,  and  that  developmental  anomalies  in  the 
dog  after  such  operations  are  not  due  to  the  loss  of  the  thymus,  but  to  con- 
finement, unsuitable  food,  etc. 

For  a  discussion  of  this  whole  question  the  reader  is  referred  to  the  paper 
of  Park  and  McClure  in  the  American  Journal  of  Diseases  of  Children. 

"Hyperplasia,"  "Abnormal  Persistence"  of  the  Thymus.— Since  thymic 
tissue  can  be  demonstrated  in  normal  individuals  at  any  age,  the  term  ab- 
normal persistence  should  be  dropped,  but  there  are  cases  in  which  the 
thymus  fails  to  undergo  involution  at  the  proper  time,  and  others  in  which 
there  is  a  renewal  of  growth  after  involution  has  been  established.  In  these 
latter  cases  it  may  attain  a  weight  several  times  that  of  the  normal  organ. 

Such  hyperplastic  glands  are  found  in  infants  usually  unassociated  with 
general  lymphoid  hyperplasia,  in  older  individuals  in  connection  with  vari- 
ous derangements  of  the  organs  of  internal  secretion,  particularly  thyroid, 
adrenals,  hypophysis,  and  genital  organs,  in  the  so-called  myasthenia. 


DISEASES   DUE   TO    DISTURBANCES   IN   FUNCTION   OF  THYMUS      889 

gravis,  and  finally  in  individuals  presenting  the  anatomical  features  in- 
cluded under  the  conception  of  status  thymicolymphaticus. 

In  the  form  found  in  infants  the  thymus  may  reach  a  weight  of  60  grams 
at  birth,  and  may  actually  constitute  an  obstruction  to  the  respiratory 
passages  or  great  veins.  In  older  persons  the  evidence  is  against  the 
possibility  of  any  such  mechanical  obstruction,  although  the  literature  is 
full  of  contradictory  statements  concerning  thymic  asthma  and  other 
effects  of  pressure.  Nevertheless,  the  immediate  relief  of  the  suffocative 
attacks  which  follows  the  partial  removal  by  the  surgeon  of  the  enlarged 
gland  is  pretty  strong  evidence  in  favor  of  the  idea.  There  is  no  evidence 
that  the  enlarged  thymus  can  interfere  with  the  function  of  the  vagus, 
phrenic,  or  recurrent  laryngeal  nerves. 

The  Thymus  in  Exophthalmic  Goitre. — Reference  has  already  been  made 
to  the  enlargement  of  the  thymus  which,  according  to  Capelle  and  Matti, 
occurs  in  75  to  79  per  cent,  of  the  cases.  That  it  is  an  actual  enlargement 
is  clear  from  the  fact  that  its  weight  may  greatly  exceed  the  normal  limits 
at  the  height  of  development.  The  descriptions  of  the  histological  changes 
are  most  contradictory,  but  it  seems  that  they  may  represent  an  accentua- 
tion of  the  condition  corresponding  to  the  age  at  which  the  disease  de- 
veloped. In  a  young  person  (twenty-three  years)  the  appearance  was  that 
of  a  child's  thymus,  the  hyperplasia  being  essentially  in  the  lymphoid 
elements.  The  interpretation  of  the  role  it  plays  and  of  the  beneficial 
effects  of  its  operative  removal  is  as  yet  entirely  speculative. 

Hyperplasia  of  the  thymus  in  Addison's  disease  and  acromegaly  and  in 
genital  hyperplasia  or  eunuchoidism  has  been  frequently  observed  and  it 
has  been  experimentally  proven  that  the  involution  of  the  thymus  is  greatly 
delayed  after  castration  at  an  early  age. 

Myasthenia  Gravis. — In  about  90  per  cent,  of  the  cases  of  this  peculiar 
disease  the  thymus  is  enlarged  into  a  bulky  mass,  variously  regarded  as  a 
new-growth  or  as  a  simple  hyperplasia.  There  are  found  lymphoid  infiltra- 
tions in  the  skeletal  muscles  and  sometimes  in  the  myocardium,  adrenal, 
and  liver. 

The  Thymus  in  Status  Thymico-lymphaticus. — This  condition  (already 
mentioned  in  Chapter  XL),  difficult  to  recognize  before  puberty,  is  more 
definite  in  adults.  There  is  at  least  a  certain  group  of  individuals  who  are 
characterized — (1)  By  anomalies  in  the  hair  distribution;  (2)  by  the 
rounded  conformation  of  the  limbs;  (3)  by  the  smooth  texture  of  the  skin; 
(4)  by  a  general  lymphatic  hyperplasia;  (5)  by  hypoplasia  of  the  aorta 
and  other  arterial  trunks,  and  (6)  by  hypoplasia  of  the  adrenals  and  the 
entire  chromaffin  system. 

It  is  generally  assumed  that  enlargement  of  the  thymus  forms  a  part  of 
this  rather  vaguely  outlined  condition,  but  it  requires  further  study  to  be 
sure  of  this.  Pappenheimer,  analyzing  28  cases  of  sudden  death  in  sub- 
jects up  to  thirty-five  years  of  age  with  the  anatomical  features  of  status 


890  TEXT-BOOK   OF   PATHOLOGY 

lymphaticus,  found  that  the  beginning  of  involution  of  the  thymus  is  de- 
layed to  the  third  decade.  The  histological  picture  is  in  no  sense  char- 
acteristic, although  Schridde  claims  that  there  is  hyperplasia  of  the  medulla 
with  underdevelopment  of  the  cortex.  The  possibility  that  there  may  have 
been  previous  involutional  changes,  thinning  the  cortex,  must  be  remem- 
bered. 

There  is  no  proof  that  the  thymus  is  concerned  in  the  development  of 
status  lymphaticus  or  in  the  sudden  death  which  sometimes  occurs  in  these 
persons.  It  is  more  logical  to  believe  that  it  is  the  incomplete  differentia- 
tion of  secondary  sexual  characters,  which  causes  the  failure  of  the  thymus 
to  undergo  involution,  and  possibly  all  the  other  features  of  status  lymphati- 
cus may  be  best  explained  in  this  way  too.  Nor  is  there  convincing  evi- 
dence that  the  sudden  death,  increased  susceptibility  to  acute  infections, 
trauma,  emotional  stress,  and  anaesthesia,  is  in  any  way  due  to  hyperfunc- 
tion  or  disordered  function  of  the  thymus. 

Accidental  Involution. — Starvation,  acute  and  chronic  wasting  disease, 
infections,  and  exposure  to  z-rays  produce  rapid  degenerative  changes  in 
the  thymus,  leading  often  to  extreme  atrophy. 

The  histological  picture  produced  in  this  condition,  which  Hammar  has 
called  "  accidental  involution/'  varies  with  the  acuteness  and  severity  of  the 
injury  and  the  previous  state  of  involution  of  the  gland.  The  small  thymus 
cells  suffer  first,  being  most  susceptible  to  injurious  influences;  their  nuclei 
become  pyknotic  and  fragmented,  and  the  debris  is  taken  up  by  the  active 
phagocytic  epithelial  elements.  The  depletion  of  the  cortex  may  lead  to 
an  inversion  of  the  normal  picture,  the  medulla  now  becoming  packed  with 
small  cells  or  their  remains.  The  reticular  cells  lose  their  protoplasmic 
connections,  become  rounded  and  vacuolated,  and  may  contain  fat-drop- 
lets. The  Hassal  bodies  are  resistant,  and  because  of  the  rarefaction  of  the 
intervening  parenchyma,  they  become  concentrated  together.  There  may 
occur  a  sort  of  sclerosis  in  this  rapid  destruction,  in  contrast  to  the  condi- 
tion seen  in  normal  involution,  in  which  the  parenchyma  merely  disappears 
without  stirring  up  the  production  of  any  scar  tissue. 

Otherwise,  except  in  the  rate  of  development,  the  accidental  involution 
is  in  principle  the  same  as  the  normal  process. 

LITERATURE 
Hammar:  "Fimgfzig  Jahre  Thymus  Forschung,"  Ergeb.  d.  Anat.  u.  Entw.,  1909,  xix,  1; 

also  Zentralbl.  d.  exp.  Med.,  1912,  i,  23;  Ibid.,  1913,  iii,  109;  Ibid.,  1914,  v,  55. 

Ziegler's  Beitr.,  1919,  Ixvi,  37.     Ztschr.  f.  Angew.  Anat.,  1918,  iii,  314;  iv.  1. 
Wiesel:  Ergebn.  d.  allg.  Path.,  1911,  xv,  416. 
Stohr:  Anat.  Hefte,  1906,  xxx,  407 
Maximow:  Arch.  f.  mikr.  Anat.,  1909,  Ixxiv,  525. 

Pappenheimer:  Jour.  Med.  Res.,  1910,  xviii,  1.     Jour.  Exp.  Med.,  1914,  xix,  319;  xx,  477. 
Matti:  Mitth.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1912,  xxiv,  665. 
Capelle:  Munch,  med.  Woch.,  1908,  Iv.,  1826. 
Park:  Jour.  Exp.  Med.,  1917,  xxv,  129.     Amer.  Jour.  Dis.  Child.,  1919,  xviii,  317. 


DISTURBANCES  IN  FUNCTIONS  OF  THE  ADRENAL  GLANDS   891 

DISTURBANCES  IN  FUNCTIONS  OF  THE  ADRENAL  GLANDS 

In  the  adrenal  glands  we  have  organs  of  complex  character  long  recognized, 
but  only  recently  known  to  be  intimately  related  to  many  other  similar 
organs  which  are  scattered  chiefly  along  the  course  of  the  chains  of  sympa- 
thetic ganglia,  and  known  as  chromaffine  bodies.  These  chromaffine 
bodies  are  of  the  same  character  as  the  medulla  of  the  adrenal  glands, 
which  is  itself  enveloped  in  a  cortical  covering  of  very  different  nature. 
In  children  the  so-called  Zuckerkandl  organ  is  a  mass  of  medullary  or 
chromaffine  substance  situated  near  the  bifurcation  of  the  aorta.  The 
carotid  glands  are  said  to  have  the  same  chromaffine  quality,  absorbing 
chrome  salts  and  thereby  stained  brown,  but  it  is  not  known  that  they 
actually  belong  to  this  system.  Practically  the  same  relations  exist  in 
other  animals  lower  than  man,  but  in  some  fishes,  such  as  the  sharks  and 
rays,  the  two  types  of  tissue  are  not  so  intimately  intermingled;  instead, 
the  cortical  substance  forms  one  mass  between  the  kidneys  (interrenal 
body),  while  the  other  tissue  (the  adrenal  bodies)  is  distributed  in  a  series 
of  nodules  with  the  sympathetic  ganglia.  On  this  account  it  is  feasible 
to  carry  out  on  these  animals  isolated  extirpations  not  possible  in  the 
higher  animals,  where  cortex  and  medulla  or  interrenal  and  adrenal  sub- 
stances are  too  inextricably  entangled. 

In  the  early  development  the  cortex  arises  as  a  new  formation  from  a 
portion  of  the  mesodermal  ridge,  while  the  medulla  appears  in  the  form  of 
tiny  groups  or  balls  of  cells  which  arise  with  the  sympathetic  ganglia  and 
from  common  forerunners.  These  cells  wander  into  the  substance  of  the 
cortex  and  take  up  a  central  position,  where  they  constitute  the  medulla. 

They  retain  the  most  abundant  and  intimate  connections  with  the 
sympathetic  system,  receiving  quantities  of  fibrils  from  the  cceliac  ganglia. 

Accessory  or  aberrant  masses  of  adrenal  character  occur  frequently 
in  man,  as  well  as  other  animals;  indeed,  they  are  practically  constant 
in  the  rat.  They  are  usually  composed  of  cortical  material,  sometimes 
of  cells  resembling  the  outermost  or  glomerular  layer,  sometimes  and  most 
often  of  cells  such  as  form  the  fasciculate  zone.  It  is  rare  to  find  an 
aberrant  adrenal  containing  medullary  substance.  They  occur  in  the  kid- 
ney, liver,  retroperitoneal  tissues,  ovary,  testis,  in  the  tissues  accompany- 
ing the  spermatic  cord,  and  elsewhere,  and  are  conspicuous  on  account 
of  their  bright  yellow  color. 

The  normal  histology  of  the  adrenal  need  not  be  described  here,  but 
attention  should  be  called  to  the  peculiar  involution  through  which  it 
passes  in  early  life.  It  is  a  relatively  large  organ  in  the  new-born  infant, 
and  in  the  first  two  weeks  during  which  the  medulla,  which  is  then  an 
extremely  inconspicuous  collection  of  cells,  begins  to  grow,  the  innermost 
zone  of  the  cortex  is  destroyed  and  converted  into  a  highly  vascular  and 
often  hsemorrhagic  connective-tissue  layer  which  collapses.  Consequently 
it  requires  some  time  for  the  adrenal  to  reach  again  the  size  it  had  at  birth, 
and  this  growth  is  partly  effected  by  the  extension  of  the  medulla  into  this 
collapsed  framework  which  represents  the  inner  layer  of  the  original  cortex 
(Thomas,  Pappenheimer  and  Lewis). 


892  TEXT-BOOK   OF   PATHOLOGY 

The  medullary  cells,  while  they  are  in  themselves  colorless  and  appear 
gray  and  translucent  in  mass,  have,  as  stated  above,  the  property  of  absorb- 
ing chromium  salts  and  assuming  a  bright  chestnutrbrown  color.  The 
peculiarities  of  granule  staining  in  the  various  zones  are  complicated,  and  as 
yet  very  inadequately  studied. 

The  cortex  is  particularly  rich  in  globules  of  anisotropic  lipoids  (cho- 
lesterine  esters),  as  well  as  ordinary  fats,  which,  however,  as  the  experiments 
of  Landau,  Hueck,  and  Rothschild  show,  cannot  be  taken  as  evidence  that 
these  organs  produce  the  lipoids,  nor  even  that  they  affect  the  combina- 
tion of  cholesterine  with  fatty  acids.  Cholesterine  fed  to  herbivorous 
animals  is  stored  in  quantity  in  the  adrenal  cortex.  It  is  abundant  there 
normally,  and  especially  so  in  pregnancy,  but  tends  to  disappear  with 
infections,  narcosis,  delirium  tremens,  etc. 

Functions. — It  is  even  yet  impossible  to  separate  accurately  the  func- 
tions of  the  cortex  and  medulla,  and  still  more  hopeless  to  distinguish 
the  activities  of  the  layers  of  the  cortex.  Doubtless  both  cortex  and  medulla 
are  vitally  important  organs,  but  there  seems  to  be  evidence  that  the  rap- 
idly fatal  effects  of  extirpation  of  the  whole  organ  are  chiefly  due  to  the  loss 
of  the  cortex,  since  animals  survive  which  possess  accessory  masses  of 
cortical  material. 

At  any  rate,  death  follows  quickly  the  loss  of  both  adrenals,  and  it  is 
certain  that  this  is  not  due  to  the  severity  of  the  operation.  Dogs  die 
usually  within  forty-eight  hours,  and  so  indeed  do  cats  and  other  animals, 
with  symptoms  of  profound  depression,  weakness,  low  temperature,  and 
low  blood-pressure.  It  is  thought,  however,  that  the  low  blood-pressure 
is  only  that  which  is  to  be  found  in  any  moribund  animal,  and  appears 
just  before  death.  Stewart  showed  that  these  phenomena  were  much  post- 
poned in  pregnant  or  lactating  animals,  and  that  this  might  possibly  be  due 
to  the  excess  of  cholesterine  in  their  blood,  since  the  injection  of  cholesterine 
esters  before  and  after  the  operation  seemed  to  prolong  life.  Extirpation  of 
one  adrenal  only  has  no  especial  effect,  except  that  the  remaining  organ 
hypertrophies,  the  hypertrophy  affecting  especially  the  cortex.  Upon  the 
loss  of  both  adrenals  the  cholesterine  content  of  the  blood  increases  at 
once.  If  the  animal  lives  long  enough,  glycogen  disappears  from  the  liver 
and  sugar  is  decreased  in  the  blood.  The  fat  of  the  body  is  mobilized  and 
wasted,  and  the  animal  rapidly  loses  weight.  Whether  the  change  in  dis- 
tribution of  the  cholesterine  causes  this  is  uncertain,  but  Landau  suggests 
that  cholesterine  is  just  as  necessary  to  the  functioning  of  the  adrenal  cor- 
tex in  its  relation  to  the  medulla  as  the  cortex  is  in  its  regulating  effect 
upon  cholesterine.  It  may  be  gathered  from  these  vague  statements  that 
little  is  known  even  about  the  mechanism  of  the  symptoms  and  death 
following  adrenal  extirpation.  Even  in  the  case  of  the  rays,  where  the  in- 
terrenal  body  has  been  extirpated  alone  by  Biedl  and  Hueck,  there  is  no 
agreement  as  to  the  symptoms  that  lead  to  death. 

It  has,  of  course,  been  suggested  that  death  may  be  due  to  lack  of 
adrenaline,  and  it  is  true  that  adrenalectomized  animals  may  be  revived 


DISTURBANCES   IN    FUNCTIONS   OF   THE    ADRENAL   GLANDS      893 

repeatedly  by  injections  of  adrenaline,  but  nevertheless  they  die  almost  as 
quickly  as  though  they  received  nothing. 

Function  of  the  Medulla.— Massage  of  the  adrenal  evidently  forces  out 
into  the  circulation  some  of  the  medullary  secretion,  for  the  effects  are  those 
of  a  small  dose  of  adrenaline.  This  extract,  presumably  derived  from  the 
medulary  substance,  is  most  remarkable  in  its  effects,  which  are  well 
known  (Biedl,  Meyer,  and  Gottlieb).  Injected  subcutaneously  or  intra- 
venously, it  stimulates  the  heart  to  violent  activity  and  raises  the  blood- 
pressure  also,  by  causing  an  intense  contraction  of  the  smaller  peripheral 
blood-vessels.  It  acts  upon  the  sympathetic  nerve-endings,  or  perhaps 
rather  upon  the  substance  of  the  neuromuscular  junction,  and  not  directly 
upon  the  muscle  itself.  The  coronary  arteries  it  causes  to  dilate.  In  the 
same  way  it  relaxes  the  intestinal  wall.  In  the  eye,  separated  from  its 
nervous  connections,  it  produces,  in  extremely  small  doses,  dilatation  of  the 
pupil,  but  has  no  effect  in  the  intact  eye  except  that  after  pancreatec- 
tomy  it  dilates  the  pupil  when  dropped  on  the  conjunctiva. 

It  causes  quite  violent  contractions  of  the  uterus,  and  may  produce  mis- 
carriages in  animals,  but  this  action  is  greatly  modified  or  even  reversed 
by  other  drugs,  such  as  ergot.  In  all  these  cases  it  is  evident  that  its 
effect  is  upon  smooth  muscle  innervated  by  the  sympathetic  system,  and 
in  all  a  striking  peculiarity  is  the  transitory  character  of  the  effect  of  a  single 
dose.  A  violent  rise  in  blood-pressure,  with  constriction  of  the  vessels  and 
energetic  heart-beat,  soon  passes  off,  possibly  because  adrenaline  is  quickly 
destroyed  in  the  organism. 

Perhaps  the  most  interesting  and  important  effects  of  the  secretion  of  the 
chromaffine  tissue,  which  we  believe  to  be  essentially  adrenaline,  are  those 
which  it  exerts  in  connection  with  the  organs  of  internal  secretion.  They 
are  probably  simple  enough,  but  in  the  present  state  of  our  knowledge 
appear  extremely  complicated.  Injections  of  adrenaline  as  well  as  the 
original  application  of  adrenaline  to  the  pancreas  (Herter  and  Wakeman) 
produce  hyperglycsemia  and  glycosuria.  The  same  thing  results  from 
massage  of  the  adrenals  or  from  stimulation  of  the  splanchnic  nerves. 
There  is  some  difference  of  opinion  as  to  whether  it  follows  splanchnic 
stimulation  after  adrenal  extirpation.  McLeod  and  others  speak  of  the 
splanchnic  impulses  as  going  to  the  liver  via  the  adrenals,  and  think  that 
the  presence  of  adrenal  secretion  is  necessary  to  their  effectiveness  in 
liberating  sugar.  Freund  and  Marchand,  however,  produced  hypergly- 
csemia  by  piqure,  or  by  splanchnic  stimulation  after  adrenal ectomy,  and 
think  the  splanchnic  fibres  go  direct  to  the  liver.  It  must,  of  course,  be 
remembered  that  there  exists  much  other  chromaffine  tissue  which  could 
furnish  adrenaline. 

Evidently  the  adrenaline  so  acts  upon  the  liver-cells  as  to  cause  them  to 
bring  about  the  rapid  depolymerization  of  their  glycogen,  and  does  this 
independently  of  the  pancreas,  since  the  hyperglycsemia  following  pan- 
createctomy  is  even  accentuated  by  injection  of  adrenaline. 

The  relation  of  other  organs  of  internal  secretion  to  this  function  of  the 


894  TEXT-BOOK    OF    PATHOLOGY 

adrenal  is  not  yet  entirely  cleared  up.  In  the  absence  of  the  thyroid  it  is 
less  easy  to  produce  hyperglycaemia  with  adrenaline,  although  pancreatec- 
tomy  still  produces  it.  In  exophthalmic  goitre,  on  the  contrary,  glycosuria 
is  apt  to  occur  spontaneously.  Thus  it  appears  that,  with  certain  con- 
trolling mechanisms,  this  particular  activity  of  the  adrenal  which  brings 
about  the  pouring  of  immediately  available  carbohydrate  into  the  blood  is 
regulated  by  the  nervous  system  through  the  splanchnic  sympathetic  nerve. 
Cannon  has  shown  that,  in  fear  or  rage  or  pain,  strong  impulses  are  sent  to 
the  gland,  and  that  the  mechanism  is  well  adapted  to  such  situations,  since 
under  those  conditions  there  is  an  immediate  supply  of  dextrose  to  the 
muscles,  which  act  violently  without  fatigue,  the  blood-pressure  being  at 
the  same  time  correspondingly  heightened,  so  that  the  animal  can  fight 
or  run  to  the  best  advantage.  The  influence  of  the  medulla  is  in  all  these 
ways  so  important  that  we  are  not  surprised  that  the  chromaffine  tissue  is 
scattered  so  widely  and  is  so  well  protected.  But  Stewart  and  Rogoff 
show  in  a  careful  experimental  study  that  by  extirpating  one  adrenal  and 
cutting  the  nerves  to  the  other  the  liberation  of  epinephrin  into  the  blood 
is  stopped.  This  does  not  affect  the  health  of  the  animal,  and  all  those 
procedures  which  cause  hyperglyca3mia,  such  as  asphyxia,  piqure,  etc.,  still 
do  so  in  the  lack  of  any  secretion  of  epinephrin  into  the  blood.  They 
find  no  definite  production  of  hyperglycsemia  by  fright  or  other  emotional 
disturbances,  and  no  increase  in  epinephrin  output  under  these  conditions. 

Functions  of  the  Cortex. — It  is  evident  that  not  much  more  can  be  stated 
definitely  as  to  the  functions  of  the  cortex  in  the  present  state  of  our  knowl- 
edge. As  a  storehouse  of  cholesterine  esters,  and  possibly  in  some  sense 
a  controller  of  the  metabolism  of  these  bodies,  it  seems  to  play  a  role,  but 
there  is  practically  nothing  else  to  impute  it  to  except  a  vague  " vital  im- 
portance." In  a  number  of  cases  in  which  tumors  have  occupied  the 
adrenals,  composed  usually  of  tissue  resembling  the  cortex  rather  than  the 
medulla,  and  containing  no  adrenaline,  there  have  been  signs  of  a  peculiar 
precocity  in  sexual  development.  Children  with  such  tumors  (Fig.  439) 
may  appear  as  mature  sexually  as  adults.  When  the  tumor  developed  in 
late  life  (after  the  menopause),  as  in  a  case  described  by  Tuffier,  the  woman 
assumed  male  characters,  heavy  beard,  baldness,  ability  to  perform  heavy 
labors  without  fatigue,  etc.  On  the  other  hand,  the  gradual  atrophy  of 
the  adrenal  is  thought  to  be  associated  with  a  condition  of  premature 
senility  called  progeria. 

Addison's  Disease. — Addison  described  in  1855  a  symptom  complex 
which  is  now  known  by  his  name,  and  found  to  depend  upon  chronic 
destructive  disease  of  the  adrenals.  The  patients  become  gradually  weak 
and  easily  fatigued,  the  circulation  is  enfeebled  and  the  blood-pressure 
low,  the  heart  beats  rapidly,  irregularly,  and  feebly,  there  are  vomiting 
and  anorexia,  and  the  skin  becomes  pigmented  at  first  only  about  the  usual 
areas  of  greatest  pigmentation;  later  the  whole  skin  may  become  brownish 
or  deep  bronze  in  color.  In  a  state  of  the  most  extreme  weakness  and 
prostration  the  patient  dies.  The  autopsy.,  reveals  most  commonly  a 


DISTURBANCES   IN   FUNCTIONS    OF    THE    ADRENAL   GLANDS      895 

tuberculous  infection  which  has  attacked  especially  the  adrenals  and  con- 
verted them  into  necrotic  caseous  masses,  but  there  are  other  cases  in  which 
some  other  destructive  process  has  so  injured  the  adrenals  as  to  leave 
only  scars  or  calcified  nodules  in  their  places.  In  a  few  cases  the  adrenals 
appear  normal,  while  there  are  others  more  numerous  in  which  they  are 
apparently  entirely  destroyed  or  converted  into  caseous  material,  although 
there  have  been  no  signs  or  symptoms  of  Addison's  disease.  To  explain 
these  things  is  not  easy,  and  the  attempt  leaves  us  with  the  conviction  that 


'&%$&&&& 


Fig.  439. — Tumor  of  adrenal  cortex  from  a  female  child  who  showed  masculine  characters. 

we  are  still  ignorant  of  the  exact  relation  of  the  adrenals  to  the  disease. 
Wiesel,  who  sees  in  the  chromaffine  tissue  the  first  part  affected,  although  by 
no  means  denying  the  important  role  that  the  cortex  may  play,  recalls  the 
fact  that  outside  the  adrenal  there  is  much  chromaffine  tissue  in  the 
paraganglionic  nodules,  so  that  the  destruction  of  the  adrenals  does  not 
mean  the  destruction  of  all  the  chromaffine  tissue.  In  several  fatal  cases  of 
outspoken  Addison's  disease  he  found  that  these  paraganglionic  masses 
had  disappeared.  If  the  symptoms  were  really  due  to  the  loss  of  the 
chromaffine  tissue  alone,  might  not  Addison's  disease  exist  with  only  very 


896  TEXT-BOOK   OF    PATHOLOGY 

inconspicuous  changes  in  the  adrenals  themselves,  and,  on  the  contrary, 
might  not  that  portion  of  the  total  chromaffine  tissue  which  is  in  the  ad- 
renals be  destroyed  without  symptoms? 

Others  have  found  lesions  in  the  sympathetic  ganglia  and  in  the  splanch- 
nic nerve  supply,  and  suggest  that  these  may  occasion  a  cessation  of  the 
activity  of  the  gland,  just  as  the  destruction  of  a  motor  nerve  does  that  of 
its  muscle.  Still  others  (Scott,  Karakascheff)  have  found  the  destructive 
change  chiefly  in  the  cortex  of  the  adrenal.  Discussion  of  all  these  argu- 
ments will  be  found  in  the  works  of  Biedl,  Neusser,  Wiesel,  Bittorf,  and 
Bayer. 

With  regard  to  the  pigmentation  of  the  skin,  the  ideas  are  vague.  Furth 
has  found  that  the  ferment,  tyrosinase,  will  produce  a  black  pigment  from 
adrenaline,  but  it  is  difficult  to  understand  how,  in  the  absence  of  the 
adrenal,  such  a  reaction  could  aid  in  the  enormous  production  of  pigment 
seen  in  Addison's  disease.  Bauer  thinks  it  a  derivative  of  uric  acid. 

Two  other  questions  may  be  briefly  discussed  in  this  place:  first,  the  idea  of  Schur 
and  Wiesel  that  the  high  blood-pressure  and  cardiac  hypertrophy  which  are  so  common  hi 
cases  of  chronic  nephritis  are  due  to  a  coincident  hypertrophy  of  the  adrenal  and  espe- 
cially of  the  chromaffine  tissue.  This  has  been  supported  by  many  who  think  they  have 
been  able  to  observe  such  hypertrophy  and  hyperadrenalinsemia,  but  contradicted  by 
many  others  who  find  no  evidence  in  favor  of  it,  and  who  point  out  that  Schur  and  Wiesel 
themselves  fail  to  find  the  hypertrophy  in  many  forms  of  nephritis  in  which  the  blood- 
pressure  is  high  and  the  heart  enlarged.  It  must  await  further  investigation,  although 
at  present  the  weight  of  evidence  is  rather  against  this  explanation. 

The  second  question  is  that  of  the  production  of  arteriosclerosis  in  the  aorta  of  rabbits 
by  the  repeated  injection  of  adrenaline.  The  lesions  can  apparently  be  produced  only 
in  rabbits,  in  which  spontaneous  lesions  of  the  same  kind  are  not  infrequent.  At  any 
rate,  dogs  and  other  carnivorous  experimental  animals  seem  quite  unsuited  to  this  ex- 
periment, possibly  just  as  they  are  for  the  production  of  arteriosclerosis  by  the  feeding 
of  cholesterine.  The  aorta  in  the  rabbit  becomes  greatly  deformed  by  the  dilatations 
and  areas  of  calcification.  The  lesion  appears  with  necrosis  and  calcification  in  the 
media,  and  later  extends  to  involve  the  intima,  although  some  writers  state  that  they 
have  found  primary  accumulations  of  fat  in  the  mtima.  At  first  it  was  thought  that  this 
might  be  due  to  the  mechanical  effect  of  the  high  blood-pressure,  but  the  same  effect  is 
produced  if  another  drug  is  given  to  counteract  the  high  pressure,  and  thereupon  the 
idea  was  adopted  that  a  toxic  action  of  the  adrenaline  was  responsible  for  the  injury. 
The  application  of  these  findings  to  the  explanation  of  human  arteriosclerosis  has  not 
yet  been  successfully  carried  out. 

At  the  same  time  destructive  lesions  of  the  walls  of  the  heart,  with  necrosis  of  the 
muscle  and  later  extensive  scarring  and  compensatory  hypertrophy,  are  produced 
(Stewart). 

LITERATURE 

Neusser  and  Wiesel:  Erkrank.  d.  Nebennieren,  Wien,  1910. 
Bittorf:  Pathologic  der  Nebennieren,  Jena,  1908. 
Elliott:   Quarterly  Journal  of  Medicine,  1914-15,  viii,  47-89. 
Biedl:  Innere  Secretion,  Berlin,  1913. 
Bayer:  Ergeb.  d.  allg.  Path.,  1911,  xiv,  1. 

Stewart:  Journal  of  Pathology  and  Bacteriology,  1912,  xvii,  64. 

Landau:  Verh.  Dtsch.  Path.  Gesell.,  1914,  xvii,  573;  Die  Nebennierenrinde,  Jena,  1915. 
Stewart  and  Rogoff:  Jour.  Pharm.  and  Exp.  Therap.,  1916,  viii,  205,  479.  Jour.  Exp. 

Med.,  1916,  xxiv,  709;  1917,  x,  1,  49;  1917,  xxvi,  613,  637.     Amer.  Jour.  Physiol., 

1917,  xliv,  149,  543;  1918,  xlvi,  90. 
Bauer:  Virch.  Arch.,  1918,  ccxxv,  2. 


CHAPTER  XLV 

DISEASES  DUE    TO  INJURY  TO  THE  ORGANS  OF    INTERNAL 
SECRETION  (Continued) 

Hypophysis.  Structure.  Properties  of  extracts  of  different  lobes.  Experimental  extirpa- 
tion. Effects  of  hyperactivity  and  hypoactivity  at  different  periods  of  life.  Gigantism. 
Acromegaly.  Frohlich's  syndrome.  Adiposity.  Relation  of  genital  function.  Diabetes 
insipidus.  Histological  changes  in  hypophysis  in  pregnancy,  acromegaly,  etc.  Hyper- 
trophic  pulmonary  osteoarthropathy. 

THE  EFFECTS  OF  INJURY  TO  THE  HYPOPHYSIS 

Structure. — The  hypophysis  is  a  complex  organ,  formed,  in  part,  of  an  up- 
growth of  the  epithelium  of  the  pharyngeal  vault,  in  part  of  a  downward 
prolongation  of  the  floor  of  the  third  ventricle  of  the  brain.  The  epithelial 
part  becomes  constricted  off  (although  remnants  are  often  found  along  the 
tract  of  a  perforation  in  the  sphenoid  bone,  the  so-called  canalis  cranio- 
pharyngeus),  and  constitutes  eventually  the  anterior  lobe  of  the  gland. 
It  retains  a  cleft  or  cavity  at  its  juncture  with  the  posterior  lobe,  which  is 
lined  by  epithelium  and  is  the  pars  intermedia.  This  anterior  portion  is 
composed  of  strands  and  networks  of  cells  which  are  often  so  loosely 
arranged  that  they  seem  to  be  in  masses.  But  they  are  held  in  a  reticulum 
which  bears  adequate  blood-vessels.  Many  of  the  cells  are  relatively 
small  and  show  no  especial  granulation  or  staining  affinity  (chromophobe 
cells),  while  others  are  granular  and  reveal  either  eosinophile  or  basophile 
granulations  (chromophile  cells) .  The  cells  of  the  pars  intermedia  are  more 
apt  to  form  alveolar  cavities  which  often  contain  a  colloid  material.  They 
also  produce  hyaline  droplets,  which  are  seen  to  spread  into  the  posterior 
lobe.  The  posterior  or  infundibular  portion,  also  sometimes  called  pars 
nervosa,  has,  in  lower  animals,  a  wide-open  cavity,  but  in  man  there  is 
none,  or  only  a  scarcely  perceptible  canal  which  extends  along  the  stalk  to 
the  third  ventricle.  The  structure  of  this  lobe  seems  not  thoroughly  well 
known.  It  is  said  to  be  composed  mostly  of  neuroglia.  No  distinct  nerve 
elements  are  described,  but  there  are  a  few  cells  scattered  here  and  there. 
As  mentioned,  the  hyaline  soluble  droplets  from  the  pars  intermedia  pass 
readily  into  its  meshes,  and  indeed  Herring,  whom  Gushing  warmly  sup- 
ports, declares  that  he  can  trace  the  passage  of  these  hyaline  droplets  to 
their  escape  into  the  cerebrospinal  fluid  in  the  third  ventricle,,  and  thinks 
that  this  is  the  mode  of  delivery  of  the  secretion  of  the  gland.  Gushing  has 
demonstrated,  by  means  to  be  discussed,  the  existence  of  the  specific 
secretion  of  the  hypophysis  in  the  cerebral  fluid. 
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Properties  of  Extracts  of  Different  Lobes. — Extracts  from  the  anterior 
lobe  seem  quite  inactive  when  injected  into  animals.  On  the  contrary, 
extracts  of  the  posterior  lobe  have  striking  effects  (Schafer,  Howell). 
They  depress  and  then  raise  the  blood-pressure,  constrict  the  coronaries, 
and  dilate  the  renal  vessels,  thus  causing  diuresis.  They  cause  contractions 
of  smooth  muscle,  as  in  the  uterus,  and  give  rise  to  a  temporary  increase  in 
the  production  of  milk.  They  also  cause  glycosuria  by  lowering  the 
glucose  tolerance.  Such  is  the  astonishing  series  of  properties  of  extracts 
of  the  inert-looking  neuroglial  mass,  while  the  extracts  of  the  active- 
looking  epithelial  part  of  the  gland  do  none  of  these  things  and  seem  to  be 
perfectly  without  effect. 

Experimental  Extirpation. — Extirpation  of  the  whole  gland  causes  death 
in  a  few  days  with  symptoms  of  collapse,  extreme  lowering  of  the  temper- 
ature, apathy,  etc.  These  symptoms  appear  to  depend  upon  the  loss  of 
the  anterior  lobe.  Perfectly  clear  experiments  with  the  extirpation  of  each 
lobe  alone  seem  not  to  have  been  accomplished,  and  one  cannot  give  a  clear- 
cut  idea  of  their  separate  functions.  Removal  of  the  posterior  lobe  alone 
seems  to  give  rise  to  no  recognizable  symptoms  although,  as  was  said,  its 
extract  is  the  only  one  with  obviously  active  properties.  Most  of  the 
experiments  in  which  animals  have  remained  alive  were  those  in  which  the 
posterior  lobe  and  a  large  part  of  the  anterior  lobe  were  removed.  Such 
animals  grow  fat,  become  stupid,  retrogress  sexually,  or,  if  very  young  at  the 
time  of  the  operation,  never  develop  sexually  beyond  the  infantile  stage. 
They  fail  to  grow  like  the  controls,  their  temperature  is  low,  they  often 
have  a  transient  polyuria,  secreting  five  times  as  much  as  normal,  and  they 
develop  an  extraordinary  sugar  tolerance,  so  that  it  is  practically  impos- 
sible to  produce  alimentary  glycosuria. 

Apparently,  then,  most  of  the  serious  symptoms  following  destruction 
of  the  gland  are  due  to  the  loss  of  the  anterior  lobe,  although  the  posterior 
lobe  seems  responsible  for  the  disturbances  of  carbohydrate  metabolism 
and  the  consequent  adiposity  or  obesity.  Unsatisfactory  as  the  experi- 
mental work  is  in  sharply  separating  the  functions  of  the  parts  of  the  gland, 
it  will  be  seen  that  the  effects  of  disease  in  human  beings,  which  on  account 
of  the  wealth  of  rather  contradictory  details  we  must  present  rather 
dogmatically,  throw  a  good  deal  of  light  upon  it. 

Disease  of  the  gland  may  be  produced  by  primary  changes  in  its  own 
tissue,  or  through  its  compression  or  destruction  by  a  tumor  or  gumma  or 
other  pathological  process,  or  by  its  compression  through  the  presence 
within  the  rigid  cranial  cavity  of  a  distant  lesion  which  heightens  the 
pressure.  In  the  contracted  limits  of  the  sella  turcica  even  the  growth 
of  the  anterior  lobe,  which  might  cause  its  hyper  activity,  can  in  time,  by 
compressing  the  posterior  lobe  and  the  outlet  of  the  secretion,  cause  an 
insufficiency. 

It  is  thought  that  the  anterior  lobe  has  an  important  influence  upon  the 
growth  of  the  skeleton  and  upon  other  organs  of  internal  secretion,  but 


THE    EFFECTS    OF   INJURY   TO    THE   HYPOPHYSIS  899 

especially  upon  the  genital  organs.  If  it  is  deficient  in  its  activity,  growth 
is  stunted  and  sexual  development  is  stopped.  If  its  activity  is  excessive, 
growth  passes  ajl  normal  bounds  and  precocious  sexual  development 
occurs.  Most  of  the  actual  observations  fit  with  this  hypothesis  and  sup- 
port it,  but  it  must  nevertheless  be  regarded  as  a  mere  hypothesis,  since 
prolonged  administration  of  extracts  of  the  anterior  lobe  have  not  been 
found  capable  of  producing  any  such  striking  effect  on  growth  nor  on  sex 
manifestations.  Possibly,  therefore,  it  is  a  qualitative  change  in  the  func- 
tion of  the  gland  which  is  responsible  for  the  remarkable  growth  phenom- 
ena, etc.,  rather  than  a  mere  quantitative  one.  The  hypothesis  goes  on  to 
state  that  if  the  gland  is  excessively  active  it  is  not  constantly  so,  but  with 
irregular  remissions,  perhaps  only  for  one  short  period.  If  this  occurs 
before  the  ossification  at  the  epiphysis  is  complete,  the  individual  grows 
to  giant  proportions;  if  it  takes  place  after  ossification  is  complete  and  the 
epiphyseal  line  of  ossification  has  disappeared,  then  the  bones  enlarge  and 
become  curiously  deformed  in  the  fingers  and  toes  and  in  the  face,  but  the 
height  is  not  necessarily  increased.  Hence  the  conditions  gigantism  and 
acromegaly  (enlargement  of  the  tips  of  the  extremities).  Further,  the 
idea  is  of  importance  that  while  this  hyperactivity  leads  to  such  astonishing 
results  which  remain  as  permanent  changes,  it  may  pass  into  a  state  in 
which  the  gland  is  inactive  and  supplies  too  little  secretion  for  the  body. 
Then  development  stops  and  retrogression  begins. 

Hyperactivity  and  Hypoactivity. — The  following  paragraphs  are  meant 
to  recount  in  more  detail  the  conditions  illustrative  of  the  effects  of  hyper- 
activity or  insufficiency  of  each  part  of  the  gland.  It  must  be  remembered, 
however,  that  hyperactivity  may  give  place  to  inactivity,  and  that  signs  of 
both  may  remain. 

1.  Hyperactivity  of  the  anterior  lobe  before  epiphyseal  ossification 

is  complete. 

2.  Hyperactivity  of  anterior  lobe  beginning  after  epiphyseal  ossifica- 

tion is  complete. 

3.  Inactivity  of  anterior  lobe  beginning  before  puberty. 

4.  Inactivity  of  anterior  lobe  beginning  late  in  life. 

1.  When  the  gland  is  excessively  active  or  enlarged  and  still  active 
in  the  period  of  epiphyseal  growth,  its  effect  is  to  exaggerate  the  growth 
of  the  skeleton  and  of  the  other  tissues  at  the  same  time.  As  a  result  the 
individual  becomes  a  giant.  An  illustration  taken  from  Cushing's  work 
will  convey  more  than  any  description  (Fig.  440).  This  one,  aged  thirty- 
six,  was  rather  weak,  had  a  high  sugar  tolerance,  was  sexually  impotent, 
and  showed  at  autopsy  a  much  reduced  hypophysis  converted  into  a  cyst. 
Evidently  the  activity  of  growth  under  the  influence  of  the  hypophysis, 
which  began  to  increase  at  the  age  of  fifteen,  gave  place,  after  the  ossifica- 
tion was  complete,  to  glandular  insufficiency.  Such  gigantism  (Figs.  441, 
442,  443)  is  not  entirely  limited  to  those  in  whom  the  activity  of  growth 
stops  with  the  completion  of  ossification,  but  may  be  combined  with  the 


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effects  of  overgrowth  which  occurs  after  the  epiphyseal  lines  are  ossified, 
and  thus  may  play  a  part  in  the  changes  in  cases  of  group  2. 

2.  When  the  anterior  lobe,  through  hyperplasia  or  increased  activity, 
causes  excessive  growth  in  adult  life,  the  result  is  acromegaly  (Marie,  1886) . 
Again  an  illustration  of  a  tj^pical  case  will  convey  more  than  a  description 
(Fig.  444).  The  bones  of  the  face  and  those  of  the  hands  and  feet  become 


Fig.  440. — Note  the  narrow  chest;  large  joints;  hypotrichosis.  Also  the  large  size 
of  the  hands  compared  with  those  of  Dr.  Crowe,  whose  height  is  5  feet  8  inches  (Harvey 
Gushing). 

enlarged,  the  jaw  projects,  and  the  soft  parts  of  the  face,  hands,  and  feet 
become  greatly  thickened  (Fig.  445).  For  a  time  there  may  be  glycosuria, 
or  at  least  a  lowered  sugar  tolerance.  The  sexual  function  is  not  impaired 
in  this  stage.  Some  acromegalics  are  also  giants,  evidently  because  the 
stimulus  to  growth  existed  before  ossification  was  complete,  although  there 
may  have  been  a  long  interval  after  the  increase  in  stature  before  the  dis- 
torting growth  of  the  facial  bones  and  extremities  took  place.  Such 


THE  EFFECTS  OF  INJURY  TO  THE  HYPOPHYSIS 


901 


remissions  in  the  activity  of  the  gland  are  recognized.  The  condition, 
acromegaly,  is  permanent,  but  in  most  cases,  owing  to  subsequent  impair- 
ment of  the  hypophysis,  symptoms  of  insufficiency  (obesity,  impotence, 
high  sugar  tolerance,  etc.)  appear. 


Fig.  441. — Gigantism.  Man  with  evidences  of  hypophyseal  disturbance,  shown  in 
contrast  with  a  normal  negro  man,  5  feet  8  inches  tall.  Hands  and  feet  are  shown  for 
comparison  (Figs.  442  and  443). 

3.  Inactivity  of  the  hypophysis  beginning  before  puberty  causes  the 
changes  observed  in  puppies  after  hypophysectomy,  namely,  stunting 
of  growth,  great  obesity,  high  sugar  tolerance,  and  failure  in  the  develop- 
ment of  the  sexual  glands  and  in  the  appearance  of  secondary  sexual 
characters.  Mental  dullness  is  a  frequent  accompaniment. 


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••••MB  flBBB^Bl  j 

Fig.  442. — Hand  of  patient  in  Fig.  441  c6mpared  with  that  of  a  normal  negro* 


Fig.  443. — Foot  of  the  patient  in  Fig.  441  compared  with  that  of  a  normal  negro. 


THE  EFFECTS  OF  INJURY  TO  THE  HYPOPHYSIS       9Q3 


Fig.  444. — Acromegaly.    Great  enlargement  of  face,  with  heavy  features.  Great  increase 
in  size  of  hands,  with  thickening  of  the  fingers. 


Fig.  445. — Acromegaly.     This  man  was  an  acromegalic  giant  aged  thirty-five,  with 
blindness  and  large  tumor  of  the  hypophysis  (Gushing). 


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Frohlich's  Syndrome. — These  are  the  fat  boys  that  one  sees  so  fre- 
quently, fairly  bursting  from  their  clothes.  They  have  a  peculiar  feminine 
habitus  (Fig.  446),  with  wide  hips,  knockknees,  and  especial  collections  or 
pads  of  fat  in  the  pectoral  regions  and  on  the  hips  (Fig.  447).  Even  in 
adult  life  there  is  no  beard,  and  hair  is  scanty  over  the  body.  If  there  is 
any  pubic  hair,  it  has  the  feminine  distribution  (Fig.  449).* 

4.  If  the  deficiency  of  the  hypophysis  begins  late  in  life,  there  is  an 
approach  to  this  condition.  Naturally 
there  is  no  retrogression  of  anatomical 
features  of  the  skeleton  already  estab- 
lished, nor  even  of  the  distribution  of  the 
hair  and  development  of  the  genitalia,  but 
obesity  comes  on  with  the  great  heighten- 


Fig.  446. — Frohlich's  syndrome.    Preadolescent 
pituitary  insufficiency  in  a  male  (Gushing) . 


Fig.  447. — Preadolescent  hy- 
pophyseal  insufficiency  in  a  male 
(Gushing,  after  Neurath). 


ing  of  the  sugar  tolerance,  and  there  is  gradual  or  rapid  loss  of  sexual 
functions.  It  is  apparently  among  these  cases  that  we  should  class  those 
extraordinary  instances  of  adiposis  dolorosa,  or  Dercum's  disease,  multiple 
lipomatosis,  etc.,  although  the  relation  is  not  clearly  established  (cf.  Lyon). 
These  are  people  in  whom  there  are  huge  irregular  accumulations  of  adipose 


*  I  am  indebted  to  Dr.  Harvey  Gushing  for  allowing  me  to  use  the  photographs  of 
3  cases. 


THE  EFFECTS  OF  INJUEY  TO  THE  HYPOPHYSIS 


905 


tissue,  or  in  whom  with  neuralgic  and  joint  pains  the  whole  adipose  tissue 
is  greatly  increased  (Figs.  450,  451). 

The  peculiar  anatomical  conditions  which  surround  the  hypophysis 
are  responsible  for  much  of  the  confusion  which  still  prevails  as  to  the  part 
played  by  each  division  of  the  gland  in  these  lesions.  If  the  hypophysis 
were  an  organ  like  the  thyroid,  situated  in  loose  tissue,  and  able  to  grow 
without  compressing  itself,  or  so  placed  that  one  part  might  grow  without 


Fig.  448. — Preadolescent  pituitary  in- 
sufficiency in  a  female  aged  sixteen. 
Skeletal  and  sexual  infantilism.  Con- 
genital pituitary  tumor.  The  child  was 
formerly  extremely  fat  (Gushing). 


Fig.  449. — Adult  pituitary  insuffi- 
ciency with  hypophyseal  tumor.  Femi- 
nine habitus  (Gushing). 


destroying  the  other,  it  might  be  easier  to  recognize  the  role  of  each  lobe. 
Furthermore,  the  fact  that  the  functions  of  all  the  organs  of  internal  secre- 
tion seem  so  closely  interrelated  makes  it  difficult  to  outline  the  part  of 
each.  The  hypophysis  seems  especially  closely  related  to  the  genital 
glands,  and  its  destruction  brings  with  it  the  loss  of  function  of  those 
glands,  amenorrhcea,  and  cessation  of  spermatogenesis.  The  thyroid  and 
adrenals  are  vaguely  associated  also,  and  changes  are  likely  to  be  found  in 
their  structure  and  function  when  there  are  hypophyseal  disturbances. 


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In  these  diseases  of  the  hypophysis,  except  when  atrophy  leads  to  its 
diminution  in  size,  there  are  mechanical  effects  produced  by  the  enlarge- 
ment of  the  gland  itself  or  by  the  tumor  which  causes  its  destruction. 
These  are  found  to  be  associated  with  either  the  signs  of  hyperactivity  or 
those  of  insufficiency,  but  since  hy- 
peractivity is  a  relatively  transient 
phenomenon  and  usually  passes 
over  into  insufficiency,  even  through 
the  very  agency  of  the  tumor  for- 
mation, the  mechanical  effects  are 
most  commonly  found  in  the  stage 
of  insufficiency.  They  are,  as  a  con- 


Fig.  450. — General  extreme  adiposity  prob- 
ably due  to  late  hypophyseal  disease. 


Fig.  451.  —  Multiple  lipomatosis. 
There  are  symmetrical  fatty  tumors 
about  the  neck,  arms,  hips,  and  femoral 
regions. 


sideration  of  the  anatomical  relations  of  the  hypophysis  would  show,  usually 
caused  by  pressure  upon  the  optic  tracts  or  upon  the  brain  as  a  whole  as  it 
lies  within  the  rigid  cranium,  or  upon  the  hypophysis  itself.  There  is  pro- 
gressive narrowing  of  the  field  of  vision,  hemianopsia  passing  on  to  com- 


THE  EFFECTS  OF  INJURY  TO  THE  HYPOPHYSIS        907 

plete  blindness,  choked  disc  and  retinal  changes,  violent  headache,  etc. 
Hydrocephalus  may  be  the  cause  of  hypophyseal  insufficiency,  just  as  any 
distant  intracranial  tumor  may,  in  the  limited  space,  give  rise  to  slight 
evidences  of  hypophyseal  impairment. 

Diabetes  insipidus,  which  is  a  name  given  to  a  symptom  complex  in  which 
extreme  thirst  and  polyuria  form  the  most  striking  features,  is  probably  in 
most  instances  due  to  an  injury  of  some  sort  to  the  hypophysis,  causing  its 
insufficiency,  although  it  is  difficult  to  explain  why  the  insufficiency  of  the 
posterior  lobe  should  cause  such  diuresis  when  the  injection  of  its  extract 
has  exactly  that  effect  (Berblinger). 

As  to  the  nature  of  the  changes  in  the  hypophysis  itself,  much  more  study 
is  required.  It  has  been  stated  that  in  the  anterior  lobe  there  are  neutro- 
phile  or  chromophobe  cells  which  form  a  great  proportion  of  the  tissue, 
but  that  there  are  also  many  eosinophile  and  basophile  cells.  Erdheim  and 
Stumme  have  shown  that  there  are  remarkable  changes  in  the  gland  during 
pregnancy.  It  becomes  much  enlarged,  and  the  chromophobe  cells,  which 
they  call  chief  cells,  are  greatly  enlarged  and  increased  in  importance,  push- 
ing aside  the  eosinophiles,  which  shrink,  and  the  basophiles,  which  become 
very  pale.  Indeed,  as  the  great  mass  of  " pregnancy  cells"  these  altered 
chief  cells  occupy  practically  the  whole  field.  With  the  end  of  pregnancy 
and  during  lactation  the  gland  undergoes  gradual  involution  to  the  normal 
condition. 

In  the  various  phases  of  the  hypophyseal  hyperactivity  or  insufficiency 
mentioned  above,  it  is  evident  that  the  destructive  effects  of  tumors,  cyst 
formation,  haemorrhages,  tuberculosis,  gumma  formation,  anemic  infarcts 
have  nothing  especially  peculiar  about  them.  They  cause  insufficiency  by 
destruction  of  the  tissue  or  by  pressure.  The  cause  of  hyperactivity  is 
more  interesting  and  not  yet  clearly  determined.  Usually  there  is  an  exces- 
sive growth  of  the  tissue  of  the  anterior  lobe  in  the  form  of  a  sort  of  tumor 
or  glandular  hyperplasia  often  spoken  of  as  an  adenomatous  growth.  Great 
variety  exists  among  these.  Erdheim  has  described  eosinophile  adeno- 
mata and  Nothdurft  a  basophile  one.  Benda  pointed  out  that  in  the  cases 
of  acromegaly  the  new  growth  found  in  the  anterior  lobe  is  rich  in  eosino- 
phile cells,  and  others  have  agreed  with  him,  while  Gushing,  in  the  strumas 
or  adenomata  found  in  cases  of  hypophyseal  insufficiency,  has  found  only 
the  chief  or  chromophobe  cells.  Nevertheless  it  would  be  hazardous  to 
state  definitely  that  the  acromegalic  changes  depend  upon  the  eosinophile 
cells. 

A  sharp  distinction  must  be  drawn  between  acromegaly  and  the  other 
condition  described  by  Marie  as  hypertrophic  secondary  pulmonary  osteoar- 
thropathy,  which  also  results  in  elongation  of  the  bones  of  the  extremities 
and  in  the  formation  of  a  rather  thick  periosteal  new  bone  formation.  In 
this  the  hands  and  feet  may  be  greatly  enlarged,  but  they  are  quite  different 
in  form  from  the  short  thick  extremities  of  acromegaly.  It  is  supposed  to 
be  due  to  the  absorption  of  some  toxic  substance,  since  it  accompanies 


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chronic  bronchiectasis,  tumors  of  the  lung  and  thorax,  and  other  analogous 
affections. 

LITERATURE 

Benda:  Dtsch.  med.  Woch.,  1901,  xxvii,  513,  536,  564. 
Gushing:  The  Pituitary  Body  and  its  Disorders,  Phila.,  1912.     Also  Jour.  Amer.  Med. 

Assoc.,  1909,  liii,  249.     With  Crowe,  Quart.  J.  Exp.  Physiol.,  1909,  ii,  389.     With 

Goetsch,  Amer.  Jour,  of  Physiol.,  1910,  xxvii,  60. 
Pick:  Dtsch.  med.  Woch.,  1911,  xxxvii,  1930,  etc. 
Erdheim:  Frankf.  Ztschr.  f.  Path.,  1910,  iv,  70. 
Kraus:  Ziegler's  Beitr.,  1914,  Iviii,  159. 
Lyon:  Archives  of  Int.  Med.,  1910,  vi,  28. 
Erdheim  and  Stumme:  Ziegler's  Beitr.,  1909,  xlvi,  1. 
Wurmbrand:  Ibid.,  1910,  xlvii,  187. 
Berblinger  and  Goldzieher:     "Diabetes  Insipidus,"   Verb.   Dtsch.   Path.   Gesellsch., 

1913,  xvi,  272. 

Simmonds  and  others:  Verb.  Dtsch.  Path.  Gesellsch.,  1914,  xvii,  184-231. 
Swale  Vincent:  Practitioner,  1915,  xciv,  147. 
Marie:  Rev.  de  Med.,  1886,  vi,  297;    1890,  x,  1. 
Thayer:  New  York  Med.  Jour.,  1896,  Ixiii,  33. 


CHAPTER  XL VI 

INJURIES    WHICH    CAUSE    METABOLIC    DISTURBANCES    AND 
CONSEQUENT  DISEASE  OF  THE  BONES 

Chemical  interchanges  in  growth  of  bone.  Importance  of  calcium.  Relation  of  internal 
secretions  to  bone  formation.  Normal  ossification.  Rickets.  Osteomalacia,  chondro- 
dystrophia  fcetalis.  Scurvy  and  M oiler-Barlow's  disease;  osteogenesis  imperfecta;  osteo- 
psathyrosis;  Paget's  disease. 

THE  structure  of  the  bones  is  so  complicated,  and  their  mode  of  growth 
involves  so  many  chemical  interchanges,  that  it  is  not  surprising  to  find 
them  extremely  sensitive  to  disturbances  of  metabolism.  In  most  cases  we 
are  ignorant  of  the  ultimate  causes  of  those  disorders  of  the  chemical  inter- 
changes of  the  body  which  bring  with  them  visible  alterations  in  the  bones, 
but  in  some  we  understand  at  least  the  principles  which  are  immediately 
concerned.  Since  mineral  substances  make  up  so  great  a  part  of  the  weight 
of  the  bones,  we  naturally  turn  at  once  to  them.  It  is  well  enough  known 
that  attention  to  the  food  of  horses  and  other  domestic  animals,  and  care 
that  they  receive  enough  lime  and  phosphorus,  is  necessary  that  their  grow- 
ing bones  be  well  formed  and  strong.  If  we  deprive  an  animal  of  the  lime 
which  should  be  in  its  food,  its  bones  become  porous  and  weak,  or  even  quite 
soft,  and  it  may  be  rendered  helpless  by  the  giving  way  and  bending  which 
can  occur  (Pexa,  Dibbelt). 

Dibbelt  found  that  for  a  growth  of  100  grams,  a  dog  uses  2.2  grams  of  CaO.  In  his 
experiments  with  calcium-poor  food,  the  deposit  of  lime  was  £  to  ^o  °^  tne  normal, 
and  the  bones  became  extremely  light  and  porous.  The  epiphyseal  cartilages  grew 
large  and  broad,  and  the  cortex  everywhere  became  rarefied  by  the  enlargement  of  the 
Haversian  canals  into  considerable  cavities.  The  broadening  of  the  epiphyseal  line  is 
due  to  the  lack  of  provisional  calcification  of  the  cartilage  and  the  consequent  inability 
of  the  marrow  capillaries  to  convert  it  into  bone.  In  spite  of  the  lack  of  calcium,  how- 
ever, there  was  abundant  formation  of  a  tissue  morphologically  like  bone,  but  devoid  of 
lime  salts  (osteoid  tissue).  Stoeltzner  thinks  that  the  formation  of  this  osteoid  tissue  is 
dependent  upon  a  stimulus  furnished  by  calcium,  and  that  osteoid  tissue  remains  so 
only  because  it  is  unable  to  take  up  the  calcium.  He  is  supported  by  Lehnerdt,  who 
substituted  the  closely  allied  strontium  for  calcium,  in  the  food,  and  found,  just  as  did 
Dibbelt  in  the  extreme  lack  of  calcium,  that  the  cartilage  cells  being  unchanged,  were  not 
normally  invaded  by  marrow  capillaries,  and  that  the  underlying  spongy  bone  was  re- 
placed by  a  thick  zone  of  osteoid  tissue.  This  latter  formation  he  states  is  due  to  a 
power  of  stimulation  possessed  by  strontium  equally  with  calcium,  but  that  since  stron- 
tium cannot  replace  calcium  as  a  hard  deposit  in  the  new-formed  tissue,  it  remains 
osteoid  tissue  and  not  bone.  Dibbelt's  observation  seems  to  disprove  the  idea  that  the 
stimulus  of  calcium  or  strontium  is  necessary  for  the  growth  of  the  osteoid  tissue. 
Phosphorus,  which,  with  carbonic  acid,  is  found  in  the  normal  lime  and  magnesia  com- 
binations which  make  up  the  hard  part  of  bone,  is  naturally  of  great  importance  for 

909 


910 


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proper  bone  formation.  Some  authors  have  looked  upon  it  as  a  special  stimulus  to  bone 
formation  too,  but  whether  it  is  in  that  role,  or  merely  in  its  obvious  part  in  furnishing 
material  for  the  ultimate  phosphates,  remains  to  be  determined.  Magnesium  salts  are 
present  in  a  much  smaller  proportion  than  those  of  calcium,  but  nevertheless  play  a  part 
to  which  it  seems  not  enough  attention  has  yet  been  paid. 

Importance  of  Calcium. — Direct  abstraction  of  lime  from  the  food  does 
not  ordinarily  occur,  and  one  must,  if  a  disease  appears  which  points 
toward  an  insufficiency  of  calcium,  determine  whether  the  failure  is  not 


Fig.  452. — Senile  osteoporosis.  Section  of  rib  showing  great  thinning  of  the  cortex 
and  atrophy  of  the  lamellse.  With  the  disappearance  of  calcium,  the  lattice  figures 
become  evident  in  the  Haversian  systems. 

rather  in  the  ability  of  the  body  to  absorb,  retain,  and  deposit  the  calcium. 
It  is  known,  of  course,  that,  in  the  period  of  growth,  and  especially  in  child- 
hood, the  deposition  of  lime  salts  is  abundant,  and  that  the  bones  become 
progressively  firmer,  while  in  old  age  the  reverse  is  true — more  lime  salts  are 
absorbed  from  the  bone  than  are  deposited  there  afresh,  so  that  the  lamellse 
become  thinner  and  disappear,  and  in  the  Haversian  systems  of  the  cortex 
so  much  of  the  solid  material  is  lost  that  the  laminae  of  bone  assume  a 
reticulated  appearance  and  become  relatively  weak  (Fig.  452).  This  is  the 


RELATION    OF   INTERNAL    SECRETIONS   TO    BONE    FORMATION   911 

senile  osteoporosis  which  is  to  be  regarded  as  a  more  or  less  normal  process, 
but  which  leads  to  obvious  atrophic  changes  in  some  bones,  such  as  the 
skull  and  jaw  bones,  and  to  such  rarefaction  of  the  others  that  fractures 
occur  with  comparatively  slight  occasion.  This  is  an  expression  of  the 
preponderance  in  old  age  of  the  process  of  absorption  of  the  bone  over  that 
of  apposition,  two  processes  which  go  on  side  by  side  through  life,  even 
during  the  period  of  most  rapid  growth. 

Relation  of  Internal  Secretions  to  Bone  Formation. — We  have  a  certain 
amount  of  vague  information  regarding  the  influence  which  the  organs  of 
internal  secretion  exert  over  the  interchange  of  calcium  and  the  other  con- 
stituents of  bone,  and  over  the  growth  of  bone  itself,  and  much  of  this  has 
already  been  detailed.  Its  vagueness  consists  largely  in  the  fact  that  while 
metabolism  and  growth  in  general  are  largely  influenced  by  these  glands, 
it  is  more  difficult  to  ascribe  specific  changes  in  the  bones  to  their  activity  or 
lack  of  activity.  Acromegaly  and  gigantism,  in  which  there  is  such  an 
excessive  growth  of  bone  (together  with  that  of  the  soft  parts),  is  fairly 
clearly  associated  with  excessive  activity  of  the  anterior  lobe  of  the  hypo- 
physis. Klose  and  Matti  find  that  the  destruction  of  the  thymus  causes 
great  defects  in  bony  growth,  but  Pappenheimer  and  many  others  dispute 
this.  Defective  metabolism  and  stunted  growth  follow  destruction  of  the 
thyroid,  but  there  is  no  specific  or  especially  pronounced  change  in  the  bones 
except  general  retardation  of  their  development.  Loss  of  the  parathyroid 
is  thought  to  disturb  the  calcium  metabolism  and  to  allow  the  tissues  to 
become  impoverished.  The  dentine  of  the  teeth  fails  to  become  calcified, 
and  the  callus  formed  in  the  healing  of  fractures  remains  soft,  but  it  has  not 
yet  been  made  clear  that  the  processes  of  bone  formation  in  general  are 
characteristically  affected.  Still  less  definite  statements  are  made  about  the 
part  played  by  the  chromaffine  system  and  by  the  ovaries  and  testes  on  the 
course  of  ossification.  This  is  one  of  the  most  obscure  but  also  one  of  the 
most  interesting  chapters  of  human  pathology,  and  as  yet  we  possess  only 
the  beginnings  of  information  on  the  subject.  We  may  examine  the  facts, 
however,  which  are  afforded  by  study  of  the  several  diseases  in  which  the 
growth  and  structure  of  the  bones  are  peculiarly  affected  (together  with 
many  changes  in  other  organs),  and  attempt  to  realize  at  least  where  the 
problems  lie. 

Normal  Ossification. — A  few  words  as  to  the  tissues  concerned  may  recall  what  is 
necessary  to  the  understanding  of  the  pathological  changes.  Bones  are  formed  either 
by  ossification  of  connective-tissue  membranes  or  by  the  replacement  of  cartilage 
by  bone  tissue.  Membranous  bones  seem  to  be  produced  by  a  change  in  the  func- 
tion of  certain  cells  which  acquire  the  power  of  laying  down  an  intercellular  matrix 
in  which  they  bury  themselves,  and  which  hi  time  becomes  calcified.  In  the  car- 
tilages of  the  foetus  which  are  covered  with  a  layer  of  such  altered  or  osteoblastic 
connective-tissue  cells  there  comes  a  time  when  blood-vessels  (later  the  nutrient 
vessels)  push  into  the  substance  of  the  cartilage,  carrying  the  perichondrial  osteoblasts 
before  them.  They  hollow  out  the  cartilage,  and  the  osteoblasts,  after  destroying  the 
cartilage  cells,  deposit  further  formless  material  upon  the  remains  of  the  matrix,  bury 


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themselves  in  it,  and  promote  its  calcification.  Thus  bone  is  formed.  It  can  be  most 
clearly  studied  along  the  line  of  demarcation  between  the  epiphyseal  cartilage  and  the 
advancing  marrow  cavity,  because  there  the  process  persists  for  a  long  time,  with  the 
formation  and  ossification  of  ever  new  cartilage,  as  is  necessary  for  the  growth  of  the 
bone  in  length.  Growth  in  thickness  is  by  this  tune  carried  out  by  the  persistent  per- 
iosteal  and  endosteal  cells  in  the  diaphysis,  which  add  to  the  mass  of  the  cortical  bone 
and  to  the  lamellae  of  the  cancellous  bone.  In  the  epiphyseal  ossification  zone  the  process 
is  clearly  seen  as  follows.  The  most  distal  of  the  cartilage  cells  near  the  joint  surface 
are  flattened;  next  is  a  great  quiescent  mass  of  small  elongated  cells  lying  in  every 
direction;  toward  the  marrow  cavity  there  is  a  broad  belt  in  which  they  begin  to  be 
more  deeply  stained  and  to  be  arranged  with  their  long  axes  more  transversely  to  the 
long  axis  of  the  bone.  Still  nearer  to  the  border  zone  they  form  straight,  closely  arranged 
columns,  like  grains  of  corn  on  a  cob,  separated  by  the  alternating  and  more  irregular 
columns  of  the  blue-staining  matrix.  Quite  at  the  line  of  ossification  these  cells  swell 
and  become  large,  rounded,  or  irregular  structures  (cf.  Fig.  44) .  A  whole  phalanx  of  cap- 
illary loops  from  the  bone-marrow  presents  itself  along  this  row  of  cartilage  cell  columns, 
and  each  capillary,  covered  loosely  with  a  mantle  of  osteoblasts,  tends  to  push  itself  into 
or  alongside  of  a  column  of  cartilage  cells.  Here,  in  the  matrix  of  the  border  zone  of 
cartilage  cell  columns,  there  is  a  provisional  or  preliminary  deposit  of  calcium  salts  in 
very  fine  granules.  This  calcification  seems  to  offer  some  obstacle  to  the  invasion  of  the 
vessels  since  in  its  absence  blood-vessels  penetrate  far  into  the  cartilage  and  branch  there 
in  a  way  which  we  shall  discuss  presently  in  connection  with  rickets. 

When  the  conditions  are  all  favorable,  the  cartilage  cells  themselves  are  broken  in 
upon  and  set  free  from  their  nests  in  the  matrix  (cf.  Fig.  44).  They  may  be  destroyed 
or  they  fall  into  the  marrow  cavity  and  are  thought  to  take  no  further  part  in  actual 
bone  formation.  The  invading  osteoblasts  range  themselves  along  the  jagged  remnant 
of  matrix  and  once  more  begin  their  process  of  burying  themselves  in  a  hyaline  substance 
which  forms  around  and  beneath  them.  After  a  time  they  show  clearly,  as  they  lie  in 
the  little  cavity  which  they  form  for  themselves,  their  numerous  long  thin  processes 
which  extend  out  in  all  directions  in  minute  canaliculi  in  the  homogeneous  matrix. 
The  tissue  at  this  stage  is  osteoid  tissue.  Quickly,  however,  there  occurs  a  deposit  of 
calcium  throughout  and  it  becomes  hard  bone.  Ordinarily  there  is  no  considerable 
amount  of  osteoid  tissue  at  any  time,  but,  as  we  shall  see,  there  are  diseases  in  which  it 
persists  as  such.  Thus  finished,  this  cancellous  bone  is  left  behind  and  the  capillaries 
with  more  osteoblasts  advance  to  meet  new  cartilage  cells.  The  epiphyseal  bony  centre 
is  formed  later  in  exactly  the  same  way  by  the  invasion  of  another  vessel  into  the  epi- 
physeal cartilage,  and  bone  formation  spreads  from  this  centre  through  the  cartilage  in 
all  directions.  Perichondral  blood-vessels  invade  the  cartilage  only  rarely,  except  in 
the  direct  process  of  entering  to  form  the  epiphyseal  ossification  centre  (and  to  some  ex- 
tent along  the  plane  between  resting  and  actively  growing  cartilage),  but  that  too  is 
much  modified  by  disease.  Along  the  epiphyseal  line  the  process  is  actually  maintained 
for  many  years  until  the  bone  has  reached  its  full  length,  when  with  a  final  replacement 
of  the  remnant  of  cartilage  the  line  is  merged  into  the  cancellous  bone. 

RICKETS  OR  RACHITIS 

The  weakened  condition  of  the  bones  probably  gave  rise  to  the  old  name, 
Tickets,  for  this  disease,  and  rachitis  is  only  a  high-sounding  Latinization  of 
the  English  word.  It  is  an  astonishing  condition  which  is  seen  at  its  height 
in  children,  beginning  usually  at  the  sixth  month  and  lasting  sometimes  for 
several  years,  with  remissions  and  final  healing.  The  disease  may,  never- 
theless, leave  behind  it  very  obvious  traces  of  the  deformities  which  are 
produced  when  the  bones  are  soft  and  fragile.  It  is  often  remarkable  to 


RICKETS    OR   RACHITIS  913 

observe  how  completely  the  healing  process,  by  the  aid  of  the  mechanical 
agencies  which  normally  act  on  the  skeleton,  can  restore  to  the  normal  form, 
bones  which  at  one  time  were  greatly  deformed.  The  signs  of  rickets  in 
adults  are  rarely  very  disfiguring,  although  in  the  case  of  the  pelvis  the 
deformity  may  have  far  reaching  consequences  in  the  obstruction  of  child- 
birth. 

The  disease  is  commonly  said  to  pass  through  three  stages  which  can  be 
distinguished  as  the  beginning,  the  florid  stage,  and  that  of  healing.  Dif- 
ferent conditions  with  regard  to  the  metabolism  prevail  in  these  stages.  At 
the  height  of  its  development  the  following  may  be  observed.  The  child  is 
pale  and  sickly,  the  anaemia  being  sometimes  quite  profound.  Such  children 
show  a  lowered  resistance  and  are  prone  to  infections  of  all  sorts.  The 
lymph  glands  are  usually  enlarged,  and  tonsils  and  other  adenoid  tissues  are 
everywhere  swollen.  The  abdomen  protrudes,  and  in  many  cases,  if  not  in 
all,  the  spleen  is  enlarged  and  fairly  firm.  The  distension  of  the  abdomen 
may  be  in  part  due  to  atony  of  the  intestinal  walls.  Flabbiness  and  softness 
of  the  skeletal  muscles  are  most  striking.  The  epiphyses,  especially  those 
of  the  wrists,  ankles,  and  knees,  are  much  enlarged.  At  each  costochondral 
junction  there  is  a  hard  swelling  which  can  be  felt  through  the  skin,  and  the 
row  of  these  nodules  on  each  side  of  the  sternum  is  often  spoken  of  as  a 
rickety  rosary.  The  enlargement  is  especially  prominent  on  the  inside  of 
the  thorax  and  may  be  due  in  part  to  the  angular  inward  dislocation  of  the 
bony  end  of  the  rib  through  respiratory  efforts  which  are  often  made  diffi- 
cult by  adenoid  growths  in  the  upper  air-passages,  associated  with  the 
general  lymphoid  swelling.  Skoliosis,  or  curvature  of  the  spine,  bending  or 
fracture  of  the  long  bones,  and  a  peculiar  flattening  or  contraction  of  the 
pelvis  are  due  to  the  general  softening  of  the  bones.  The  anterior  bowing 
of  the  tibiae  (sabre  tibia),  and  the  consequent  flat  foot,  are  particularly  strik- 
ing features  in  those  children  who  walk  about. 

The  skull  is  made  square,  and  the  forehead  very  prominent,  by  the  growth 
of  convex  spongy  thickenings  over  the  frontal  and  parietal  bosses.  There 
is  often  an  actual  erosion  deep  into  the  bone  of  the  skull  over  the  back  of 
the  head  as  the  child  lies  on  the  pillow,  but  Ziegler  regards  this  "osteotabes" 
as  a  totally  different  affection,  and  he  is  probably  right. 

Most  cases,  if  the  child  survives,  end  with  the  gradual  restoration  of  the 
normal  consistency  of  the  bones  and  afterward  with  the  far  more  gradual 
rearrangement  of  the  bony  structure  and  readaptation  to  the  mechanical 
needs  and  normal  form  of  the  bones.  There  are  some,  however,  in  which 
such  extreme  distortion  of  the  whole  skeleton  takes  place  in  the  florid  stage 
that  the  deformity  is  never  really  overcome,  and  the  patients  remain  per- 
manently disabled.  Such  skeletons  are  seen  in  European  museums  showing 
extreme  bending  and  twisting  of  the  long  bones,  but  the  extremely  severe 
cases  seem  at  least  very  rare  in  this  country.  M.  B.  Schmidt  thinks  that 
different  forms  occur  in  different  regions,  those  seen  in  Zurich  having  large 
epiphyses  with  straight  hard  diaphyses,  while  those  seen  in  Strassburg  have 
59 


914  TEXT-BOOK   OF    PATHOLOGY 

large  epiphyses  also,  but  show  bent  and  deformed  or  fractured  diaphyses 
with  a  thick  covering  of  soft  periosteal  new  bone.  In  this  country  we  occa- 
sionally see  the  latter  type,  but  the  former  is  more  common. 

At  autopsy  it  is  rather  easy  to  cut  with  a  knife  down  through  the  epi- 
physeal  end  of  the  bone  deep  into  the  shaft,  and  the  cut  surface  presents  an 
extraordinary  contrast  with  the  normal  bone  (Fig.  453).  It  is  seen  that  in 
the  normal  bone  the  line  of  ossification  is  perfectly  sharp,  even,  and  really 
a  narrow  line.  In  rickets  it  is  replaced  by  a  wide  irregular  band  of  rather 


Fig.  453. — Rickets,  a,  Normal  bone  with  clear  line  of  ossification.  6  and  c  show 
broad  bands  of  osteoid  tissue  instead  of  this  line;  their  diaphyses  are  firm,  delicate,  and 
straight,  d,  Form  of  rickets  in  which  the  diaphysis  is  weakened,  covered  with  perios- 
teal new  bone,  and  fractured. 

soft  gray  translucent  tissue,  in  which  white  opacities  and  gritty  particles 
represent  the  calcified  lamellae,  but  throughout  which  islands  of  bluish 
cartilage  can  also  be  seen.  The  cortex  of  the  shaft  often  shows  soft,  spongy 
growths  both  inside  and  outside.  These  changes  are  especially  well  seen  in 
the  lower  end  of  the  femur,  the  upper  end  of  the  tibia,  etc.,  but  to  a  slighter 
degree  they  are  found  in  every  bone  and  are  very  prominent  in  the  costo- 
chondral  junction  of  the  ribs.  A  section  through  the  epiphysis  and  shaft  of 
such  a  bone  shows  (Fig.  454),  on  analysis  of  the  confusing  scene,  that  the 
border  zone  of  the  cartilage  where  it  should  abut  on  the  advancing  marrow 


RICKETS    OR   RACHITIS 


915 


vessels  has  failed  to  undergo  the  usual  provisional  calcification  or  is  calcified 
in  irregularly  scattered  places  only.     Where  there  is  no  calcification,  the 


Fig.  454.— Rickets.  Rib  at  site  of  line  of  ossification.  The  preparatory  zone  of 
cartilage  is  irregularly  invaded  by  perichondral  and  marrow  vessels.  Calcification  of 
cartilage  lacking,  except  in  two  or  three  foci.  Invading  blood-vessels  surrounded  by 
osteoid  tissue.  Lamellae  of  bone  remain  partly  covered  with  osteoid  tissue. 

marrow  vessels  push  far  into  the  cartilage  and  branch  here  and  there,  leav- 
ing long  tongues  of  the  calcified  cartilage  projecting  toward  the  marrow 


916 


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cavity.  So  sluggish  is  the  process  of  invasion  of  the  cartilage  cells  that 
much  uncalcified  cartilage  is  also  left  in  these  tongues  or  islands  of  tissue. 
Where  the  capillaries  do  lay  open  the  cartilage  cells  and  spread  their  osteo- 
blasts  on  the  remaining  cartilage  matrix,  the  result  is  the  formation  of 
highly  irregular,  thick  laminae,  morphologically  like  bone  (though  much 
more  bulky),  but  not  calcined.  This  is  the  osteoid  tissue  described  before, 
and  this  it  is  which  makes  up  practically  all  of  the  thick  grayish  band  which 
lies  where  the  line  of  ossification  should  be.  Where  the  capillaries  grow  far 
into  the  cartilage,  they  may  surround  themselves  with  zones  or  mantles  of 
osteoid  tissue.  So  too  the  margins  of  the  cartilage  masses  left  behind  in  the 


Fig.  455. — Periosteal  osteoid  formation  about  a  rib  in  rickets. 

advance  of  the  growth  become  changed  into  osteoid  tissue,  and  when,  in 
healing,  this  becomes  bone,  the  rest  remains  as  a  cartilage  island  enclosed  in 
bone.  There  is  much  of  this  osteoid  tissue  in  the  shaft  of  the  bone  also, 
making  up  the  superficial  layers  of  the  lamina?  of  the  cancellous  bone  and  of 
the  periosteal  exostoses  (Fig.  455).  Even  in  the  denser  bone  of  the  cortex 
one  finds  osteoid  tissue,  especially  about  the  vessels,  which  lie  in  the  so- 
called  perforating  canals,  but  also  at  times  occupying  a  quadrant  or  more  of 
an  otherwise  well-calcified  Haversian  system.  The  point  most  disputed  in 
the  recent  discussion  of  rickets  and  osteomalacia  before  the  German  Patho- 
logical Society  was  the  question  whether  this  calcium-free  bone  should  be 
regarded  as  the  result  of  the  absorption  of  lime  from  old  bone  previously 


RICKETS    OR   RACHITIS  917 

calcified  (halisteresis),  or  new  bone  laid  down  calcium  free.  The  strongest 
evidence  seemed  to  be  in  favor  of  the  wide-spread  existence  of  halisteresis, 
although,  of  course,  it  is  clear  that  much  osteoid  tissue  is  newly  formed. 

Another  process  characteristic  of  rickets  is  the  abundant  ingrowth  of 
blood-vessels  into  the  epiphyseal  cartilage  from  the  perichondrium.  These 
split  up  the  resting  cartilage  in  every  direction,  and  end  in  a  network  of 
small  vessels  parallel  with  the  transverse  plane  of  ossification.  Several 
such  layers  or  "stages"  of  vessels  may  be  formed,  and  may  be  visible  at 
once,  although  as  the  irregular  region  of  ossification  advances  they  become 
in  turn  confluent  with  the  vessels  from  the  marrow  cavity  and  lose  their 
identity.  As  they  lie  in  the  cartilage  ("cartilage  marrow  canals")  the 
matrix  jround  them  loses  its  blue  stain  and  assumes  the  power  of  staining 
with  eosin.  This  collagenous  material  soon  becomes  converted  by  the 
accompanying  osteoblasts  into  osteoid  tissue,  which  finally  adds  itself  to  the 
mass  of  osteoid  tissue  formed  by  the  marrow  vessels. 

The  marrow  is  in  itself  changed  into  a  tissue  much  more  fibrous  than 
normal  ("endostitis  fibrosa"),  and  laminae  of  bone  or  osteoid  tissue  may  be 
formed  in  this  fibrous  marrow.  It  is  easy  to  see  that  an  extremely  compli- 
cated condition  can  be  produced  in  this  way,  especially  when  it  is  remem- 
bered that  similar  processes  in  modified  form  occur  in  the  shaft  of  the  bone 
as  well.  It  is  remarkable  that  any  adequate  return  to  the  normal  architec- 
ture of  the  line  of  ossification  is  possible  in  the  course  of  healing.  The 
enlargement  of  the  epiphyses  is  due,  not  so  much  to  any  excessive  produc- 
tion of  cartilage,  as  to  the  fact  that  ossification  is  extremely  sluggish  and  the 
cartilage  does  not  become  converted  into  the  calcified  and  less  bulky  bone. 
The  exostoses  on  the  skull  are  soft,  spongy  masses  of  lenticular  form  com- 
posed of  porous  osteoid  tissue  which  becomes  partly  calcified  and  later  may 
be  absorbed  in  large  part  or  completely  converted  into  bone. 

The  spleen  is  often  enlarged,  and  shows  an  increase  in  the  reticulum 
fibres  without  any  parallel  increase  in  connective  tissue.  Giant-cells  occur, 
the  Malpighian  bodies  are  small,  and  the  pulp  hypersemic  (Hayaski).  In 
our  cases  the  condition  is  variable,  and  in  some  there  is  a  distinct  induration 
from  an  excess  of  connective  tissue.  There  is  atony  or  hypotony  of  the  skele- 
tal muscles,  as  well  as  of  the  smooth  muscles  of  the  intestines  and  arteries. 

With  regard  to  the  mineral  metabolism  in  rickets,  Schabad  and  Dibbelt 
have  shown  that  the  excretion  of  calcium  in  the  florid  stage  is  especially 
high  in  the  faeces,  while  the  proportion  in  the  urine  sinks.  There  is  fre- 
quently an  absolute  loss  or  negative  balance,  dependent  upon  the  excessive 
amount  discharged  with  the  faeces.  Healing  is  preceded  by  hyper-retention 
and  a  relative  increase  in  the  output  of  calcium  in  the  urine.  After  healing, 
the  proportions  are  normal.  Dibbelt  thinks  that  rickets  is  due  to  a  specific 
disturbance  of  the  calcium  metabolism,  and  not  merely  to  inability  of  the 
bone  to  take  up  calcium,  since  in  that  case  the  excretion  of  the  excess  would 
retain  its  relative  proportions  in  urine  and  faeces.  The  output  of  phos- 
phates is  also  increased. 


918  TEXT-BOOK   OF   PATHOLOGY 

The  cause  of  rickets  is  unknown.  It  seems  clear  that  the  deficiency  of 
calcium  is  a  most  important  factor,  and  Dibbelt  thinks  it  adequate  to  pro- 
duce the  typical  lesions  of  rickets.  Others,  however,  deem  it  necessary  to 
assume  that  there  are  specific  changes  in  the  bone-forming  tissue  which 
make  them  unable  to  retain  the  calcium.  The  elements  of  unhygienic 
surroundings,  poor  food,  etc.,  have  always  been  emphasized  as  the  causes  of 
the  disease,  but  recently  attention  has  been  turned  to  something  more  defi- 
nite. Various  deficiencies  of  the  organs  of  internal  secretion  have  been  held 
responsible, — thymus  (Matti),  parathyroid  (Erdheim  thinks  the  parathy- 
roid deficiency  probably  responsible  for  the  allied  osteomalacia),  chromaf- 
fine  system  (Stoeltzner), — but  none  of  these  is  supported  by  much  evidence. 
Infections  of  various  sorts  have  also  been  thought  capable  of  causing  the 
disease.  Morpurgo  found  it  possible  to  produce  rickety  changes  in  rats 
which  he  infected  with  an  organism  isolated  from  spontaneously  rickety 
rats,  and  J.  Koch  claims  that  it  is  possible  to  reproduce  the  skeletal  changes 
with  precision  by  the  injection  of  cultures  of  the  Streptococcus  longus  seu 
erysipelatis  into  the  veins  of  young  dogs. 

Osteomalacia  is  a  very  similar  disease  which  occurs  in  adults,  especially 
in  women,  with  exacerbations  during  pregnancy  and  lactation.  It  is 
thought  by  many  to  be  practically  identical  with  rickets,  except  in  occurring 
in  persons  whose  endochondral  ossification  is  complete.  Otherwise  the 
histological  modifications  of  the  bones  are  nearly  identical.  Here  the 
softening  of  bones  which  were  quite  calcified  and  hard  a  short  time  before 
must  be  due  to  halisteresis,  and  in  section  the  bones  show  clearly  the  osteoid 
margin  along  each  lamina  of  bone,  covering  in  the  still  calcified  central  part. 
The  most  extraordinary  deformities  through  bending  of  the  soft  bones  are 
produced  during  the  florid  stages,  when  the  decalcification  is  at  its  height, 
and  this  is  accentuated  by  the  greater  weight  of  the  adult  body.  The  pres- 
sure of  the  heads  of  the  femora  flattens  the  pelvis  laterally  and  forces  the 
symphysis  pubis  forward  into  a  sort  of  beak.  With  returning  rigidity  such 
a  pelvis  is,  of  course,  incompatible  with  childbirth.  The  loss  of  calcium 
may  be  relatively  high  in  each  day's  excreta  (Holtz'  case,  0.1809  gm.  daily; 
Sauerbruch's,  0.07  to  0.17  gm.  daily). 

Adrenal  insufficiency  and  ovarian  hyperactivity  have  been  looked  upon 
as  the  cause  of  the  affection,  and  adrenaline  treatment  or  castration  carried 
out  with  alleged  good  effect.  But  the  matter  is  still  debated.  Erdheim 
found  lesions  of  various  sorts  in  the  parathyroid  glands,  and  calls  attention 
to  the  parallelism  between  this  condition  and  the  escape  of  calcium  in 
parathyroid  insufficiency. 

LITERATURE 

Rickets.— Schmidt,  Stoeltzner,  Dibbelt,  Schmorl:  Verb.  Dtsch.  Path.  Gesellsch.,  1909, 
xiii,  1-54. 

Ziegler:  Ctbl.  f.  allg.  Path.,  1901,  xii,  865. 

Schmorl:  Munch,  med.  Woch.,  1909,  Ivi,  1256. 

C.  Meyer:  Jahrb.  f.  Kinderh.,  1913,  Ixxvii,  28. 

Dibbelt:  Dtsch.  med.  Woch.,  1913,  xxxix,  551. 


RICKETS    OR   RACHITIS  919 

Rickets.— Grosser:  Med.  Klinik,  1914,  x,  577. 

Aschenheim:  Jahrb.  f.  Kinderh.,  1914,  Ixxix,  446. 
Koch:  Ctbl.  f.  Bakt.,  1.  Abth.  Ref.,  1913,  Ivii,  Beih.  250. 
Osteomalacia. — Marinesco,  Parhon,  and  Minea:  Nouv.  iconogr.  de  la  Salp6triere,  1911, 

xxiv,  1. 
Erdheim:  Sitz.  d.  k.  Akad.  d.  Wiss.,  Wien,  Math.  Naturw.  Kl.,  1907, 

cxvi,  Abth.  iii,  311. 
Bauer:  Frankf.  Ztschr.  f.  Path.,  1911,  vii,  231. 

Chondrodystrophia  foetalis  is  a  disease  of  the  cartilage  occurring  in  fcetal 
life,  and  leading  to  a  partial  or  complete  cessation  of  the  endochondral  ossifi- 
cation, while  periosteal  bone  formation  proceeds  vigorously.  The  result  of 
this  is  that  the  infant  is  brought  into  the  world  with  extraordinarily  short- 
ened arms  and  legs  and  with  other  deformities,  among  which  are  distortion 
of  the  pelvis,  malformation  of  the  vertebral  column  and  thoracic  skeleton, 
and  great  enlargement  of  the  skull,  with  retraction  of  the  nose.  Every  one 
is  familiar  with  the  peculiar  short-limbed  dwarfs,  with  their  large  heads  and 
characteristic  faces,  in  which  the  nostrils  seem  directed  almost  straight 
forward.  They  are  intelligent,  active,  and  strong,  and  make  their  way  in 
life,  often  as  clowns  in  circuses,  where  their  strength  and  agility  find  them 
occupation.  They  may  reach  an  advanced  age  and  bear  children,  although 
on  account  of  the  deformity  of  the  pelvis  these  must  be  removed  by  Csesa- 
rean  section.  That  the  disease  is  hereditary  is  seen  from  the  fact  that  these 
are  commonly  also  dwarfs,  but  cases  of  chondrodystrophia  occur  often 
enough  in  families  in  which  no  other  instances  are  known. 

The  cause  of  the  disease  is  quite  unknown.  The  organs,  including  all  the 
glands  of  internal  secretion,  are  found  to  be  quite  normal,  and  all  the 
changes  are  explained  on  the  basis  of  the  disturbances  in  the  cartilages. 
Kaufmann  distinguishes  chondromalacic,  hyperplastic,  and  hypoplastic 
alterations  of  the  cartilage,  but,  as  Siegert  points  out,  all  these  may  occur 
together  in  the  same  case.  The  epiphyseal  cartilages  are  found  abundantly 
penetrated  by  blood-vessels  from  the  perichondrium  (Fig.  456) .  The  carti- 
lage cells  may  be  very  small  and  widely  separated  by  a  rather  soft  fibrillar 
intercellular  substance.  Often  they  lie  in  great  spaces  which  produce  a 
spongy  appearance.  Along  the  line  of  ossification  there  is  in  patches  a  col- 
umnar arrangement  of  cells,  while  for  the  rest  the  cells  are  enlarged  and  to- 
tally irregular  in  their  arrangement.  In  other  instances  the  zone  of  columnar 
arrangement  of  cartilage  cells  is  separated  from  the  marrow  cavity  by  other 
cartilage  cells  arranged  in  a  network.  Often,  but  not  always,  a  lamella  of 
periosteum  with  blood-vessels  extends  across  the  epiphyseal  cartilage,  just 
above  the  line  of  ossification,  and  causes  a  complete  cessation  of  that  process. 
Invasion  of  the  cartilage  by  marrow  capillaries  is  almost  at  a  standstill,  and 
usually  the  spaces  are  limited  by  a  film  of  completed  bone.  Calcification  of 
the  cartilage  is  rather  slight,  but  some  remnants  of  blue-staining  material 
are  found  in  the  centres  of  the  terminal  bone  lamella.  In  spite  of  these 
anatomical  conditions,  which  express  the  result,  it  is  hard  to  say  exactly 


920 


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why  such  slight  obstacles  are  not  overcome,  so  that  growth  of  the  cartilage 
into  orderly  columns  and  consequent  ossification  may  proceed.     Periosteal 

growth,  building  up  and 
breaking  down  of  the  la- 
mellae of  the  diaphysis,  and 
bone-marrow  formation  are 

B^^^^S0P***l^  normal.     Premature  synos- 

tosis  of  the  portions  of  the 
sphenoid  with  one  another 
and  with  the  basilar  por- 
tion of  the  occipital  bone 
is  common,  and  in  sharp 
contrast  with  the  condition 
in  myxcedema  or  cretinism, 
in  which  this  connection  re- 
mains cartilaginous  a  very 
long  time.  It  may  be  re- 
sponsible in  part  for  the  re- 
traction of  the  nose.  Dandy 
has  recently  observed  that 
there  is  a  distinct  hydro- 
cephalus  in  these  cases. 
There  is  a  lumbar  lordosis, 
and  the  promontory  of  the 
sacrum  projects  into  the  up- 
per strait  of  the  pelvis,  so 
as  to  make  it  very  narrow. 
In  adults  of  this  type,  as  in 
the  case  of  a  woman  aged 
seventy-five  seen  at  au- 
topsy recently,  ossification 
is  quite  complete,  and  no 
trace  of  intermediary  car- 
tilage remains.  Endochon- 
dral  ossification  with  some 
growth  does,  therefore,  go 
on  to  completion,  but  with- 
out adding  much  to  the 
length  of  the  bones.  This  condition  is  not  to  be  confused  with  cretinism, 
in  which  the  whole  process  of  ossification  is  retarded,  nor  with  rickets,  in 
which  there  is  a  period  during  which  osteoid  tissue,  and  not  bone,  is  formed 
abundantly. 

LITERATURE 

Kirchberg,  Marchand:  Ziegler's  Beitr.,  1889,  v,  183. 
Kaufmann:  Die  sog.  foetale  Rachitis,  Berlin,  1892. 
Siegert:   Ergeb.  d.  inn.  Med.  u.  Kinderh.,  1912,  viii,  64. 
MacCallum:  Johns  Hopkins  Hosp.  Bull.,  1915,  xxvi,  1§2. 


Fig.  456. — Chondrodystrophy  in  an  infant.  Me- 
dian section  of  the  femur,  showing  softening  and 
displacement  of  the  epiphyseal  cartilage. 


SCURVY   AND    MOLLER-BARLOW  S    DISEASE 


921 


SCURVY  AND  MOLLER-BARLOW'S  DISEASE 

Prolonged  subsistence  upon  such  food  as  salted  meats,  canned  meat  with 
biscuits  or  bread,  and  boiled  or  condensed  milk,  without  fresh  fruits,  milk, 
vegetables,  or  fresh  meat,  is  known  to  produce  a  complex  disease  charac- 
terized by  anaemia,  swelling  and  infection  of  the  gums,  painful  hemorrhages 
in  the  joints  and  under  the  periosteum,  and  purpuric  haemorrhages  in  the 
skin.  This  may  lead  to  death,  but  can  be  cured  by  giving  the  so-called 


a 


Fig.  457. — Infantile  scurvy.  Line  of  ossification  of  the  lower  end  of  the  femur:  (a) 
Calcified  cartilage;  (6)  haemorrhage  in  the  fibrous  bone-marrow.  The  process  of  ossifi- 
cation in  almost  entirely  interrupted. 


antiscorbutic  substances  which  are  contained  in  fresh  fruits  and  vegetables 
and  in  fresh  meat  and  milk.  It  is  a  disease  which  raged  among  sailors  in 
times  when  it  was  difficult  to  carry  these  things,  and  voyages  were  of  longer 
duration.  In  adults  it  is  now  rather  rare,  and  occurs  only  among  the  very 
poor,  or  in  conditions  of  isolation  where  fresh  food  is  not  obtainable.  It  is 
still  observed  in  children,  especially  when  they  must  be  artificially  fed.  The 
scurvy  or  scorbutus  of  adults  seems  to  be  identical  with  the  infantile  scurvy 


922 


TEXT-BOOK    OF    PATHOLOGY 


r 


I 


or  M  oiler-Barlow's  disease  of  children,  except  in  some  trifling  details  which 
depend  upon  anatomical  differences.  It  may  be  experimentally  produced 
in  animals  by  intentional  feeding  with  a  "scorbutic" 
diet,  and  prevented  or  cured  by  giving  the  antiscor- 
butic substances.  The  lesions  in  animals  are  iden- 
tical with  those  in  man. 

Among  antiscorbutic  substances,  lemon-  and  lime- 
juice  are  well  known.     They  resist  heating,  are  acid, 
,_  and  keep  well.     Extracts  of  vegetables,  such  as  cab- 

bage and  potatoes,  or  dandelions  are  effective,  but 
deteriorate  on  standing,  are  alkaline,  and  are  de- 
stroyed by  heating.  The  beneficial  properties  of 
milk  are  destroyed  by  heat.  Attempts  to  isolate 
the  active  substance  have  as  yet  led  to  no  clear  re- 
sult. 

The  lesions,  which  develop  in  the  course  of  a  few 
weeks  or  months  of  the  unfavorable  diet,  affect  chiefly 
the  bones.  The  bone-marrow  loses  its  blood-forming 
elements  and  becomes  converted  into  an  oedematous 
fibrous  tissue  in  which  the  blood-vessels  and  osteo- 
blastic  cells  seem  relatively  few.  As  a  result,  bone 
formation  becomes  almost  stagnant  everywhere,  and 
since  the  resorption  of  bone  goes  on  normally,  the 
whole  structure  shortly  becomes  rarefied.  At  the 
epiphyseal  line  the  lack  of  proper  and  orderly  inva- 
sion of  the  cartilage  columns  is  very  marked  (Fig. 
457).  Sometimes  there  is  irregular  or  oblique  inva- 
sion, and  the  zone  of  osteogenesis  becomes  broad- 
ened where  there  is  a  network  of  capillaries,  but  this 
is  also  an  ineffectual  method  of  bone  formation. 
Usually  only  scattered  lamina?  are  produced,  and  in 
some  cases  a  sort  of  bony  wall  is  formed  transversely 
which  obstructs  further  ossification.  Haemorrhages 
occur  as  elsewhere  in  the  body,  in  the  joints,  under- 
neath the  periosteum,  and  in  the  substance  of  the 
bone-marrow.  The  periosteum  may  be  elevated 
from  a  large  part  of  the  shaft  of  the  bone  by  the  effu- 
sion of  blood  (Fig.  458).  Periosteal  growth  of  bone 
tends  to  replace  the  clot,  but  the  cortex  continues  to 
be  rarefied.  The  disturbances  of  ossification  do  not 
depend  on  the  haemorrhages,  since  they  precede 
them  (Ingier). 

Healing  takes  place  after  the  proper  food  is  once  more  given  by  the 
rearrangement  of  the  disturbed  cartilage  cells  in  their  columnar  order,  by 
the  reappearance  of  blood-forming  cells  and  abundant  capillaries  with  osteo- 


Fig.  458.— Infantile 
scurvy.  Section  of  fe- 
mur showing  subperi- 
osteal  haemorrhages 
with  periosteal  bone 
formation.  There  are 
haemorrhages  in  the 
bone-marrow  and  dis- 
tortion of  the  line  of 
ossification  at  the 
lower  end. 


PAGET'S  DISEASE  (OSTEITIS  DEFORMANS)  923 

blasts  in  the  impoverished  bone-marrow,  which  then  go  on  to  the  normal 
processes  of  ossification.  The  disease  is  quite  different  from  rickets,  in 
which  the  chief  feature  is  the  absence  of  calcification  of  the  cartilage,  and 
the  consequent  rapid  ingrowth  of  capillaries  which  form  osteoid  tissue,  in 
the  lack  of  calcium. 

LITERATURE 

Aschoff  and  Koch,  W. :  Skorbut,  Jena,  1919. 
Schmorl:  Ziegler's  Beitrage,  1901,  xxx,  215. 
Hoist  and  Frohlich:  Ztschr.  f.  Hyg.,  1912,  Ixxii,  1. 
Ingier:  Frankf.  Ztschr.  f.  Path.,  1913,  xiv,  1. 
Hess  and  others:   Proc.  Soc.  Exp.  Biol.  and  Med.,  1914,  xi,  130;  1916,  xiii,  145;  1918, 

xv,  74,  141.     Amer.  Jour.  Dis.  of  Child.,  1914,  viii,  386;  1916,  xii,  152;  1917,  xiii, 

98;  1917,  xiv,  337. 

OSTEOGENESIS  IMPERFECTA 

Osteogenesis  imperfecta  is  a  condition  in  which,  in  infants  and  young  chil- 
dren, multiple  fractures  of  the  ribs  and  long  bones  occur.  Niklas,  in  describ- 
ing a  still-born  infant  in  whom  there  were  more  than  60  fractures,  most  of 
them  produced  some  time  before  birth,  regards  the  process  as  different  from 
osteopsathyrosis  or  osteogenesis  imperfecta  tarda,  which  occurs  in  adult  life 
and  the  nature  of  which  is  still  doubtful.  Study  of  the  bones  in  osteogenesis 
imperfecta  shows  normal  cartilage  with  normal  preparatory  calcification,  a 
normal  line  of  ossification,  with  normal-looking  osteoblasts.  These,  how- 
ever, must  function  imperfectly,  since  the  lamellae  of  bone  are  extremely 
delicate  and  thin.  Periosteal  bone  formation  is  greatly  reduced,  and  many 
lamellae  of  the  cortex  are  disconnected  and  run  transversely.  Resorption  of 
bone  is  normal  in  the  presence  of  this  faulty  or  deficient  apposition — hence 
the  numerous  fractures.  Niklas  found  a  hyperplastic  thyroid  and  ovaries, 
and  suggests  the  possibility  that  disturbances  of  internal  secretion  may  be 
concerned. 

LITERATURE 

Bamberg  and  Huldschinsky :  Jahrb.  f.  Kinderheilk.,  1913,  Ixxviii,  Ergnzngsheft.,  214. 
Hart:    Ziegler's  Beitrage,  1914,  lix,  207. 
Niklas:  Ibid.,  1915,  Ixi,  101. 

FACET'S  DISEASE   (OSTEITIS  DEFORMANS) 

In  1876  Paget  described  a  disease  in  which  the  bones  of  the  extremities  and 
of  the  skull  became  greatly  thickened,  and  to  some  extent  softened,  so  that 
bowing  of  the  legs  occurred.  The  enlargement  of  the  head  was  extreme, 
and  the  person  sank  in  stature.  Many  cases  of  this  disease  have  been 
studied,  and  although  the  cause  is  still  unknown,  the  anatomical  changes 
are  fairly  clear.  It  begins  usually  after  the  age  of  forty,  and  progresses 
slowly  with  some  pain  and  tenderness  in  the  altered  bones.  In  some  cases 
the  changes  are  unilateral  or  limited  to  one  or  two  bones.  In  those  in  which 
the  skull  and  facial  bones  alone  are  affected  the  condition  is  spoken  of  as 
leontiasis  ossea.  In  them  the  softened  bone  mav  later  assume  an  ivory-like 


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hardness.  The  tibiae  and  femora  commonly  become  thickened  and  bent 
forward.  The  skull  (Fig.  459)  may  reach  a  thickness  of  two  or  three  or  even 
four  centimetres,  and,  as  a  rule,  the  bone  is  easily  cut  with  a  knife.  Since  it 
is  a  disease  of  advanced  life,  there  is  no  question  of  disturbance  of  ossifica- 
tion along  the  epiphyseal  line.  Instead,  there  are  concerned  especially 
extensive  resorption  of  the  normal  bone  by  osteoclasts,  and  the  excessive 


Fig.  459. — Paget's  disease,  or  osteitis  deformans.    Thickened  skull  and   cross-section 
of  femur.     Marrow  cavity  filled  with  osteoid  tissue. 

new  formation  of  irregular  bony  lamellae  by  the  osteoblasts  which  accompany 
the  fibrous  marrow.  The  marrow  actually  loses  its  blood-forming  elements 
and  becomes  converted  into  a  vascular  fibrous  tissue  which  produces  much 
soft,  bone-like  tissue.  The  architecture  of  the  bone  is  disorganized,  and  the 
cortex  loses  its  dense  character  and  sharp  outline.  The  marrow  cavity  is 
encroached  upon  or  filled  completely,  and  a  thick  subperiosteal  layer  is 
formed  (Fig.  459).  In  this  new  tissue  the  lamellae  run  in  every  direction. 


PAGET'S  DISEASE  (OSTEITIS  DEFORMANS)  925 

Occasionally  there  are  cysts  or  spaces  in  it  filled  with  fluid,  or  tumor-like 
growths  may  appear.     There  is  no  halisteresis,  as  in  osteomalacia. 

Various  theories  have  been  proposed  as  to  the  causation,  and  many 
infectious  agents  have  been  held  responsible,  including  syphilis.  There  is 
little  evidence  for  these  views.  Others  have  thought  of  it  as  an  effect  of  the 
disturbance  of  some  internal  secretion.  DaCosta  and  his  coworkers  find 
that  there  is  a  retention  of  calcium,  magnesium,  and  phosphorus,  with 
excessive  excretion  of  sulphur,  and  state  that  there  have  been  analyses 
which  show  that,  in  spite  of  their  softness,  the  bones  are  especially  rich  in 
calcium. 

LITERATURE 

Paget:  Medico-Chir.  Transactions,  1877,  Ix,  37;  1882,  Ixv,  225. 
Higbee  and  Ellis:  Jour.  Med.  Research,  1911,  xxiv,  43. 
Watson:  Johns  Hopkins  Hosp.  Bull.,  1898,  ix,  133. 
Hurwitz:  Ibid.,  1913,  xxiv,  263. 
DaCosta  and  others:  Publications  of  Jefferson  Med.  College,  Phila.,  1915,  vi,  1. 


CHAPTER  XLVII 
ARTHRITIS  DEFORMANS 

Confusion  as  to  classification;  infectious,  traumatic,  neuropathic,  and  gouty  forms.  Ar- 
thritis deformans:  terminology.  1.  Proliferative  arthritis  deformans  or  progressive  poly- 
arthritis; clinical  and  gross  pathological  characters;  histology.  Spondylitis  of  Bechtereiv 
and  Marie.  2.  Degenerative  arthritis  deformans.  Clinical  and  gross  pathological  changes; 
histology.  Malum  coxae,  senile;  spondylitis  deformans. 

THE  recent  discussion  of  chronic  affections  of  the  joints  at  the  International 
Congress  of  Medicine  in  London  showed  how  confused  our  ideas  are  as  to 
the  classification  of  these  affections.  We  have  learnt  that  there  are  many 
infections  in  the  course  of  which  recognizable  organisms  lodge  in  the  tissues 
of  the  joints  and  produce  acute  or  chronic  forms  of  arthritis  and  periarthri- 
tis.  This  is  particularly  true  of  the  pyogenic  micrococci,  and  perhaps 
especially  of  the  gonococcus.  There  are  also,  as  is  well  known,  articular 
and  periarticular  inflammations  due  to  the  unknown  infectious  agent  of 
rheumatism  (and  to  avoid  confusion  we  shall  use  the  term  rheumatism  for 
that  affection  only  in  which  fever,  arthritis,  and  peri-,  endo-,  and  myocardi- 
tis are  found,  often  associated  with  tonsillitis  and  chorea). 

The  part  played  by  the  tubercle  bacillus  in  producing  destructive  and 
reactive  changes  in  joints  has  been  dwelt  upon,  and  there  are  other  cases  in 
which  the  spirochaeta  of  syphilis  plays  a  similar  role. 

These  are,  with  many  others,  the  infectious  forms  of  arthritis  usually 
easily  recognized  to  be  the  sequelae  of  the  existence  of  a  focus  of  similar 
infection  elsewhere.  While  this  primary  infectious  lesion  may  sometimes 
be  very  evident,  it  is  less  so  at  other  times,  as,  for  example,  those  cases  in 
which  pyorrhoea  alveolaris,  or  some  nasal  suppuration,  is  the  real,  though 
unsuspected,  source  of  the  spread  of  bacteria.  The  lesions  of  the  joints  are 
sometimes  suppurative  inflammations;  sometimes  there  are  only  effusions 
of  fluid;  adhesions  and  even  complete  ankylosis  of  fibrous  or  bony  character 
often  occur.  Traumatism,  especially  when  bacteria  are  introdued  into  the 
joint  cavity,  is  naturally  often  productive  of  an  arthritis,  and  in  haemophilia 
and  allied  conditions  there  arises  haemorrhage  into  the  joints  which  may 
simulate  in  its  effects  those  of  an  inflammation. 

In  the  course  of  some  diseases  of  the  spinal  cord,  notably  tabes  dorsalis 
and  syringomyelia,  there  occur  curious  changes  in  some  of  the  joints,  caus- 
ing complete  disorganization  not  only  of  the  joint  structures  themselves, 
but  of  the  neighboring  bones,  with  the  most  deforming  dislocations.  The 
tabetic  arthropathies  have  already  been  mentioned,  and  one  of  them  at 
least  represented  in  an  illustration  (Fig.  365) . 

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ARTHRITIS   DEFORMANS  927 

A  fourth  type  is  that  already  described  and  figured  in  speaking  of  gout,  in 
which  the  deposition  of  crystalline  masses  of  urates  in  the  joint  cartilages 
and  in  the  periarticular  tissues  is  the  cause  of  intense  inflammatory  reac- 
tions (Fig.  34). 

When  all  these  forms  of  arthropathy  have  been  considered,  there  still 
remain  many  which  cannot  be  regarded  as  definitely  belonging  to  any  of 
those  groups.  These  are  commonly  chronic  and  extremely  persistent  affec- 
tions, which,  although  they  may  sometimes  begin  suddenly  enough  with 
pain  and  fever,  and  even  in  quite  young  people,  drag  on  through  years,  and 
cause  the  most  extreme  deformities  and  disabilities,  which  are  permanent. 
Indeed,  they  appear  to  be  gradually  progressive  during  all  that  time  in 
producing  atrophy  and  disorganization  of  the  cartilages  and  of  the  bone 
itself,  accompanied  by  extraordinary  new  formations  both  of  cartilage  and 
bone,  as  well  as  of  scar  tissue,  in  and  about  the  joint. 

It  may  as  well  be  admitted  at  the  beginning  that,  since  every  author  who 
writes  upon  the  subject  seems  to  use  a  different  terminology,  it  is  extremely 
difficult  to  compare  their  results  and  to  decide  upon  the  limits  of  the  disease 
and  its  most  satisfactory  subdivision.  Barker  has  reviewed  the  subject, 
and  in  his  tabulations  he  separates  osteoarthritis  deformans  from  chronic 
progressive  polyarthritis  (the  rheumatoid  arthritis  of  Garrod).  German 
writers,  such  as  M.  B.  Schmidt  and  Kaufmann,  divide  arthritis  deformans 
into  three  groups:  (1)  A.  ulcer osa  sicca,  which  is  often  monarticular  and  is 
essentially  a  degenerative  and  destructive  process;  (2)  Arthritis  adhcesiva, 
in  which  many  joints  are  involved,  and  while  destructive  in  a  sense,  is  espe- 
cially characterized  by  the  growth  of  granulation  tissue  forming  adhesions 
and  even  a  firm  fibrous  ankylosis;  and  (3)  Arthritis  deformans,  in  which 
atrophic  or  degenerative  changes  in  the  cartilage  and  bone  are  accompanied 
by  extraordinary  new  formation  of  both  bone  and  cartilage  in  such  a  way 
that  the  ends  of  the  bone  forming  the  joint  become  profoundly  deformed 
and  often  dislocated.  Nichols  and  Richardson  regard  all  the  cases  as 
examples  of  one  disease,  but  recognize  an  essentially  degenerative  form  in 
contrast  with  another  in  which  proliferation  of  connective  tissue,  cartilage, 
or  bone  is  predominant.  It  seems  that  their  proliferative  form  must  cor- 
respond with  the  A.  adhaesiva,  while  their  degenerative  form  comprises  the 
other  two  classes.  In  the  same  way  in  comparing  their  terminology  with 
that  of  Barker  it  seems  that  the  proliferative  form  is  the  same  as  the  chronic 
progressive  polyarthritis  or  rheumatoid  arthritis,  while  the  degenerative 
form  is  co-extensive  with  osteoarthritis  deformans. 

Proliferative  Arthritis  Deformans. — The  first  part  of  these,  the  prolifera- 
tive form  of  arthritis  deformans  of  Nichols,  or  progressive  polyarthritis  of 
other  writers,  begins  often  with  fever  and  sudden  pain  in  the  joints,  almost 
as  in  an  attack  of  rheumatism.  It  affects  young  people  as  well  as  old,  and 
quickly  leads  to  lameness,  disability,  and  stiffness  of  the  joints.  It  affects 
many  joints,  including  those  of  the  knees,  shoulders,  etc.,  as  well  as  those  of 
the  hands  and  feet.  The  joints  become  enlarged,  but  remain  soft  and 


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doughy,  without  any  irregular  nodules  (Fig.  460).  X-rays  show  rarefac- 
tion of  the  bone,  which  may  be  due  to  a  withdrawal  of  calcium  salts,  but  no 
exostoses.  If  such  a  joint  be  opened,  its  articular  surface  is  found  partly 
covered  with  red  granulation  tissue  and  the  synovial  membrane  generally 
thickened.  At  a  later  stage  the  cavity  may  be  partly  or  completely  obliter- 


Fig.  460. — Proliferative  arthritis;    soft  swelling  of  the  joints  of  the  hand. 

ated  by  adhesions,  and  the  cartilages  partly  replaced  by  new  bone  or  by 
fibrous  tissue.  Fibrous  or  even  bony  ankylosis  may  occur,  and  in  extreme 
cases  the  two  bones  become  united  with  continuous  marrow  cavity. 
Partial  dislocations  are  sometimes  found,  but  even  in  such  late  stages  there 
is  no  new  formation  of  bony  nodules  about  the  joints. 


Fig.  461. — Proliferative  arthritis  with  ankylosis  of  phalangeal  joint.  Spongy  bone 
of  the  phalanx  (1).  Growth  of  fibrous  tissue  and  fibrocartilage  (2)  has  almost  entirely 
obliterated  the  joint  cavity  (3)  (Nichols  and  Richardson). 

Histologically,  the  following  is  found  to  occur.  As  a  result,  no  doubt,  of 
some  primary  injury,  there  is  formed  a  layer  of  granulation  tissue  on  the 
surface  of  the  synovial  membrane  and  spreading  over  the  cartilage  of  the 
articular  surfaces.  This  reduces  the  extent  of  exposure  of  the  cartilage,  and 
through  adhering  to  the  similar  granulation  tissue  of  the  opposite  side, 


ARTHRITIS   DEFORMANS  929 

causes  partial  obliteration  of  the  joint  cavity  (Fig.  461).  The  granulation 
tissue  also  extends  into  the  substance  of  the  underlying  cartilage  and  tends  to 
destroy  it.  The  bone  beneath  shows,  for  a  time  at  least,  no  morphological 
evidence  of  rarefaction,  but  the  bone-marrow  becomes  converted  into  an 
cedematous  fibrous  tissue  with  many  osteoblasts  and  capillaries.  This 
invades  the  cartilage  from  below,  causing  its  ossification  as  it  goes,  and  may 
penetrate  to  join  the  overlying  layer  of  granulation  tissue.  The  activity  of 
the  osteoblasts  may  cause  much  condensation  of  the  bone  beneath  the  carti- 
lage, but  it  also  causes  much  new  bone  formation  within  and  overspreading 
the  cartilage,  often  with  new  cartilage  formation  as  well,  so  that  Nichols 
even  pictures  a  bone  in  which,  while  part  of  the  original  cartilage  remains, 
there  is  a  layer  of  bone  surmounted  by  cartilage  covering  it.  All  these 
things  explain  the  tendency  to  the  formation  of  dense  fibrous  ankylosis 
which  may  be  more  or  less  complete.  One  type  of  this  disease  which  in- 
volves fibrous  or  bony  ankylosis  of  the  articular  processes  of  the  vertebrae, 
including  the  costovertebral  articulations,  is  particularly  striking.  Occasion- 
ally the  ligaments  are  ossified  also.  The  result  is  the  solidification  of  the 


Fig.  462. — Degenerative  arthritis;  characteristic  deformities  of  the  hands  with  nodular 

enlargements  of  the  joints. 

spinal  column  into  a  rigid  curved  structure,  concave  throughout  on  the 
anterior  aspect.  In  the  so-called  Bechterew's  disease  the  ankylosis  is  limited 
to  the  spine  or  part  of  it,  beginning  above,  but  in  other  cases  the  hip-  and 
shoulder-joints  are  also  involved  (spondylose  rhizomelique  of  Marie-Strum- 
pell). 

Degenerative  Arthritis  Deformans. — The  second  group,  the  degenerative 
form  of  Nichols  or  osteoarthritis  deformans  of  others,  is  more  particularly 
found  in  elderly  people,  and  is  often  an  affection  of  fewer  joints.  It  usually 
begins  insidiously,  without  fever,  and  progresses  slowly  to  extreme  deformi- 
ties and  disabilities  of  the  joints.  These  become  enlarged  by  the  appear- 
ance of  firm  or  hard  nodules,  and  are  tender  and  painful.  The  joints  of  the 
hands  and  feet  often  show  the  most  striking  changes,  although  the  knees 
and  hips  and  other  large  joints  are  equally  characteristically  affected  (Fig. 
462) .  The  hands  of  these  patients  present  an  especially  remarkable  appear- 
ance. There  is  flexion  of  the  fingers,  as  a  rule,  with  deflection  to  the  ulnar 
side.  Great  knobby  enlargements  of  the  knuckles  and  of  the  terminal 
phalangeal  joints  are  often  associated  with  relatively  slight  enlargement  of 
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the  middle  joints  of  the  fingers,  so  that  these  tend,  on  account  of  the  relaxa- 
tion or  atrophy  of  their  ligaments,  to  bend  backward  (Fig.  463) .  Between 
the  knuckles  and  the  wrist-joint  the  back  of  the  hand  over  the  metacarpal 
bones  sinks  into  a  hollow  over  which  the  skin  is  extremely  thin,  like  crinkled 
tissue  paper,  shiny  and  translucent,  so  that  the  veins  show  through  dis- 
tinctly. 

On  opening  one  of  these  joints  no  new  growth  of  granulation  tissue  is 


Fig.  463. — Degenerative  arthritis;  typical  deformity  of  the  hands,  with  ulnar  deflection. 

found,  nor  any  tendency  to  ankylosis.  Instead,  the  changes  are  predomi- 
nantly in  the  cartilage  and  secondarily  in  the  bone.  The  cartilage  is  at 
first  fibrillated  and  plush-like,  so  that  its  shaggy  surface  can  be  smoothed 
over  from  one  side  to  the  other.  This  causes  such  softening  and  disintegra- 
tion that  it  is  readily  eroded  away,  leaving  deep  ulcers  and  sometimes  expos- 
ing the  bone  (Fig.  464).  In  the  gross  specimen  this  uncovered  bone  is  in 
most  cases  found  to  be  smooth  and  hard.  Opposite  such  an  ulceration  of 


Fig.  464. — Degenerative  arthritis.    Phalangeal  joint,  showing  irregular  joint  surface, 
(1)  with  exposed  eburnated  bone  (2,2)  (Nichols  and  Richardson). 

the  cartilage  the  cartilage  of  the  other  joint  surface  tends  to  thicken  itself 
and  fill  up  the  space,  often  becoming  partly  or  completely  ossified  in  this 
process.  But  sometimes  both  of  the  opposed  surfaces  are  denuded  of  carti- 
lage and  bone  grinds  against  bone.  Ordinarily  this  sets  up  the  formation 
of  much  new  bone  in  the  substance  of  that  which  is  exposed,  and  the  surface 
layers  become  very  compact  and  hard.  In  such  joints  as  move  like  hinges 


ARTHRITIS   DEFORMANS 


931 


these  opposing  surfaces  of  dense  bone  grind  upon  one  another  until  they 
become  brilliantly  polished.  Sometimes  this  condition  arises  only  after 
inequalities  in  one  surface  have  been  filled  up  by  overgrowths  from  the  other 
which  have  become  bony.  Then  the  grinding  produces  parallel  grooves, 


Fig.  465. — Arthritis  deformans  (degen- 
erative form).  Head  of  femur  showing 
erosion  and  marginal  osteophyte  forma- 
tion. 


Fig.  466. — Arthritis  deformans  (de- 
generative form).  Extreme  erosion  of 
the  head  of  the  femur,  with  polishing 
and  exostosis  formation. 


which  are  fitted  by  ridges  of  the  opposite  side.  In  joints  which  work  in 
many  directions  these  parallel  grooves  do  not  appear  (Fig.  465).  Where 
the  bone  is  very  atrophic  and  unable  to  respond,  or  in  retired  places  where 
the  pressure  is  insufficient  to  stimulate  much  new  bone  formation,  the  sur- 


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Fig.  467. — Arthritis  deformans  (degenerative  form) .    Acetabulum  with  marginal  osteo 

phytes. 


Fig.  468. — Arthritis  deformans  (degenerative  form).     Shallow  acetabulum  surrounded 
by  marginal  osteophytes.     (Another  view  of  Fig.  467.) 


ARTHRITIS    DEFORMANS 


933 


face  does  not  become  smooth  and  shiny,  but  remains  porous,  as  though  one 
had  tried  to  polish  pumice  stone  (Walkhoff). 

All  round  the  margin  of  the  joint  (Fig.  466),  which  is  much  enlarged 
thereby,  there  is  usually  formed  a  series  of  cartilaginous  or  bony  nodular 
outgrowths.  These  may  interlock  in  such  a  way  as  to  limit  the  motion  of 
the  joint  very  seriously.  From  the  capsular  synovial  membrane  there  often 
hang  villous,  branched,  fat-containing  masses  which  are  spoken  of  as  lipoma 


Fig.  469. — Arthritis  deformans  (degenerative  form).    Erosion  of  head  of  femur  with 
dislocation  to  a  new  flattened  joint  surface  on  the  ilium. 

arborescens.  In  this  capsule,  also  calcified  or  cartilaginous  masses  of  tissue 
may  form  and  become  pedunculated.  Through  constriction  of  their  stalk 
they  may  come  to  be  free  in  the  cavity,  where  they  cause  much  disturbance 
(joint  mice). 

Histologically  the  first  changes  are  found  in  the  cartilage,  which  loses  its 
normal  elasticity  and  homogeneous  character  and  becomes  vertically  split 
into  fine  fibrillse.  The  cartilage  cells  degenerate  and  disappear.  The 
whole  layer  may  be  ground  away,  exposing  the  bone,  which  has  in  the  mean- 


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while,  by  the  activity  of  the  subchondral  osteoblasts,  become  eburnated  or 
condensed,  so  that  the  cancellous  laminae  lie  close  together  in  a  compact 
mass.  Great  proliferation  of  the  remaining  cartilage  around  the  margin  of 
the  joint  occurs,  and  into  this  cartilage  the  blood  capillaries  of  the  osteo- 
genic  marrow  grow,  converting  it  into  bone.  There  is  little  or  no  formation 
of  granulation  tissue  from  the  synovial  membrane  or  perichondrium  over 
the  surface  of  the  joint,  and  anky loses  do  not  occur.  The  erosion  can  go 


Fig.  470. — Spondylitis  deformans,  showing  fusion  of  the  bodies  of  the  vertebrae  by 
exostoses  which  stretch  across  the  intervertebral  discs.  The  smaller  articulations  show 
no  ankylosis,  in  which  this  condition  differs  somewhat  from  the  spondylose  rhizomelique. 

much  further  than  the  mere  thickness  of  the  original  layer  of  cartilage. 
The  exposed  bone  is  worn  away  deep  into  the  head  of  the  epiphysis  until  the 
most  extreme  deformity  is  produced,  constantly  made  up  in  a  futile  way  by 
the  growth  of  the  marginal  osteophytes  (Fig.  467) .  In  the  hip  such  changes 
produce  a  flattening  of  the  head  of  the  femur  into  a  mushroom-like  mass 
fringed  with  hanging  osteophytes  which  plays  in  the  partly  filled-up  and 
very  shallow  acetabulum  (Fig.  468),  or  the  erosions  may  be  more  lateral  and 
the  head  of  the  femur,  now  a  laterally  flattened  mass,  becomes;  dislocated  to 


ARTHRITIS   DEFORMANS  935 

some  point  on  the  ilium  where  it  lies  against  a  new-formed  acetabulum 
(Fig.  469) .  In  all  the  more  advanced  cases  of  this  type  there  is  much  rare- 
faction of  the  bones,  and  a  dried  femur  is  extraordinarily  light  as  compared 
with  one  from  a  normal  person.  In  one  case  which  I  observed  for  a  long 
time  the  bones  were  so  fragile  that  one  of  them  broke  on  lifting  the  body  of 
the  woman  from  the  bed  after  death.  A  section  showed  the  cancellous  bone 
to  be  extensively  atrophied  and  the  cortex  greatly  reduced  in  thickness. 
This  group  comprises,  beside  the  forms  in  which  the  joints  of  hands  and 
feet  are  affected  together  with  other  larger  articulations,  those  in  which 
erosion  of  the  cartilage  and  atrophy  of  the  bones  found  in  one  hip-joint 
(malum  coxce  senile) ,  and  those  in  which  the  cartilaginous  intervertebral 
discs  form  the  starting-point,  and  in  which  the  production  of  exostoses  and 
ecchondroses  round  the  centre  of  the  vertebrae  results  in  a  rigidity  of  the 
spinal  column  not  dependent  upon  ankylosis  of  its  smaller  articulations 
(spondylitis  deformans)  (Fig.  470). 

LITERATURE 

Pommer:    Mikr.  Befunde  bei  Arthritis  deformans,  Wien,  1913. 
Pribram:  Spez.  Path.  u.  Therapie  v.  Nothnagel,  1902,  7ter  Theil,  v. 
Kimura:   Ziegler's  Beitrage,  1900,  xxvii,  225. 
v.  Stubenrauch:   Munch,  med.  Woch.,  1914,  Ixi,  1494,  1565. 
Barker:  XVII.  Internat.  Cong,  of  Med.,  London,  1893,  vi,  Part  I,  253. 
Nichols  and  Richardson:  Jour,  of  Med.  Research,  1909,  xxi,  149. 
Walkhoff :  Verb.  Dtsch.  Path.  Gesellsch.,  1906,  ix,  229. 


CHAPTER  XL VIII 
TUMORS 

General  nature  of  tumors;  difficulty  of  classification.  Fibromata.  Neurofibromata, 
keloids.  Lipomata.  Chondromata.  Osteomata.  (Xanthomata.)  Myomata;  leiomyomata, 
rhabdomyomata . 

General  Nature  of  Tumors. — It  seems  quite  impossible  to  discuss  the  gen- 
eral nature  of  tumors  or  to  attempt  any  definition  of  a  tumor  until  after 
some  survey  of  their  varying  anatomical  characters  and  modes  of  growth 
is  made.  In  the  meanwhile  it  may  be  said  that  they  are  masses  of  tissue 
resembling,  but  not  perfectly  identical  with,  the  normal  tissues,  which  grow 
without  any  regard  for  the  laws  which  govern  and  restrain  the  growth  of 
normal  tissue.  They  are  supplied  with  blood-vessels  and  a  sufficient  sup- 
porting framework  by  the  host,  and  derive  their  nourishment  from  the 
circulation  of  the  host.  Therefore,  like  any  parasite,  they  are  harmful  to  the 
person  in  whose  body  they  grow,  but  the  injury  which  they  do  becomes 
intolerable  when  they  not  only  absorb  this  essential  nourishment,  but  also 
invade  and  destroy  the  normal  tissues.  In  olden  times  they  were  actually 
looked  upon  as  parasites  foreign  to  the  body,  but  such  a  vague  idea  was 
forced  to  disappear  when  Johannes  Miiller  showed  that  they  were  always 
composed  of  tissue  of  their  host.  If,  now,  we  speak  of  a  fibrous  tumor  as  a 
fibroma,  a  fatty  tumor  as  a  lipoma,  and  cartilaginous  or  bony  tumors  as 
chondromata  or  osteomata,  it  is  rather  because  their  tissues  closely  resemble 
fibrous,  fatty,  cartilaginous,  or  bony  tissue,  than  that  we  can  actually  trace 
their  origin  to  these  tissues.  Our  classification  is,  therefore,  rather  a  tissue 
of  assumptions  than  one  formed  on  a  true  histogenetic  basis.  Probably  it 
is  -true  that  an  epithelioma  is  definitely  derived  from  the  epithelium  in 
which  it  began,  and  a  fibroma  from  the  preexistent  connective  tissue.  It 
would  be  difficult  to  conceive  of  any  other  explanation,  but  the  absolute 
proof  is  not  at  hand.  Classification  is  at  best  unsatisfactory  on  a  histo- 
genetic basis,  since  so  often  we  cannot  make  a  good  guess  at  the  tissue  which 
the  tumor  most  resembles,  and  since  then,  in  so  many  cases,  we  have  no 
clue  as  to  the  point  from  which  it  actually  sprang.  It  is  greatly  aided  by 
observations  on  the  histological  characters  of  the  new-growths,  and  in  our 
ignorance  of  their  aetiology,  we  adopt  a  subdivision  in  which  the  type  of  the 
tissue  and  the  mode  of  growth  form  the  main  lines  upon  which  separation 
into  classes  is  carried  out.  Such  a  classification  will  be  given  (p.  1090)  after 
we  have  examined  the  tumors  themselves. 

936 


FIBROMATA 


937 


FIBROMATA 

A  fibroma  is  a  tumor  composed  of  tissue  which  resembles  more  or  less 
closely  one  of  the  many  types  of  normal  connective  tissue.  There  is  such 
variety  in  the  relations  of  intercellular  substance  and  cells  in  these  normal 
types  (tendon,  fascia,  areolar  tissue,  dermis,  etc.)  that  it  is  not  surprising 
that  the  fibrous  tumors,  which  can  diverge  in  every  way  from  the  character 


•>  e 

c  *    y*     ** 

V  ^*"  *•• 


'  x    /     ''  '/      ;«^.  <rs  «  a^o 

'MW$$ 
•*\     ?&ftf 

'     ' ,  /  ;r;'  ''Ss00»t96 


Fig.  471. — Types  of  fibroma.  C,  Nasal  polyp  or  oadematous  fibroma.  The  others 
(A,  B,  D,  E)  are  fibromata  of  different  consistence,  formed  in  various  situations  in  the 
body. 

of  the  tissue  from  which  they  may  be  supposed  to  arise,  may  show  a  much 
greater  variety.  In  every  case  one  is  impressed  by  the  purposeless  arrange- 
ment of  the  fibres,  which  stand  in  no  especial  relation  to  adjacent  tissues,  as 
they  do  in  normal  connective  tissue,  but  are  merely  woven  together  in  a 
mass.  Some  fibromata  are  extremely  soft  and  loose  in  texture — others  are 
dense  and  hard  (Figs.  471  and  472).  When  the  intercellular  fibres  are  little 


938 


TEXT-BOOK   OF   PATHOLOGY 


developed  and  the  tumor  is  made  up  chiefly  of  closely  packed  cells,  it  may  be 
found  that  its  growth  is  rapid  and  invasive,  and  that  the  tumor  should  really 
be  called  a  sarcoma.  This  is  one  of  the  points  at  which  mere  histological 
examination  may  fail  to  afford  a  correct  interpretation  and  the  biological 
characters  must  be  known.  To  coin  for  such  tumors  the  name  fibrosarcoma 
is  probably  only  to  add  to  the  difficulties  of  classification. 


'4*    0*  >'*«;    %T>     m  ^  UQ   **\l ^^AT*1***^  «-"     T^^t^V^ 


•    -  f       r      V 

>    f        ^     '.  M    >  s- 
*<j,  ^.yx    tv'  04-.> 


Fig.  472.—  Types  of  fibroma: 


(a)  Cellular  fibroma  resembling  a  spindle-cell  sarcoma, 
but  benign;  (d)  keloid. 


Fibromata  occur  almost  anywhere  in  the  body  and  are  frequently  mul- 
tiple. They  arise  most  commonly  in  the  skin,  the  fasciae,  and  the  inter- 
muscular  tissues,  about  the  joints  or  in  connection  with  nerves.  In  the 
internal  organs  they  are  found  in  the  submucosse,  in  the  kidney,  ovaries, 
etc.,  but  in  many  cases,  especially  in  the  breast  and  uterus,  the  excessive 
growth  of  fibrous  tissue  accompanies  that  of  other  cells,  such  as  epithelium 
or  smooth  muscle,  and  although  such  tumors  are  commonly  spoken  of  as 


FIBROMATA 


939 


adenofibromata  or  fibromyomata,  it  seems  probable  that  they  are  rather  to 
be  regarded  as  tumors  of  epithelium  or  muscle  with  merely  a  very  abundant 
stroma.  Fibromata  of  the  skin  are  sometimes  hard,  solid  tumors  embedded 
deep  in  the  skin  and  extending  into  the  subcutaneous  tissue  (Fig.  473). 
One  which  was  studied  after  its  removal  by  operation  formed  a  thick  cap 
over  the  whole  scalp,  projecting  down  with  thick  rounded  edges  as  far  as 
the  ears.  It  was  so  rigid  and  so  densely  connected  with  the  skin  that  much 


Fig.  473. — Subcutaneous  hard  fibroma. 

skin  had  to  be  grafted  to  cover  the  skull  after  its  extirpation.  Others  are  soft 
and  project  above  the  skin  surface,  often  hanging  by  a  relatively  thin  stalk 
(Fig.  474).  Occasionally  very  large  tumors  composed  of  soft  fibrous  tissue 
are  found  hanging  by  a  long  stalk  from  the  labium  majus  or  from  some  other 
site  about  the  external  genitalia.  Single  tumors  of  this  sort  occur,  but  the 
most  characteristic  form  is  that  described  as  fibroma  molluscum,  in  which 
great  numbers  of  soft,  partly  pedunculated  nodules  are  scattered  over  the 


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TEXT-BOOK   OF   PATHOLOGY 


whole  body  (Fig.  475).  This  condition  is  often  called  von  Recklinghausen's 
disease,  and  it  has  been  learned  that  it  is  a  more  complicated  condition  than 
might  appear  at  first  sight.  It  is  congenital  or  hereditary,  although  the 
nodules  may  become  conspicuous  only  in  later  life.  There  are  areas  of 
pigmentation  scattered  among  them,  and  the  nodules  themselves  are  devel- 
oped around  nerves  in  the  substance  of  which  fibrous  masses  also  appear. 
Dissection  of  such  a  mass  will  often  reveal  a  cutaneous  nerve  embedded  in 
loose  fibrous  tissue  and  beaded  along  its  course  by  small  denser  fibromata 

which  spread  apart  its  fibres.  There 
is  also  in  some  cases  a  peculiar  re- 
laxation of  the  skin,  usually  over 
the  scalp,  which  allows  great  folds  to 
hang  down  over  the  ears  or  over  the 
face.  In  such  folds  similar  nerves 
beaded  with  fibromata  have  been 
found.  Fabyan  found  no  nerves  in 
the  tumors  in  his  case. 

Keloids  are  extremely  dense,  scar- 
Jike  tumors  which  appear  in  some 
people  (especially  in  negroes)  in  the 
scars  of  wounds.  Even  when  the 
wound  has  been  very  slight  great 
nodules  may  result.  I  have  seen  one 
or  two  negresses  in  whom  puncture 
of  the  ear-lobes  for  earrings  had  set 
up  the  formation  of  great  lobulated 
keloids.  In  other  cases  scratches, 
burns,  or  even  healed  acne  pustules 
ceem  sufficient  to  start  the  growth. 
Extirpation  leaves  another  scar  in 
which,  of  course,  the  process  may 
repeat  itself.  It  seems  that  there 
must  be  some  individual  predisposi- 

Fig.    474.-Small   soft    pedunculated    fi-      tion  in  such  cases  for>  of  course>  this 
broma  of  the  skin.  does  not  happen  in  every  one.    The 

tumors  are  composed  of  very  dense 

fibrous  tissue  in  which  blood-vessels  and  cells  are  far  apart  (Fig.  472,  d). 
In  the  nose  fibromata  grow  in  clusters  from  the  nasal  septum,  pushing  up 
the  Schneiderian  membrane  to  cover  them.  These  become  extremely  oede- 
matous  since  they  are  loose  in  texture  and  hang  in  the  cavity  of  the  nose  as 
translucent,  rather  turgid  rounded  bodies  almost  like  white  grapes  (nasal 
polyps).  They  cause  obstruction  of  the  air-passage  and  are  exposed  to 
trauma.  Microscopically  they  are  found  to  show  sparsely  arranged  con- 
nective-tissue cells,  but  are  infiltrated  with  all  sorts  of  wandering  cells, 
including  many  eosinophiles  and  the  most  beautiful  mast  cells  (Fig.  471,  c).. 


FIBROMATA 


941 


In  connection  with  fasciae,  ligaments,  and  periosteum  there  are  found 
larger,  dense  fibrous  tumors  in  which  the  cells  and  their  abundant  inter- 
cellular fibres  are  closely  packed  together  in  a  hard  mass  which,  on  section, 
shows  a  shining,  pearly  white  surface.  These  too  may  present  softer  areas, 
but  usually  the  consistence  is 
pretty  uniform.  Sometimes  the 
fibres  are  gathered  into  interlacing 
bundles,  an  arrangement  which  is 
particularly  common  in  those  which 
are  associated  with  the  sheaths  of 
the  nerves.  These  tumors,  often 
mistakenly  called  neuromata,  are 
sometimes  found  in  large  numbers 
even  along  the  course  of  the  larger 
nerves,  and  not  only,  as  in  the  case 
of  von  "Recklinghausen's  disease, 
as  small  nodules  near  the  termin- 
ation. Dr.  Prudden  has  described 
one  case  from  which  specimens  are 
preserved  in  the  museum,  and  his 
illustrations  show  the  extraordin- 
arily wide  distribution  of  the  tu- 
mor masses.  Here  the  nerve-fibres 
are  stretched  out  over  the  nodules 
so  as  to  enclose  them.  Such  rela- 
tions with  the  nerves  seem  com- 
moner than  with  the  blood-vessels, 
although  there  are  found,  in  the 
nose  and  elsewhere,  fibromata  of 
extraordinary  vascularity. 

Pure  fibromata  are  rare  in  the 
uterus  and  in  the  mammary  gland. 
In  the  ovary  they  occur  in  the  form 
of  hard  nodules  which  may  reach 
a  great  size.  These  show  micro- 
scopically closely  arranged  spin- 


Fig.  475. — Multiple  neurofibromatosis 
(von  Recklinghausen's  disease).  Observe 
the  great  relaxed  mass  of  skin  which  hangs 
from  the  side  of  the  head. 


die-shaped  connective-tissue  cells 
with  compact  intercellular  fibres. 
In  the  kidney  there  are  often  seen 
rather  small,  round,  grayish  white 

glistening  nodules  embedded  in  the  cortex  or  pyramids  and  crowding  aside 
the  tubules.  These  on  section  show  an  atypical  fibrous  tissue  with  vary- 
ing proportions  of  cells  and  fibrous  material.  So  too  in  the  submucosse 
of  the  alimentary  tract  firm  gray  nodules  are  found  lifting  up  the  mucosa. 
While  some  of  these  are  true  fibromata,  most  of  them  are  made  up  of 
smooth  muscle  with  a  fibrous  stroma. 


TEXT-BOOK   OF   PATHOLOGY 

Mention  is  usually  made  in  this  connection  of  elephantiasis  and  of 
localized  giant  growths,  although  it  seems  that  they  have  little  to  do  with 
tumor  formation.  Elephantiasis,  aside  from  the  type  produced  by  filariaa, 
is  probably  congenital  and  consists  in  the  enormous  enlargement  of  an 
extremity  with  cedema  and  fibrous  induration  of  the  subcutaneous  tissue 
and  extreme  thickening  of  the  skin,  which  becomes  very  rough  and  folded. 
Many  of  these  conditions  seem  to  be  caused  by  inflammatory  processes, 
while  others  are  related  to  von  Recklinghausen's  multiple  neurofibroma- 
tosis  and  occur  with  it.  Partial  gigantism,  in  which  one  extremity  is 
merely  developed  on  a  larger  scale  than  the  rest,  is  evidently  the  result  of 
disturbances  of  embryonic  development. 

LITERATURE 

Fibroma.— Gergo:   Virch.  Arch.,  1913,  ccxiii,  317. 
Neurofibromata. — Harbitz:  Arch.  Int.  Med.,  1909,  iii,  32. 

Helmholtz  and  Gushing:  Amer.  Jour.  Med.  Sci.,  1906,  cxxxii,  355. 


LIPOMATA 

These  are  tumors  composed  of  fat  tissue  and  occurring  in  the  form  of 
circumscribed  and  sometimes  lobulated  flattened  or  rounded  masses.  Since 
fat  tissue  is  not  very  sharply  characterized  histologically,  it  is  difficult  to 
make  out  differences  between  that  which  occurs  in  tumors  and  the  normal 
fat.  In  some  cases,  however,  the  fat  is  associated  with  such  a  dense  fibrous 
growth  that  the  name  fibrolipoma  may  be  appropriate.  In  others  an  exces- 
sive vascular  supply  may  suggest  the  name  angiolipoma. 

The  tumors  occur  most  commonly  in  the  subcutaneous  tissue,  and  especi- 
ally over  the  back,  the  neck  and  shoulders,  and  the  buttocks.  They  project 
as  rather  soft,  lobulated  masses  which  are  sometimes  quite  tender  or  even 
spontaneously  painful.  They  can  be  shelled  out  of  their  bed  in  the  tissue 
and  do  not  tend  to  recur.  Microscopically  there  is  merely  fat  in  hugely 
dilated  cells,  arranged  in  compact  lobules  held  together  by  the  fibrous 
stroma.  Coalescence  of  fat-cells  with  loss  of  their  walls  so  that  pools  of  oil 
are  formed  is  an  uncommon  occurrence.  Calcification  or  even  ossification 
in  necrotic  areas  is  sometimes  observed. 

Other  sites  for  lipomata  are  in  the  mesentery,  the  submucous  and  sub- 
serous  tissues  of  the  whole  alimentary  tract,  in  the  kidney,  heart,  uterus, 
and  even  in  the  meninges.  In  the  kidney  the  lipomata  are  usually  rather 
small,  but  a  few  larger  ones  have  been  studied  and  have  shown,  beside  the 
fat,  an  admixture  with  muscle  and  other  elements,  often  with  nodules  of 
adrenal-like  tissue. 

Very  interesting  are  the  symmetrical  multiple  lipomata  which  have  been 
mentioned  before  as  related  somehow  with  the  irregular  adiposis  dolorosa  of 
Dercum.  The  figure  (Fig.  451)  gives  the  impression  better  than  any  des- 
cription. These  are  often  tender  or  painful,  and  are  associated  with  mental, 
motor,  sensory,  and  trophic  disturbances  of  various  sorts.  Lyon  thinks 


CHONDROMATA 


943 


they  shade  off  into  the  more  general  adiposis  and  may  prove  to  be  due  to 
some  disturbance  of  internal  secretions. 

Lipomata  are  practically  invariably  slow-growing  tumors  which  increase 
from  within  themselves,  expanding  so  as  to  compress  surrounding  tissues  or 
to  project  on  the  body  surface. 

LITERATURE 
Lipoma. — Lyon:   Arch.  Int.  Med.,  1910,  vi,  28. 

Keenan  and  Archibald:  Jour.  Med.  Research,  1907,  xvi,  121. 
Ebner:   Beitr.  z.  kl.  Chir.,  1913,  Ixxxvi,  186. 
Schridde:   Ergebn.  d.  allg.  Path.,  1906,  x,  674. 


CHONDROMATA 

Tumors  composed  of  cartilage  of  a  somewhat  irregular  and  atypical  charac- 
ter occur  in  connection  with  preexisting  cartilage  in  the  joints,  in  the  bones, 
or  occasionally  in  the  bronchi. 
Those  which  spring  from  the 
bone  or  skeletal  cartilage 
appear  as  nodular  tumors 
(Fig.  476)  composed  of  elastic, 
pale-bluish  cartilage  which  is 
covered  with  a  fibrous  envel- 
ope and  divided,  as  a  rule, 
into  lobules  by  a  framework 
of  connective  tissue  which 
bears  blood-vessels.  They  j 
are  broadly  connected  with 
the  bones  or  cartilage,  or 
are  partly  embedded  in  the 
bone,  occupying  much  of  its 
marrow  cavity  and  extending 
through  the  cortex  to  project 
upon  the  surface.  The  bone 
is  often  greatly  distended  by 
such  a  mass,  and  especially 
in  the  case  of  the  fingers  be- 
comes greatly  distorted  (Fig. 
477).  Large  kimors  of  this 
kind  are  not  uncommon  in 
the  hand,  where  several  fin- 
gers may  be  converted  into  unwieldy  lumps  which  become  absolutely 
useless.  In  the  pelvis  enormous  cartilaginous  masses  have  been  seen, 
projecting  from  the  symphysis  pub  is  or  from  the  sacro-iliac  synchondrosis, 
and  so  occupying  the  cavity  of  the  pelvis  as  to  obstruct  childbirth.  Simi- 
lar tumors  are  described  for  the  scapulae,  the  ribs,  the  hyoid  bone,  etc. 


Fig.  476. — Chondroma  of  phalanx. 


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TEXT-BOOK   OF    PATHOLOGY 


Chondromata  arising  in  the  trachea  or  bronchi  are  often  flattened  clumps 
of  tissue  which,  even  though  they  lie  in  the  spaces  between  the  cartilaginous 
rings,  are  found  to  have  a  connection  with  them  or  with  the  perichondrium. 
In  other  cases  large  nodules  have  been  observed  blocking  the  bronchus  or 
extending  into  the  lung  tissue. 

Since  normal  cartilage  is  not  vascular  and  depends  for  its  nutrition  upon 
the  absorption  of  fluid  from  the  vessels  of  the  perichondrium,  no  great  bulk 
of  it  can  maintain  itself  alive.  In  the  cartilaginous  tumor,  however,  the 
tissue  is  in  relatively  small  districts  well  supplied  with  nourishment  from 
abundant  blood-vessels  which  accompany  its  fibrous  stroma.  The  inter- 
cellular substance  is  more  variable  in  consistence  and  less  dense  than  that 
of  normal  cartilage,  and  often  shows  a  distinctly  fibrillar  structure.  The 

cells  vary  greatly  in  size,  and  in  their  arrange- 
ment in  groups,  and  thus  differ  markedly  from 
those  of  normal  cartilage  (Fig.  478),  but,  on 
the  whole,  the  resemblance  is  very  close,  and 
as  a  rule  it  is  not  easy  to  be  sure  of  their  tumor 
nature  without  recourse  to  information  about 
the  general  features  of  the  growth.  Blood- 
vessels sometimes  grow  into  the  cartilage,  as  in 
normal  endochondral  ossification,  and  convert 
it  into  bone,  so  that  the  chondroma  eventually 
becomes  a  kind  of  osteoma.  Usually  a  layer  of 
cartilage  remains  over  the  surface.  In  other 
cases  extensive  calcification  occurs  in  patches, 
or  the  tumor  may  undergo  a  softening  which 
leaves  a  cavity  filled  with  a  gelatinous,  semi- 
fluid material  in  which  large  radiating  cells  are 
found.  Actual  cysts  are  formed  finally  if  the 
liquefaction  continues. 

Virchow  and  others  have  attempted  to  show 
that  since  these  tumors  are  commonly  found 

in  young  people,  they  may  have  arisen  from  congenitally  misplaced  carti- 
lage or  from  disarranged  cartilage  islands  cut  off  in  the  ordinary  process 
of  endochondral  ossification.  Such  little  islands  do  occur  and  remain  un- 
changed. Virchow  thought  for  a  time  that  rickets,  with  its  exaggerated 
and  disorderly  process  of  ossification,  might  present  an  especially  favor- 
able condition  for  such  displacement  of  cartilage,  but  the  cases  seldom, 
if  ever,  show  signs  of  healed  rickets.  It  seems  hardly  necessary  to 
insist  upon  the  existence  of  such  latent  displaced  cartilage  islands,  however, 
since  periosteum  and  endosteum  are  so  readily  capable  of  producing  carti- 
lage whenever,  as  in  a  fracture,  the  new  formation  of  tissue  is  required. 
Since  we  have  other  atypical  tumor  growths  arising  everywhere  without 
special  preparatory  displacement  of  the  tissue  which  exactly  corresponds 
with  them,  it  is  not  difficult  to  imagine  the  growth  of  a  cartilaginous  tumor 


Fig.  477.— Chondroma  of 
phalanx.  The  tumor  appears 
to  begin  in  several  places, 
perforating  the  cortex  and 
lifting  up  the  periosteum. 


OSTEOMATA 


945 


from  the  cells  which  form  bone  by  the  way  of  cartilage.  So,  too,  in  the  lung 
the  new  cartilage  growths,  which  are  often  called  ecchondroses,  when  they 
seem  to  represent  a  mere  hyperplasia,  are  easily  derived  from  the  peri- 
chondrium. 

Combination  of  cartilage  with  other  tumor  elements  is  frequently  found. 


Fig.  478. — Chondroma  with  irregular  blood-vessels  and  atypical  bony  areas. 

LITERATURE 
Chondroma. — Ribbert:   Geschwulstlehre,  Bonn,  1904. 

Ehrenfried:  Jour.  Amer.  Med.  Assoc.,  1915,  Ixiv,  1642. 
Johns  Hopkins  Hosp.  Bull.,  1913,  xxiv,  210. 


OSTEOMATA 

It  has  already  been  stated  that  at  many  points  throughout  the  body  ossifica- 
tion of  tissue  may  take  place  if  degenerative  changes  and  deposition  of 
calcium  salts  have  occurred.  At  points  in  relation  with  cartilage  and  bones, 
instances  have  already  been  met  with  in  which,  as,  for  example,  in  the  case 
61 


946 


TEXT-BOOK    OF    PATHOLOGY 


of  arthritis  deformans,  rather  extensive  new  bone  formation  occurs.  Injuries 
to  muscles  and  fasciae  and  inflammations  of  various  sorts  seem  capable  of 
giving  rise  to  some  change  which  finally  leads  to  bone  formation.  Thus  it 
is  said  that  cavalrymen  acquire  bony  plates  in  the  muscles  of  the  insides  of 
their  thighs,  and  soldiers  and  others,  similar  plates  in  their  deltoid  muscles 
where  gun  or  heavy  burden  rests.  It  is  difficult  to  regard  such  things  as 
tumors,  since  they  seem  to  be  merely  an  osteoplastic  healing  process  which 

follows  upon  injury  to  the 
tissues.  The  so-called  pro- 
gressive myositis  ossificans 
which,  after  inflammatory 
stages,  ends  in  the  forma- 
tion of  extensive  bony  shells 
in  the  muscles  is  doubtless 
similar  in  character. 

More  difficult  to  interpret 
properly  are  the  multiple  ex- 
ostoses  which  appear  about 
the  epiphyses  in  young  per- 
sons and  are  left  along  the 
shaft  as  the  bone  grows. 
They  are  often  partly  carti- 
laginous for  a  time,  but  in 
the  end  are  bony.  They 
can  stretch  some  distance, 
and  sometimes  interarticu- 
late  in  a  way,  with  one  an- 
other, or,  by  fusing,  limit 
the  motion  of  the  extremi- 
ties. These  growths  are 
often  observed  to  occur  in 
one  family  and  seem  to  have 
an  hereditary  element.  Of 
course,  any  collection  of 
bones  will  be  found  to  pre- 
sent at  least  a  few  examples 
in  which  extensive  exostoses 
are  found  in  the  form  of 

irregular,  rather  thin,  sharp  outgrowths,  but  these  are  usually  recognized 
to  be  the  accompaniments  of  an  old  fracture  or  of  some  long-standing 
inflammatory  disease.  Growths  of  this  kind  from  the  surface  of  a  bone 
are  called  exostoses;  those  which  appear  in  the  interior  of  a  bone,  enostoses, 
while  a  diffuse  thickening  of  the  bone  is  called  hyperostosis. 

The  nodules  of  bone  found  in  the  lungs  sometimes  reach  a  considerable 
They  are  thought  by  many  to  depend  upon  preexisting  inflammatory 


Fig.  479. — Large  osteoma  of  very  dense  texture 
surrounding  the  elongated  optic  nerve,  and  dislo- 
cating the  eye  by  extending  into  the  orbit.  The 
tumor  bulged  into  the  cranial  cavity,  and  over  it 
the  brain  was  adherent. 


OSTEOMATA 


947 


processes,  and  so  too  are  those  tiny  bone  masses  which  form  in  the  trachea 
and  roughen  its  mucosa.  These  are  not  in  direct  connection  with  the 
tracheal  cartilage  rings. 

Tumor-like  growths  of  bony  consistence,  usually  masses  more  or  less 
closely  connected  with  the  bones,  may  be  very  compact  and  hard,  "ebur- 
nated, "  or  soft  and  spongy.  Much  has  been  said  of  such  bony  growths  in 
other  connections,  and  it  will  suffice  to  recall  attention  to  the  rounded  masses 
of  osteoid  tissue  which  appear  on  the  skull  in  rickets  and  later  become  hard- 
ened into  bone ;  to  the  extensive  new  bone  formation  in  chronic  osteomyeli- 
tis around  the  areas  of  infection  and  in  the  neighborhood  of  ulcers  which 
overlie  such  bones  as  the  tibia.  Chronic  syphilitic  forms  of  periostitis  in 
the  same  way  lead  to 
the  production  of  rough 
periosteal  growths  which 
deform  the  bone.  Men- 
tion may  also  be  made  of 
the  so-called  osteophytes 
of  pregnancy,  which  are 
thin,  white,  chalk  -  like 
deposits  on  the  inner  sur- 
face of  the  skull.  These 
seem  to  be  reabsorbed  or 
merged  with  the  cranial 
bones  later,  and  are  prob- 
ably the  result  of  changes 
in  the  distribution  of  cal- 
cium which  characterize 
the  altered  metabolism 
of  pregnancy. 

Osteomata  or  bony  tu- 
mors in  which  the  bone 
is  growing  independently 
and  without  a  limited  aim 
are  rare.  They  some- 
times occur  in  connection 

with  the  long  bones  and  sometimes  with  pelvis,  shoulder-girdle,  etc.  Occa- 
sionally they  are  more  independent  of  the  skeleton  and  arise  in  tendons  or 
muscles  as  actual  growing  nodules.  It  appears  that  the  bones  of  the  skull, 
especially  about  the  nose  and  orbit  and  middle  ear,  offer  the  most  favorable 
chance  for  their  development,  and  it  is  not  infrequent  to  find  rounded 
masses  developing  in  the  nasal  cavity  from  the  ethmoid  or  other  bones  or  in 
the  accessory  nasal  sinuses.  These  sometimes  become  loose  and  are  known 
as  dead  osteomata.  One  which  we  studied  last  year  showed  a  compact, 
extremely  hard  mass,  which  had  grown  to  occupy  the  upper  maxilla,  and 
part  of  the  temporal  bone,  projecting  far  into  the  orbit  so  as  to  displace  the 


Fig.  480. — Ivory-like  exostosis  or  osteoma  of  skull. 


948  TEXT-BOOK   OF   PATHOLOGY 

eye.  When  sawed  through  (with  great  difficulty),  it  presented  a  perfectly 
smooth,  ivory-like  surface,  and  was  seen  to  project  in  all  directions  so  as  to 
occupy  space  in  the  cranial  and  other  cavities  (Fig.  479) .  There  are  other 
ivory-like  tumors  which  occur  like  buttons  on  the  skull,  and  sometimes  form 
hemispherical  masses  of  considerable  size .  They  are  usually  a  little  separated 
from  the  skull  around  the  edges  so  as  to  appear  pedunculated.  These  cause 
ho  especial  inconvenience  (Fig.  480). 

LITERATURE 

Osteoma—  E.  Bruckmann:  Virch.  Arch.,  1910,  cc,  433. 
Heymann:  Virch.  Arch.,  1886,  civ,  145. 
Zimmermann:  Dtsch.  Ztschr.  f.  Chir.,  1900,  Ivii,  354. 
Fischer:  Ergebn.  d.  allg.  Path.,  1906,  x,  678. 

XANTHOMA 

Although  commonly  described  with  tumors,  the  forms  of  xanthoma  seem  hardly  to  be 
true  tumors,  but  rather  the  result  of  local  or  wide-spread  accumulations  of  lipoid  sub- 
stances in  degenerated  cells.  Although  this  suspicion  is  not  justified  entirely  by  the 
histological  study,  it  does  seem  to  be  upheld  by  the  transient  character  of  many  of  these 
growths  and  by  their  usual  association  with  jaundice,  diabetes,  pregnancy,  etc.,  all 
conditions  in  which  the  lipoid  content  of  the  blood  is  altered. 

There  are  found — (1)  xanthoma  palpebrarum,  in  which  flat,  slightly  elevated  yellow 
patches  are  developed  on  the  eyelids.  These  contain  cholesterine  esters  with  other 
lipoids  in  large  cells  in  the  cutis.  These  are  thought  by  Pollitzer  to  be  degenerated 
muscle  cells;  (2)  multiple  xanthoma  which  resembles  (3)  xanthoma  diabeticorum  in 
forming  nodules  in  various  places  in  the  body,  composed  of  somewhat  similar  large 
lipoid-laden  cells,  together  with  connective-tissue  cells  and  a  fibrous  stroma.  These 
nodules  occur  also  in  the  internal  organs,  and  are  in  most  cases  associated  with  jaundice. 

LITERATURE 

Pollitzer:  N.  Y.  Med.  Jour.,  1899,  Ixx,  73. 
Sikemeier:  Frankfurter  Zeitschr.  f.  Path.,  1913,  xiv,  428. 

MYOMA 

The  term  myoma  is  applied  to  tumors  which  are  composed  largely  of  muscle, 
those  in  which  smooth  muscle  or  non-striated  muscle  constitutes  the  pre- 
dominant tissue  being  called  leiomyomata,  while  the  rather  more  compli- 
cated tumors,  which  contain  striated  muscle,  are  spoken  of  as  rhabdomy- 
omata.  Since  these  types  of  tissue  are  not  very  closely  related,  it  is  not 
surprising  to  find  that  the  corresponding  tumors  stand  very  far  apart. 

LEIOMYOMATA 

Tumors  composed  of  smooth  muscle  occur  very  commonly  in  the  walls  of 
the  uterus.  Although  they  are  found  elsewhere,  as  in  the  walls  of  the 
stomach  and  intestine,  in  the  bladder,  kidneys,  skin,  etc.,  they  are  only 
rarely  encountered  in  those  situations  and  constitute  a  group  of  little  impor- 
tance as  compared  with  those  of  the  uterus. 

Myomata  (or  fibromyomata)  of  the  uterus,  often  loosely  spoken  of  as 


MYOMA 


949 


fibroids,  appear  as  rounded  or  nodular  tumors  situated  in  the  uterine  wall, 
although  they  frequently  project  from  the  outer  surface  in  such  a  way  that 
they  seem  to  be  attached  to  the  uterus  by  a  slender  peduncle  only.  The 
thin  layer  of  uterine  muscle  which  envelopes  them  becomes  more  and  more 
inconspicuous  as  they  project  in  their  growth  from  the  uterine  surface.  On 
the  other  hand,  there  are  also  fibromyomata  which  project  into  the  cavity 
of  the  uterus,  carrying  with  them  a  very  thin  layer  of  the  uterine  muscula- 
ture and  the  mucosa.  They,  too,  become  pedunculated  and  hang  by  this 


Fig.  481. — Subperitoneal,  submucous,  and  intramural  myomata  of  the  uterus  (Kelly  - 

Cullen). 

stalk  in  the  cavity,  sometimes  projecting  from  the  external  os  uteri.  In 
these  three  positions  the  tumors  are  given  the  epithets  intramural,  sub- 
serous,  and  submucous. 

Uterine  myomata  vary  greatly  in  size,  some  being  found  embedded  in  the 
wall,  and  no  more  than  2  or  3  mm.  in  diameter,  while  others  reach  enormous 
dimensions.  Often  several  tumors  of  different  sizes  are  found  in  the  same 
uterus,  and  these  may  occupy  all  three  situations  (Fig.  481).  In  the  cases 
in  which  large  submucous  myomata  are  found,  the  cavity  of  the  uterus  is 


950  TEXT-BOOK   OF   PATHOLOGY 

greatly  enlarged  and  distorted  by  the  presence  of  the  mass,  and  indeed  this 
is  true  also  in  those  cases  in  which  large  tumors  occupy  an  intramural 
position. 

They  are  dense,  hard,  pearly-white  masses,  which  on  section  are  found  to 
be  sharply  marked  out  from  the  surrounding  uterine  musculature  by  pro- 
jecting above  its  cut  surface.  They  are  further  distinguished  from  it  by 
their  greater  density  and  by  their  poverty  in  blood-vessels,  for  whereas  the 
uterine  wall  is  rather  reddish-gray  and  vascular,  the  tumor  is  usually  com- 
posed of  whorls  of  fibres  intimately  woven  together  so  as  to  shine  with  a 
tendon-like  lustre,  reflected  separately  from  each  bundle,  and  is  much  more 
rigid  than  the  surrounding  tissue.  It's  blood-vessels,  although  sometimes 
rather  large  in  the  superficial  zone,  are  quickly  reduced  to  a  very  small 
calibre  as  they  penetrate  into  the  interior.  Clarke  has  shown  that  this 
vascularization  often  becomes  quite  inadequate  to  nourish  with  blood  the 
innermost  parts,  so  that  most  extensive  necroses  appear,  recognizable  as 
hyaline  areas  or  patches  in  which  calcification  or  even  bone  formation  has 
occurred.  Great  cyst-like  cavities  filled  with  brownish,  turbid  fluid  are 
also  found  as  a  result  of  the  disintegration  of  the  tissue. 

Such  tumors  grow  by  new  formation  of  tissue  from  within,  expanding  and 
compressing  adjacent  structures,  but  showing  no  tendency  to  invade  nor  to 
set  up,  by  metastasis,  similar  growths  in  distant  organs.  Nevertheless, 
they  may  cause  great  distortions  in  the  uterus  and  interfere  seriously  with 
its  function.  Although  childbirth  may  be  possible  when  the  tumor  is  not 
too  large,  or  when  it  is  situated  high  in  the  fundus  of  the  uterus,  it  may 
readily  be  understood  that  a  large  tumor,  especially  when  situated  low  in 
the  uterus,  can  effectively  obstruct  parturition.  Submucous  myomata 
tend  also  to  interfere  with  pregnancy  and  may,  in  case  pregnancy  does 
occur,  offer  a  serious  obstacle  to  the  birth  of  the  child. 

The  submucous  myomata  are  especially  productive  of  serious  symptoms 
at  all  times,  since  the  uterus  tends  to  expel  them  into  the  vagina,  exposing 
the  surface  to  infection.  Circulatory  disturbances  aid  in  causing  the  mass 
to  soften  and  disintegrate,  and  from  the  putrefying  tissue  absorption  of 
poisonous  substances  soon  leads  to  a  cachectic  condition  in  the  woman  who 
bears  such  a  tumor.  In  addition,  these  growths  usually  cause  frequent 
haemorrhages  from  the  uterus,  which  may  bring  about  extreme  anaemia. 

The  many  other  details  in  the  biology  of  these  tumors  may  be  read  in  the 
book  of  Kelly  and  Cullen  on  Myomata  of  the  Uterus,  in  which  a  great  wealth 
of  material  is  described.  One  of  the  most  interesting  phenomena  is  the 
formation  of  vascular  adhesions  between  large  subperitoneal  uterine  myo- 
mata and  the  omentum  or  intestine,  or  other  abdominal  organ,  after  which 
the  tumor  becomes  dependent  upon  that  organ  for  its  blood  supply  and  may 
even  be  separated  finally  from  all  connection  with  the  uterus  (parasitic 
myoma). 

Microscopically,  fibromyomata  are  found  to  be  composed  of  smooth 
muscle-fibres  arranged  in  parallel  rows  in  bundles  which  interlace  in  every 


MYOMA  951 

direction.  These  are  embedded  in  an  abundant  stroma  of  connective  tissue 
which  bears  the  blood-vessels.  According  to  the  proportion  of  muscle  to 
fibrous  stroma,  the  consistence  of  the  tumor  varies,  increase  in  the  fibrous 
tissue  adding  to  its  hardness.  The  muscle-fibres  are  recognizable  by  their 
rod-shaped  nuclei  and  by  their  relatively  plump  cell-body,  which  takes  a 
greenish  color  with  Van  Gieson's  stain,  in  contrast  with  the  bright  red 
fibrous  stroma.  Of  course,  the  actual  bodies  of  the  connective-tissue  cells 
stain  greenish  yellow  also,  but  they  are  rather  sparsely  scattered  in  the 
stroma. 

Several  theories  as  to  the  origin  of  these  tumors  have  been  advanced,  but 
none  are  as  yet  firmly  established.  While  it  seems  probable  that  they 
arise  from  abnormal  portions  of  the  uterine  musculature  itself,  there  are 
those  who  assert  their  origin  from  the  musculature  of  the  walls  of  the  blood- 
vessels. The  fact  that  myomata  relax  and  soften  during  pregnancy,  recover- 
ing their  hardness  afterward,  seems  to  point  to  their  relation  to  the  uterine 
musculature. 

The  greatest  interest  has  been  roused  by  certain  rather  diffuse  myoma- 
tous  tumors  which  occur  in  the  uterine  wall,  especially  at  the  angle  where 
the  Fallopian  tube  enters,  and  also  in  the  tube  itself  and  in  the  round  liga- 
ment. These  are  peculiar  in  containing  epithelium-lined,  gland-like  cavi- 
ties scattered  in  the  mass  of  smooth  muscle.  They  were  called  adenomy- 
omata  by  von  Recklinghausen,  who  ascribed  them  to  misplaced  rudiments 
derived  from  the  mesonephros  or  Wolffian  body.  This  view  has  been 
widely  accepted.  The  proof  is  not  complete,  however,  and  R.  Meyer, 
Lockstaedt,  and  others  bring  forward  arguments  against  it  showing  that  it 
is  quite  possible  that  such  glandular  tumors  might  arise  from  inclusion  of 
uterine  glands  in  a  muscular  mass.  Cullen,  in  his  volume  on  the  subject, 
has  shown,  by  careful  study  of  73  cases,  that  in  56  it  was  possible  to  trace 
the  uterine  mucosa  directly  into  continuity  with  the  glands  of  the  tumor,  a 
finding  which  seems  to  decide  the  matter  definitely. 

Myomata  of  the  stomach  and  intestine  are  usually  small  nodules  lying 
beneath  the  mucosa  or  projecting  on  the  peritoneal  surface.  They  show 
no  degenerative  changes,  and  are,  as  a  rule,  too  small  to  cause  any  symp- 
toms. Those  in  the  vagina  and  in  the  urinary  bladder  are  sometimes  much 
larger,  while  nodules  of  smooth  muscle  in  the  kidneys  are  usually  quite 
small.  In  the  skin,  myomata  develop  as  subcutaneous  or  intracutaneous 
nodules  arising  probably  from  the  tissue  of  the  arre ctores  pilorum,  although 
other  explanations  have  been  given. 

Malignant  tumors  composed  of  smooth  muscle  occur.  Ghon  and  Hintz 
described  one  which  arose  from  the  intestinal  tract  with  secondary  growths 
in  pancreas,  liver,  heart,  etc.,  and  give  references  to  the  literature  which 
show  that  many  cases  have  been  observed.  The  development  of  such 
malignant  characters  is  most  important  in  the  case  of  the  common  uterine 
myomata.  In  those  tumors  there  are  observed  changes  in  the  microscopi- 
cal appearance  of  the  cells,  leading  to  their  extreme  irregularity  in  size  and 


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form.  Corresponding  with  these  peculiar  appearances  it  has  been  found 
that  the  tumors  assume  a  rapid  and  irregular  growth  and  give  rise  to 
secondary  growths  or  colonies  in  other  organs  or  in  adjacent  tissues.  It 
seems  clear  that  malignant  tumors  spring  out  of  benign  myomata  which 
have  already  existed  for  a  long  time,  but  the  question  remains  as  to  their 
exact  origin.  They  may  be  due  to  the  acquisition  of  malignant  powers  of 
growth  by  the  smooth  muscle-cells,  in  which  case  we  should  speak  of  them 
as  malignant  myomata,  or  the  invasive  tumor  may  be  the  offspring  of  the 


Ur. 


Fig.  482. — Rhabdomyoma  beginning  in  the  vaginal  wall  in  a  child,  and  extending 
into  the  bladder.  Grape-like  polypoid  masses  hang  from  the  infiltrated  vaginal  walls 
(Dr.  C.  Cone's  case,  from  Kelly-Noble). 

stroma  of  the  myoma,  and  then  it  would  be  justifiable  to  call  the  tumor  a 
sarcoma.  It  is  only  in  the  latter  case,  in  which  there  is  a  true  sarcoma 
mixed  with  the  muscle  tissue  of  the  myoma,  that  such  a  term  as  myosar- 
coma  is  justifiable.  A  sarcoma  is  not  a  tumor  derived  from  muscle,  but 
rather  one  arising  from  connective  tissue. 

LITERATURE 

Leiomyomata.— Kelly  and  Cullen:   Myomata  of  the  Uterus,  Phila. 
Cullen:  Adenomyoma  of  Uterus,  Phila.,  1908. 


MYOMA  953 

Leiomyomata. — Ghon  and  Hintz:  Ziegler's  Beitrage,  1909,  xlv,  89. 

Lubarsch:  Ergebn.  d.  allg.  Path.,  1895,  i,  330;   1897,  ii,  574. 

Aschoff:   Ibid.,  1900,  v,  97. 

Zieler  u.  Fischer:  Ibid.,  1906,  x,  700. 

RHABDOMYOMA 

In  these  tumors,  which  are  found  usually  in  young  persons  or  children  in 
such  positions  as  the  heart-wall,  bladder  and  vagina,  kidney,  oesophagus, 
etc.,  the  tissue  frequently  contains  cells  of  various  kinds,  among  which 
there  are  found  striated  muscle-fibres.  It  seems  to  be  rare  to  find  a  whole 


Fig.  483. — Rhabdomyoma,  from  same  case  as  Fig.  482;  long,  ribbon-like,  striated 
fibres  (c)  are  mingled  with  round-  and  spindle-shaped  cells  (a,  d) .  There  are  some  wan- 
dering eosinophiles  (e)  (from  Kelly-Noble) . 

tumor  made  up  of  muscle-fibres,  and  the  admixture  is  often  with  such  ele- 
ments as  cartilage,  loose  cellular  connective  tissue,  and  even  epithelial 
structures.  The  suspicion  is,  therefore,  aroused  that  rhabdomyomata  are 
closely  related  to  the  mixed  tumors  or  teratomata. 

These  are  usually  benign  tumors,  but  in  many  cases  they  develop  invasive 
characters  and  may  metastasize  widely.  Those  in  the  heart-wall  form 
single  or  multiple  nodules  which  often  project  into  the  cavity  of  the  heart. 
Those  in  the  bladder,  of  which  we  were  able  to  study  one  case,  hang  in 
polypoid  masses  which  often  appear  in  the  vagina  as  well  and  protrude  from 
its  orifice  (Fig.  482). 


954  TEXT-BOOK   OF   PATHOLOGY 

Microscopically,  these  are  soft,  often  oedematous  tumors,  which  show 
numerous  small,  irregular,  and  spindle-shaped  cells  which  make  up  a  con- 
siderable part  of  their  bulk,  but  scattered  among  these,  and  sometimes  in 
compact  masses,  are  larger  elements  in  whose  protoplasm  a  delicate  striation 
is  visible  (Fig.  483).  These  do  not  resemble  muscle-fibres  closely,  but  show 
transitions  to  other  greatly  elongated  cells  which  do  resemble  the  earlier 
developmental  stages  of  striated  muscle.  These  are  narrow,  ribbon-like 
cells  with  a  central  space  which  may  contain  many  nuclei.  The  proto- 
plasm is  not  only  longitudinally  striated,  but  shows  distinct  transverse  stri- 
ations.  The  rhabdomyomata  usually  have  an  abundant  content  of  glyco- 
gen.  They  are  regarded  by  most  writers  as  arising  from  a  rudiment  derived 
from  an  early  embryonic  stage,  which,  displaced  in  the  course  of  develop- 
ment, has  grown  in  its  unusual  situation. 

LITERATURE 

Seiffert:  Ziegler's  Beitrage,  1900,  xxvii,  145. 
Stumpf :  Ibid.,  1911, 1,  171. 


CHAPTER  XLIX 
TUMORS  (Continued) 

Tumors  derived  from  elements  of  the  nervous  system:  General  relations  to  various  stages  in 
development  of  the  nervous  system.  Neurocytoma,  neuroblastoma,  chromaffine  tumors. 
Gliomata.  Angiomata:  hcemangiomata,  lymphangiomata.  Sarcomata:  General  charac- 
ters. Spindle-cell,  mixed-cell,  round-cell,  and  alveolar  sarcomata.  Giant-cell  sarcomata. 
Osteo sarcomata.  Myxomata. 

TUMORS  DERIVED  FROM  ELEMENTS  OF  THE  NERVOUS  SYSTEM 

THE  interpretation  of  tumors  of  the  nervous  system  has  recently  undergone 
many  changes,  and  certain  tumors  growing  in  other  parts  of  the  body  and 
formerly  regarded  as  peculiar  sarcomata,  have  been  recognized  as  belonging 
to  this  group. 

Tumors  are  found  composed  of  neuroglia  in  its  various  modifications; 
others  contain  certain  ganglion-cells,  often  with  abundant  nerve-fibres,  others 
are  composed  largely  of  antecedents  of  these  structures  capable  sometimes 
of  forming  in  the  tumor  ganglion-cells  or  fibres,  elements  of  the  type  of  the 
chromaffine  tissue  or  any  of  the  modifications  of  neuroglia.  The  type  of 
tumor  finally  evolved  seems  to  depend  upon  the  stage  in  embryonic  develop- 
ment at  which  the  formative  cells  were  diverted  to  the  formation  of  a  tumor. 

Originally,  the  epiblastic  cells  which  line  the  medullary  groove  are  capable  of  develop- 
ing into  nervous  elements  or  into  supporting  glial  cells.  The  production  of  the  peri- 
pheral nervous  system  is  due  to  the  outgrowth  of  nerve-fibres  from  this  central  region,  but 
in  addition  to  this,  many  of  the  neuro-epithelial  cells  wander  into  the  interior  of  the 
body  and  assume  certain  positions  in  relation  to  the  organs  where  they  give  rise  to  the 
cells  and  fibres  of  the  sympathetic  system.  Their  invasion  into  the  interior  of  the  rudi- 
ments of  the  adrenal  glands  results  inxthe  formation  of  the  medulla  of  those  glands  in 
close  relationship  to  the  adjacent  sympathetic  ganglia.  Similar  modifications  of  some 
of  these  invading  neurocytes  in  other  situations  lead  to  the  formation  of  the  analogous 
chromaffine  bodies  which  are  found  in  close  association  with  the  sympathetic  ganglia 
in  the  thorax  and  retroperitoneal  tract.  It  is  necessary  to  believe  that  these  cells  may 
also  give  rise  to  less  specialized  attendant  or  supporting  cells  in  each  of  these  situations. 

The  relations  to  one  another  of  the  elements  derived  from  the  original  medullary 
groove  may  be  expressed  as  follows  in  a  table  which  is  partly  derived  from  Wahl  and 

Landau : 

Neuro-ectoderm 


Sympathetic  formative  cells 

Sympathogonia  or  neurocytes 

of  the  sympathetic  system 


Neurocyte  (neuroblast?) 
the  cerebrospinal  system 


Sympathpblasts, 
transitions  to 

Ganglion-cells    Peripheral 
Sheath  cells        glial  cells 


Sympathetic  system 


Ganglion-cells 
Phseochromoblasts 

Phseochromocytes 
or  chromaffine  cells 

Chromaffine  system 

955 


"Neurogliocytes  (spongio- 
blasts?)  of  the  cerebro- 
spinal system 

Neuroglial  cells 


956  TEXT-BOOK   OF   PATHOLOGY 

The  known  limitation  of  the  power  of  mature  nerve-cells  and  fibres  to 
reproduce  themselves  has  made  it  seem  probable  that  those  tumors  which 
contain  ganglion-cells  and  nerve-fibres  must  have  arisen  from  some  less 
differentiated  stage.  Indeed,  since  the  weight  of  evidence  is  distinctly 
opposed  to  the  idea  that  the  cells  of  the  sheath  of  Schwann,  even  if  they  do 
prove  to  be  of  nervous  origin,  can  give  rise  to  a  new  axis-cylinder,  little 
credence  is  given  to  any  report  of  tumors  composed  solely  of  tangles  of 
nerve-fibres.  There  is  probably  no  such  tumor. 

Tumors  of  Nerves. — The  tumors  which  actually  appear  in  the  course  of 
the  nerves  are  usually  derived  from  the  supporting  structures  and  are  some- 
times called  false  neuromata  or  neurofibromata.  They  have  already  been 
described  in  connection  with  fibromata.  Those  which  show  a  cirsoid 
arrangement  under  the  skin  of  the  scalp  or  face  are  also  of  epineural  or 
perineural  origin,  but  do  involve  a  great  elongation  of  the  nerve-fibres. 
Similarly  the  so-called  amputation  neuromata,  which  are  round  or  nodular 
masses  of  whorled  nerve-fibres,  developing  at  the  ends  of  nerves  severed 
in  the  course  of  an  amputation,  are  not  tumors  in  the  true  sense.  They 
are  merely  masses  of  twisted  nerve-fibres  frustrated  in  their  attempt  to 
grow  down  to  the  end-organ.  Having  excluded  these  growths  from  the 
group  of  tumors  belonging  strictly  to  the  nervous  system,  it  is  found  that 
nearly  every  stage  in  the  table  given  above  is  represented  by  tumor  for- 
mation. Wahl  has  discussed  all  these  forms  in  an  able  paper  in  which  he 
tabulates  clearly  all  the  tumors  which  have  as  yet  been  described  and 
which  can  now  be  recognized  as  belonging  to  this  group. 

Neurocytoma. — Marchand  has  described  a  small  tumor  composed  of  cells 
resembling  lymphoid  cells,  with  fine  fibrillar  ground  substance,  which  he 
regarded  as  a  neurocytoma,  or  tumor  derived  from  the  undifferentiated 
neuroectoderm.  This  tumor  was  found  in  the  Gasserian  ganglion,  and  no 
similar  growth  has  as  yet  been  discovered  in  the,  sympathetic  system. 

Neuroblastoma. — J.  H.  Wright  was  the  first  to  recognize  clearly  the 
existence  of  a  group  of  tumors  originating  from  the  sympathetic  formative 
cells  or  sympathogonia,  and  to  these  he  gave  the  name  neuroblastoma. 
These  are  growths  which  appear,  as  a  rule,  in  infants  and  young  children, 
although  occasionally  in  adults,  and  in  most  cases  arise  from  the  adrenals, 
with  abundant  metastases  in  the  liver.  When  they  spring  from  other 
situations,  such  as  the  retroperitoneal  or  pelvic  region,  they  are  found  to  be 
associated  with  the  sympathetic  nervous  system,  and  thence  metastasize 
with  great  malignancy.  They  are  often  very  extensive  tumors,  composed 
of  small  cells  which  are  frequently  arranged  in  characteristic  rosettes,  and 
the  processes  of  these  cells  form  a  fine  fibrillar  intercellular  stroma  which 
gives  none  of  the  staining  reactions  of  neuroglia  or  connective  tissue. 

Sympathoblastoma. — Martius  has  described  one  case  in  which,  side  by  side 
with  ganglionic  elements,  the  tumor  which  lay  at  the  root  of  the  neck  con- 
tained cells  transitional  in  appearance  between  those  of  the  neuroblastoma 
and  ganglion-cells.  He  thinks,  therefore,  that  this  tumor  represents  Poll's 
sympathoblast  or  transitional  stage. 


TUMORS    DERIVED    FROM    ELEMENTS    OF   THE    NERVOUS    SYSTEM    957 

Ganglioneuroma. — Many  tumors  containing  ganglion-cells  have  been 
described  from  all  parts  of  the  body,  but  most  often  from  some  situation 
such  as  the  retroperitoneal  or  pelvic  or  retrocervical  regions,  where  they 
might  have  arisen  in  connection  with  the  sympathetic  system.  These  con- 
tain nerve-fibres  also,  though  chiefly  those  of  the  non-medullated  sort.  The 
ganglion-cells  are  usually  imperfectly  developed  and  irregular  in  form,  and 
the  fibres  are  twisted  and  irregular  in  appearance,  with,  of  course,  no  proper 
connection  with  any  end-organ.  While  most  ganglioneuromata  are 
thought  to  be  derived  from  the  later  developmental  stages  of  the  sympa- 
thetic system,  there  are  some  which  arise  in  the  same  way  in  connection 
with  the  ganglia  of  the  cerebrospinal  system  (Risel)  or  even  in  the  brain 
itself.  They  are  usually  benign  tumors,  but  a  few,  such  as  the  second  of 
Beneke's  cases,  show  numerous  metastases  which  seem  to  be  derived  from 
the  smaller  and  less  differentiated  cells. 

In  connection  with  these  there  is  sometimes  a  marked  new  formation  of 
neuroglial  elements  which  spring  from  the  peripheral  glial-cells,  and  such 
tumors  have  been  called  ganglioglioneuromata. 

Chromaffine  Tumors,  Paragangliomata. — Benign  and  solitary  tumors 
have  been  found  in  old  people,  arising  usually  in  the  adrenal  medulla  and 
containing,  as  a  rule,  sympathetic  formative  cells.  These  are  composed 
largely  of  masses  of  cells  which  are  sufficiently  developed  to  give  the  brown 
staining  reaction  with  chromic  salts.  No  one  has  yet  discovered  a  tumor 
which  could  be  assigned  to  the  earlier  stage  in  the 
development  of  these  cells  (phaBOchromoblasts) . 

It  is  seen  that  practically  all  these  active 
tumors  are  derived  from  some  stage  in  the 
development  of  the  sympathetic  system  and  its 
allied  tissues,  only  rare  examples  of  ganglio- 
neuromata derived  from  developmental  stages 
of  the  cerebrospinal  system  being  mentioned. 
In  contrast  with  this  the  tumors  arising  from 
the  neuroglia  of  the  cerebrospinal  system  are 
relatively  common  and  occupy  an  important  t 
place  in  the  surgery  of  the  nervous  system.  FiS-  483A.— Choked  disc 

Gliomata.-From  the  neuroglia  there  develop     with  sma11  h"haf  s> from 

.  .a  case  in  which  a  glioma  of 

tumors  in  the  brain,  in  the  spinal  cord,  and  in     the  cerebeiium  produced  hy- 

the  eye.     These  are  benign  growths  in  the  sense      drocephalus  and  increased  in- 
that  they  give  rise  to  no  distant  colonies  or      tracranial  pressure, 
metastases,  but  they  are  extremely  destructive, 

inasmuch  as  they  grow  expansively,  and  in  an  infiltrating  way,  into  the 
important  structures  of  the  nervous  system.  Since  they  are  confined  in 
the  bony  cavities  of  the  skull  and  spinal  canal,  they  soon  cause  the  most 
serious  symptoms  through  pressure  on  the  brain  or  cord.  Even  though  a 
glioma  embedded  in  the  brain  may  not  itself  increase  the  intracranial 
pressure  enough  to  cause  these  well-known  symptoms,  it  is  constantly  liable 
to  sudden  extravasations  of  blood  into  its  substance,  which  are  followed  by 


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apoplectiform  attacks,  with  loss  of   consciousness,  high  blood-pressure, 
choked  disc  (Fig.  483 A),  and  even  generalized  paralysis. 

The  gliomata  of  the  brain  may  be  situated  at  any  point  in  the  cerebrum, 


Fig.  484. — Glioma  of  pons  with  moderate  haemorrhage. 


Fig.  485. — Glioma  of  brain  with  hemorrhage. 

cerebellum,  pons  (Fig.  484),  etc.,  and  vary  in  size  from  very  small  nodules, 
up  to  huge  masses  which  occupy  nearly  the  whole  of  a  hemisphere.  They 
are  rarely  sharply  outlined,  either  by  their  color  or  their  consistence,  but 


TUMORS   DERIVED    FROM   ELEMENTS   OF   THE    NERVOUS   SYSTEM   959 

shade  off  insensibly  into  the  surrounding  brain  substance  (Fig.  485).  Their 
position  can  be  made  out  in  the  cut  surface  fairly  well,  however,  by  the 
swelling,  the  increased  vascularity  and  translucence,  and  by  the  haemor- 
rhages and  necroses  which  are  usually  present.  There  are  some  forms, 
indeed,  which  are  so  diffused  through  the  brain  substance  that  it  is  difficult 
to  determine  their  outline  even  with  the  microscope.  The  adjacent  tissue 
is  pushed  aside,  and  is  much  torn  by  the  growth  of  the  tumor.  Neverthe- 
less, gliomata  do  not,  as  a  rule,  extend  to  the  surface  of  the  brain  and  never 
pierce  the  meninges.  A  small  group  of  these  tumors  presents  an  appearance 


Fig.  486. — Glioma  of  the  cerebrum  composed  of  loosely  arranged  neuroglia  cells  and 

fibres. 

very  different  from  that  of  the  common  ones.  Instead  of  being  gray, 
translucent,  soft,  and  rather  cedematous,  they  are  small,  compact,  and  even 
quite  hard.  These  generally  project  in  relation  to  the  ependyma. 

Under  the  microscope  most  gliomata  present  a  fairly  uniform  mass  of 
cells  of  rather  small  size,  with  numerous  protoplasmic  processes  which  extend 
into  a  tangle  with  those  of  other  cells  and  thus  produce  a  feltwork  of  delicate 
filaments  (Fig.  486) .  The  question  as  to  the  independence  of  some  of  these 
neuroglia  fibres  seems  to  be  unsettled  in  the  minds  of  some  writers,  but 
Mallory  has  shown  by  special  stains  that  the  neuroglia  fibres  bear  the  same 


960  TEXT-BOOK    OF    PATHOLOGY 

relation  to  the  neuroglia  cells  as  the  collagen  fibres  to  the  cells  of  the  con- 
nective tissue.  They  are  differentiated  products  sometimes  still  traversing 
the  edge  of  the  body  of  the  cell,  sometimes  lying  free.  Nevertheless,  the 
actual  protoplasmic  processes  of  the  cells  play  a  considerable  part  in  forming 
the  fine  intercellular  network. 

Great  variety  is  seen  in  the  form  and  arrangement  of  these  cells.  They 
are  frequently  found  to  have  a  rather  abundant  cytoplasm,  with  many  long 
processes  extending  in  all  directions,  so  that  they  have  acquired  the  name 
astrocyte  or  spider  cell.  Others  are  much  simpler  in  outline  and  may  have 


.-  -.^  *  «.:.• "'  ?L:'X-  .''•*  >\  *  .t   •'  „*;  '.*..  +  -V 
TV-.*-.  O-.  -.VJg«-  ^r.-:- :.-.»,'"  v>  ».v.  vfv.  -> 

;••?.>  ^-v..-/^  .^-  *«-•  AV-J-i  ":  '5  • 

:  "-•.  »-> -;;  ;"„«—-  •-«•:: -.^.- .-y;  * ; -r  ,.»-.-- 

•--'•  r' ;.  *V  \  -->•  -  ^  '• , ••-.  .-  J"  %  *  '*  *.  *•»"  , . 

^;2^ f.^^5 4v-f::£^\;.: -v"  • :-' 


: .-- .  -.. 


V«'*-'.°'«..  *     *:^ 


Fig.  487. — Glioma  of  cerebrum. 

very  few  prolongations  (Fig.  487).  In  many  gliomata  they  are  especially 
condensed  about  the  blood-vessels;  in  others  there  are  minute  spaces  about 
which  cells  are  arranged  radially  with  a  flat  or  curved  foot  at  the  edge  of  the 
space,  and  a  long,  frayed-out  cell-body  extending  peripherally  to  become 
entangled  with  the  other  cells.  About  larger  spaces  the  same  presentation 
of  a  smooth  surface  to  the  cavity  is  seen.  Ganglion-cells  and  other  nerve- 
cells  of  smaller  size  are  quite  frequently  found  in  the  substance  of  a  glioma. 
It  seems  clear  that  these  must  be  remnants  of  the  original  nervous  tissue 
which  have  been  caught  in  the  advance  of  the  tumor  and  surrounded  (Fig. 
488). 


TUMORS  DERIVED  FROM  ELEMENTS  OF  THE  NERVOUS  SYSTEM    961 

The  degenerative  changes,  haemorrhages,  and  necroses  which  are  so  fre- 
quent in  these  tumors  have  already  been  mentioned.  They  may  lead  to 
such  wide-spread  destruction  of  the  tumor  that  only  a  thin  rim  of  tumor 
tissue  is  left.  It  is  not  infrequent  in  such  cases  to  find  that  the  debris  of  the 
tumor-cells  and  blood  has  been  replaced  by  a  clear  fluid,  so  that  the  whole 
area  appears  as  a  thin-walled  cyst  with  only  some  pigment  and  fast  vanish- 
ing traces  of  tumor  tissue  in  its  walls  to  indicate  its  original  nature.  I  have 
seen  two  cysts  of  this  kind  in  the  cerebellum  which  had  had  time  to  reach 
this  state  in  spite  of  the  great  destruction  of  the  cerebellar  tissue. 


Fig.  488. — Glioma  of  cerebrum  with  inclusion  of  many  ganglion-cells. 


Gliomata  developing  in  the  pons  or  in  the  medulla  may  cause  even  more 
serious  and  quickly  fatal  destruction  than  those  embedded  in  the  brain.  In 
the  spinal  cord  these  tumors  are  less  common.  They  may  exist  in  the  form 
of  a  nodular  mass,  but  are  usually  centrally  placed  and  much  elongated, 
forming,  in  the  midst  of  the  cord,  a  pencil-like  growth  which  pushes  aside 
all  the  nervous  elements  and  compresses  them.  Many  of  these  central 
tumors  have  a  lumen  and  then  appear  as  tubes.  While  an  overgrowth  of 
neuroglia  or  gliosis  may  occur  in  the  cord  from  other  causes,  the  presence  of 
62 


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such  tubular  glioma  can  give  rise  to  one,  at  least,  of  the  forms  of  syringo- 
myelia. 

Syringomyelia  is  a  curious  affection  of  the  spinal  cord  in  which,  as  its  name  implies,  a 
pipe  or  tube  of  neuroglia  is  embedded  in  the  cord,  and  extends,  sometimes,  upward  into 
the  medulla.  The  most  extraordinary  symptoms  follow:  loss  of  temperature  sense,  and 
later  of  tactile  sense,  extreme  contractures  and  deformities  of  the  extremities  and  thorax, 
etc. 

In  the  eye,  gliomata  arise  from  the  glial  constituents  of  the  retina,  or  from 
some  earlier  developmental  stage  of  the  cells  of  the  retina  which  can  give 
rise  to  glial  tissue,  and  grow  out  into  the  vitreous  humor,  pushing  the  retina 
forward.  Frequently  they  begin  near  the  anterior  margin  of  the  retina, 
and  extend  thence  so  as  to  occupy  much  or  all  of  the  cavity  of  the  eye. 
Necroses  are  extremely  frequent  in  the  tissue,  and  the  whole  tumor  may  be 
reduced  to  a  non-staining  debris,  except  for  the  cells  which  immediately 
surround  the  blood-vessels.  In  other  cases,  in  which  there  is  no  such  necro- 
sis, the  nodular  mass  pushes  through  the  sclera  or  through  the  cornea  and 
appears  in  the  orbit  or  on  the  surface  of  the  eyeball.  When  removed  by  the 
enucleation  of  the  eye,  it  tends  to  recur  and  to  spread  rapidly  in  the  orbit 
and  backward  into  the  brain.  The  opposite  eye  is  commonly  involved. 

The  tumor  itself  is  usually  composed  of  small  cells  with  little  protoplasm 
and  very  few  inconspicuous  fibrils.  There  is  another  type  first  described, 
as  far  as  I  can  determine,  by  Flexner,  in  which  the  cells  are  frequently  ar- 
ranged in  rosettes.  This  tumor,  he  thought,  should  be  designated  neuro- 
epithelioma,  since  it  apparently  arose  from  an  undifferentiated  element 
of  the  retinal  neuro-epit helium. 

Ependymal  Gliomata. — Several  authors  have  described  gliomatous 
tumors  in  which,  on  account  of  the  presence  of  peculiar  gland-like  spaces 
lined  with  cells  resembling  epithelium,  they  have  traced  a  relationship  to 
the  ependymal  cells.  Mallory  was  able  to  show  that  these  peculiar  cells 
have  in  their  protoplasm  certain  small  rodlets  or  granules  which  are  charac- 
teristic of  the  ependymal  cells,  and  therefore  had  no  hesitation  in  regarding 
them  as  ependymal  gliomata.  Saxer  described  other  tumors  in  which  the 
ependymal  elements  occupy  the  predominant  place  and  grow  up  into  papil- 
lary masses  resembling  those  seen  on  mucous  surfaces.  These  cells  are, 
however,  of  the  same  origin  as  the  neuroglial  elements  in  general. 

LITERATURE 

J.  H.  Wright:  Jour.  Exp.  Med.,  1910,  xii,  556. 
Landau:  Frankfurter  Ztschr.  f.  Path.,  1912,  xi,  2G. 
Wahl:   Jour.  Med.  Research,  1914,  xxx,  205. 
Herde:  Archiv  f.  kl.  Chir.,  1912,  xcvii,  937. 
Wegelin:  Verb.  Dtsch.  Path.  Gesellsch.,  1912,  xv,  225. 
Symmers:  Jour.  Amer.  Med.  Assoc.,  1913,  Ix,  337. 
Glioma.— Landau:   Frankfurter  Ztschr.  f.  Path.,  1910,  v,  439. 

Mallory:  Jour.  Med.  Research,  1902,  viii,  1. 

Stroebe:  Ziegler's  Beitrage,  1895,  xviii,  405. 

Saxer:  Ibid.,  1902,  xxxii,  276. 

Flexner:  Johns  Hopkins  Hosp.  Bull.,  1891,  ii,  115. 


ANGIOMATA  963 

ANGIOMATA 

Hsemangioma. — A  haemangioma  is  a  tumor  composed  essentially  of 
blood-channels,  in  contradistinction  to  a  lymphangioma,  whose  cavities 
contain  lymph  instead  of  blood.  A  true  haBmangioma  is  distinguished  from 
a  mere  dilatation  of  capillaries  or  venules  belonging  to  the  general  circula- 
tion by  the  fact  that  its  blood-channels  grow  independently,  without  regard 
to  the  laws  which  govern  the  distribution  of  such  vessels.  It  thereby 
forms  a  mass  which  is  somewhat  withdrawn  from  the  general  circulation, 
and  although  supplied  with  artery  and  vein,  does  not  stand  in  any  intimate 
anastomotic  relations  with  the  adjacent  circulation.  Ribbert  lays  great 
stress  upon  this  lack  of  communication  between  the  capillaries  of  an 
angioma  and  those  of  the  contiguous  tissue,  and  has  proved  his  point  by 
injections.  Further,  he  insists  that  such  tumors  grow  from  their  own  vas- 
cular substance  and  not  through  the  widening  and  assimilation  of  adjacent 
vessels.  There  are  some  border-line  forms  in  which  it  is  difficult  to  say 
whether  one  is  dealing  with  a  tumor  or  not,  such  as  the  plexiform  or  cirsoid 
angiomata  of  the  scalp,  which  are  made  up  of  tangled  masses  of  pulsating 
arteries,  and  others  of  even  less  tumor-like  nature,  such  as  the  bluish  vas- 
cular flecks  seen  in  the  skin  of  old  people.  True  hsemangiomata  are  most 
commonly  divided  into  a  simple  or  telangiectatic  form,  in  which  the  abun- 
dant capillaries,  though  widened,  maintain  fairly  well  their  form  as  tubes 
with  parallel  walls,  and  the  cavernous  form,  in  which  the  character  of  erec- 
tile tissue  is  approached,  with  large,  irregular  blood  -spaces  opening  abun- 
dantly into  one  another.  It  is  not  very  apparent,  however,  where  the  line 
of  division  can  be  sharply  drawn  between  these  groups.  Certainly  it  is 
difficult  to  determine  from  sections  in  some  cases  whether  one  should  regard 
the  tumor  as  verging  on  the  cavernous  or  not.  Doubtless  if  the  channels 
were  injected  and  a  slice  of  the  tumor  rendered  transparent,  a  most  beautiful 
proof  of  this  distinction  might  be  obtained. 

These  tumors  occur  most  commonly  in  the  skin,  especially  on  the  face 
and  scalp,  but  also  in  all  other  parts  of  the  body.  The  more  definitely 
simple  forms  through  which  blood  runs  fairly  rapidly  present  themselves  as 
flat  or  slightly  elevated,  bright-red  patches  from  which  the  blood  may  be 
squeezed  out  (nsevus  flammeus).  Many  of  these  are  found  in  the  neighbor- 
hood of  angles  or  fissures  about  the  face  and  neck  so  that  they  have  been 
thought  to  be  congenital  displacements.  Hanes  has  recently  reviewed  the 
history  of  a  peculiar  hereditary  form  of  multiple  telangiectasis  with  num- 
erous bluish  nodules  in  the  skin  and  nose  from  which  any  trifling  injury 
would  serve  to  start  a  profuse  hemorrhage.  In  these,  the  irregularly 
widened  capillaries  lay  just  under  the  thin  smooth  skin.  Other  examples 
of  simple  angiomata  are  found  in  the  muscles,  where  they  reach  a  con- 
siderable size.  In  the  tongue,  nose  (Fig.  489),  and  lips  they  are  also  found, 
but  in  all  these  latter  situations  the  tumor  is  likely  to  have  more  of  the 
cavernous  character. 


964 


TEXT-BOOK    OF    PATHOLOGY 


Cavernous  angiomata  are  also  common  in  the  skin,  where  they  form 
most  of  the  so-called  birthmarks  which  are  so  frequently  seen  on  the  face. 
These  are  usually  dark  purple,  and  are  often  covered  with  rough,  nodular 
skin  (naevus  vinosus).  They  are,  as  a  rule,  distributed  over  the  region  of 
one  or  more  divisions  of  the  fifth  cranial  nerve  and  seldom  cross  the  mid- 
line  of  the  face.  It  is  said  that  they  sometimes  appear  in  the  meninges  in  a 


Fig.  489. — Angioma  from  the  nose.    The  blood-channels  are  of  fairly  uniform  calibre. 

corresponding  distribution,  and  that  they  may  give  rise  to  haemorrhage 
there  (Gushing).  In  the  lips  or  tongue  they  form  large,  nodular,  purple 
masses  very  prone  to  injury  and  haemorrhage  and  very  distorting.  I  have 
seen  one  or  two  cases  of  multiple  cavernous  hsemangiomata  in  the  walls  of 
the  intestine  (Fig.  490).  Haemorrhage  may  occur  from  these,  although  it 
had  not  done  so  in  my  cases.  In  the  muscles,  masses  of  spongy  vascular 
tissue  are  found,  extending  between  the  fibres  and  into  the  intermuscular 


ANGIOMATA 


965 


spaces.     In  these,  too,  the  blood-channels  are  frequently  irregular  in  form, 
with  wide  communications. 

The  cavernous  angiomata  of  the  liver  constitute  perhaps  the  best  studied 
type  (Fig.  491).  They  are  found,  as  a  rule,  at  autopsy,  without  having 
given  rise  to  any  symptoms,  and  may  be  very  small  or  reach  a  diameter  of 
several  centimetres.  Frequently  there  are  four  or  five  in  the  same  liver,  of 


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Fig.  490. — Cavernous  haemangioma  of  the  small  intestine. 

which  some  may  be  visible  through  the  capsule,  while  others  are  buried  deep 
in  the  substance.  On  section,  they  appear  as  deep,  purplish-red,  sharply 
outlined  areas,  from  which  dark  blood  can  be  squeezed  or  washed  out,  leav- 
ing a  grayish-white,  spongy  framework.  We  have  recently  seen  at  autopsy 
a  huge  angioma  of  the  liver  which  was  only  partly  surrounded  by  liver 
tissue,  and  hung  as  by  a  stalk  from  the  right  lobe.  It  measured  24  cm.  in 
diameter,  and  corresponded  in  structure  with  the  smaller  ones.  Micro- 


966  TEXT-BOOK   OF   PATHOLOGY 

scopically,  this  framework  is  seen  to  inclose  quite  large  spaces  which  open 
into  one  another,  and  which  are  evidently  interposed  between  artery  and 
vein.  They  are  lined  with  endothelium  and  do  not  seem  to  communicate 
with  the  adjacent  capillaries,  although  some  of  them  occasionally  extend 
into  the  adjacent  liver  substance  as  though  forming  an  outpost  of  growth. 
Liver-cell  strands  are  often  found  to  lie  in  the  connective  tissue  of  the 
angioma,  practically  surrounded  by  it.  Nevertheless,  as  Ribbert  points 
out,  an  injection  of  the  angioma  passes  very  little,  if  at  all,  into  the  circula- 
tion of  the  liver. 

In  all  these  angiomata  circulatory  disturbances  can  occur.  Infection  may 
cause  an  inflammatory  reaction  in  their  substance,  thrombosis  of  the  blood- 
channels  is  common,  and  phleboliths  may  be  formed.  It  is  not  infrequent 
to  find  parts  of  them  scarred  and  obliterated  by  such  processes  with  abun- 
dant pigmentation. 

Ribbert's  idea  of  their  origin  from  a  rudiment  which  is  destined  to  form 
blood-vessels,  from  which  they  grow  independently,  is  generally  accepted, 
and  the  ideas  as  to  their  being  due  to  mere  dilatation  of  capillaries,  or  to  the 


Fig.  491. — Cavernous  hsemangioma  of  the  liver. 

organization  of  haemorrhages,  should  be  abandoned.  That  they  may  be  the 
result  of  fcetal  displacement  of  tissue  is,  of  course,  prominent  in  all  discus- 
sions, and  applies  here  just  as  it  does  in  the  case  of  most  other  tumors.  These 
are  among  the  displacements  or  perverted  formations  of  tissue  which 
Albrecht  separates  as  "Hamartomata." 

In  the  edges  of  the  heart  valves  of  infants  there  are  frequently  seen 
minute,  tense,  deep-red  nodules  which  project  like  tiny  red  berries.  On 
section  they  look  like  cavernous  hsemangiomata,  but  they  persist  only  a 
short  time,  and  are  probably  not  to  be  regarded  as  tumors  (Fig.  492). 

Lymphangioma.— Quite  analogous  tumors,  except  that  they  are  composed 
of  spaces  and  channels  containing  lymph,  are  the  lymphangiomata.  They 
are  telangiectatic  or  simple,  cavernous,  and  cystic.  Of  these,  the  first  type 
is  especially  common  in  the  skin,  lips,  tongue,  and  subcutaneous  or  inter- 
muscular  tissue.  They  form  nodular  masses  or  diffuse  enlargements  which, 
on  injury,  may  allow  the  escape  of  lymph.  In  the  case  of  the  tongue,  they 
cause  an  enlargement  which  constitutes  one  of  the  forms  of  macroglossia, 
and  in  the  extremities  the  diffuse  distribution  of  such  a  cutaneous  and  sub- 
cutaneous tumor  may  give  rise  to  a  great  enlargement  which  constitutes 


ANGIOMATA 


967 


one  of  the  numerous  divergent  forms  of  elephantiasis.  In  section  such 
tumors  are  found  to  be  made  up  of  anastomosing  channels  or  spaces  lined 
with  thin  endothelium  and  filled  with  clear  fluid  with  a  few  lymphoid  cells. 
Naturally  haemorrhages  into  these  spaces  may  confuse  the  picture  and  sug- 
gest the  existence  of  a  haBmangioma,  but  the  history  of  the  case  will  prevent 
such  an  error  in  diagnosis.  In  these  tumors,  as  in  the  haBmangiomata,  the 
interstitial  connective  tissue  grows,  together  with  the  lymph-channels,  to 


Fig.  492. — Angiomatoid  nodule  upon  the  heart-valve  of  an  infant. 

produce  the  tumor  which  again  is  more  or  less  independent  of  communica- 
tion with  adjacent  lymphatics.  In  the  intestinal  wall  one  may  observe 
nodules  of  considerable  size  filled  with  clear  or  with  milk-white  fluid,  and 
composed  of  cavernous  arrangements  of  lymph-channels.  It  is  important 
here  to  distinguish  between  true  cavernous  lymphangiomata  and  mere 
dilatations  of  the  chyle-ducts. 

The  cystic  lymphangiomata  are,  as  a  rule,  still  more  circumscribed,  and 
are  composed  of  masses  of  rounded  or  irregular  cystic  structures  with  the 


TEXT-BOOK    OF    PATHOLOGY 

same  thin  endothelial  lining.  They  occur  sometimes  in  the  internal  organs, 
as  in  the  liver,  spleen,  adrenals,  etc.,  where  they  are  usually  pretty  sharply 
marked  out  from  the  organ  itself.  In  the  neck  and  sacral  regions  the  so- 
called  cystic  hygromata  are  found,  and  are  especially  easily  recognized  as 
the  results  of  developmental  disarrangements  of  tissues.  They  are  cystic 
lymphangiomata  which  are  less  circumscribed,  and  in  the  neck  form  large, 
ramifying  masses  which  extend  far  up  behind  the  ear  and  down  between  the 
muscles  of  the  thorax  and  in  the  soft  tissues  of  the  shoulder.  One,  which 
we  saw  recently  in  a  child,  had  become  infected,  so  that  all  the  cavities  were 
filled  with  a  purulent  exudate  which  infiltrated  the  tissue  between  them. 
When,  as  in  the  so-called  lymphangioma  tuberosum  multiplex  of  Kaposi, 
there  are  more  complex  strands  of  endothelial  cells  in  place  of  simple  endo- 
thelial lined  channels,  it  is  better  to  speak  of  the  tumor  as  an  endothelioma. 

LITERATURE 

Hcemangioma—  Ribbert:  Virch.  Arch.,  1898,  cli,  381. 

Hanes:  Johns  Hopkins  Hosp.  Bull.,  1909,  xx,  63. 
Roggenbau:  Ziegler's  Beitrage,  1910,  xlix,  313. 
Fischer  and  Zieler:  Ergebn.  d.  allg.  Path.,  1908,  x,  815. 
Lymphangioma.— Sick:  Virch.  Arch.,  1902,  clxx,  9;   1903,  clxxii,  445. 
Fischer  and  Zieler:  Loc.  cit.,  842. 
Paltauf:  Verb.  d.  Dtsch.  Path.  Gesellsch.,  1908,  xi,  255. 

SARCOMATA 

A  sarcoma  is  a  tumor  arising  from  connective  tissue  and  retaining  most  of 
the  general  characteristics  of  connective  tissue,  but  endowed  with  the  new 
power  of  invading  and  actively  destroying  adjacent  structures  and  of  form- 
ing colonies  of  its  own  tissue  in  distant  organs.  In  this  respect  sarcomata 
are  typically  malignant  tumors. 

It  has  been  showTi  that  benign  tumors  may  be  derived  from  any  of  the 
various  forms  of  connective  tissue  which  make  up  the  framework  of  the 
body,  and  that  they  depart  somewhat,  in  each  instance,  in  the  character  of 
their  cells,  from  the  normal  standard.  All  this  is  equally  true  of  the  sar- 
comata, and  while  they,  too,  may  originate  in  any  kind  of  connective  tissue, 
their  cells  are  far  more  unlike  those  of  the  normal  tissue  in  appearance  and 
totally  unlike  them  in  their  biological  characters. 

It  is  scarcely  possible  to  decide  from  the  study  of  a  microscopical  prepara- 
tion as  to  the  point  of  origin  of  any  sarcoma,  since  almost  any  region  may 
be  the  starting-point  for  any  type  of  tumor.  When  the  tumor  contains 
bone  or  cartilage,  it  is  fairly  safe  to  say  that  it  sprang  from  some  part  of  the 
skeleton,  although  this,  too,  would  be  indiscreet,  since  such  tumors  occasion- 
ally arise  elsewhere. 

The  sarcomata  are  tumors  preeminently  characterized  by  the  energy  and 
rapidity  of  growth  of  their  cells,  and  this  in  itself  brings  about  the  striking 
morphological  differences  between  them  and  the  corresponding  benign 
tumors  arising  from  similar  situations  in  the  connective  tissue.  It  would 


SARCOMATA  969 

doubtless  be  quite  misleading  to  describe  the  lack  of  a  capsule  or  of  a  dense 
stroma  as  mechanical  factors  favoring  their  rapid  growth.  On  the  con- 
trary, they  grow  so  quickly  and  irresistibly  that  there  is  no  time  for  the 
formation  of  a  dense  stroma  nor  any  opportunity  for  their  encapsulation. 
There  may  be  differences  between  these  cells  and  those  of  a  fibroma  with 
regard  to  the  process  of  mitosis.  It  is  possible  that  irregularities  in  mitosis 
are  associated  with  their  precipitate  growth,  and  that  this  explains  the 
irregularities  in  the  form  of  the  cells  sometimes  met  with,  but  in  general 
they  grow  and  develop  in  much  the  same  way.  Cultures  in  vitro  from  nor- 
mal connective  tissue  and  sarcoma  tissue  are  almost  indistinguishable  from 
one  another,  except  by  most  careful  comparison  of  such  things  as  the  mitotic 
figures  just  mentioned.  In  both  cases  the  cells  grow  out  in  scattered 
strands  or  isolated  groups,  quite  unlike  epithelial  cells,  and  through  their 
power  of  stretching  themselves  along  a  support  and  responding  to  tactile 
stimuli  make  considerable  progress  away  from  the  point  of  origin.  In  the 
tumors,  as  they  occur  in  the  body,  the  impression  is  given  in  many  cases  that 
such  cells  form  the  whole  compact  mass,  but  in  every  case  it  is  found  that  in 
addition  there  is  a  distinct  framework  of  ordinary  connective  tissue  with 
very  abundant  blood-vessels  and  some  nerve-fibrils.  Just  as  in  all  other 
tumors,  the  sarcoma  elements  demand  this  service  of  the  normal  tissues,  and 
force  the  development  of  a  mechanism  for  support  and  blood  supply.  Some- 
times the  framework  is  extremely  delicate  and  seems  to  consist  of  little 
beside  thin- walled  blood-vessels  (Fig.  493,  c) .  In  other  cases  it  is  very  abun- 
dant and  dense,  so  that  the  tumor-cells  are  separated  into  strands  and 
compact  masses  which  anastomose  with  one  another,  but  appear  in  sections 
as  the  contents  of  alveolar  spaces.  (Fig.  493,  6)  There  are  also  types  of 
sarcoma  in  which  the  tumor  cells  themselves  have  the  power  of  producing 
abundant  intercellular  fibres. 

The  malignant  character  of  the  tumor  is  evident  in  the  infiltrating, 
destructive  manner  of  its  growth  when  it  is  well  established,  but  in  the 
beginning  it  may  be  difficult  to  recognize  this.  Nevertheless,  unless  the 
tumor  is  extirpated  it  soon  reveals  its  true  nature,  and  even  if  it  is  removed 
at  operation,  the  tendency  to  recur  in  the  same  place  from  traces  of  the  tissue 
left  behind  is  associated  with  other  evidence  of  its  malignancy.  Above  all, 
the  appearance  of  colonies  of  the  same  tissue  elsewhere  in  the  body  leaves 
no  room  for  doubt.  It  appears,  then,  that  in  order  to  decide  upon  the 
nature  of  a  connective-tissue  tumor  which,  as  far  as  its  microscopical  mor- 
phology is  concerned,  might  be  a  benign  fibroma  or  a  malignant  sarcoma, 
it  is  necessary  to  know  the  history  of  the  growth  and  its  gross  relations  to 
the  adjacent  tissues.  Even  then  it  may  be  impossible  to  be  completely 
sure  until  recurrence  or  metastases  have  appeared.  It  is  at  this  point  that 
the  greatest  uncertainty  may  exist,  but  ordinarily,  as  will  be  explained,  the 
morphology  of  the  tumors  has  become  sufficiently  well  known  in  connection 
with  the  history  of  their  growth  to  allow  one  to  foretell  the  progress  of  the 
growth  and  to  decide  upon  its  nature. 


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There  are  great  difficulties  in  outlining  this  group  of  tumors,  since  there 
are  so  many  malignant  growths  composed  of  ill-characterized  cells  upon 
whose  origin  it  is  almost  impossible  to  decide  exactly.  Many  authors  are 
willing  to  speak  of  malignant  tumors  arising  from  muscle,  neuroglia,  etc., 
by  such  names  as  myosarcoma  and  gliosarcoma.  Ribbert  is  among  those 


Fig.  493.— Several  types  of  sarcoma:     (a)     Spindle-cell  sarcoma  from  chest-wall; 
)  alveolar  sarcoma  of  mesentery;    (c)  spindle-cell  sarcoma;   the  blood-vessels  are  in- 
jected and  are  seen  to  be  very  numerous;    (d)  mixed-cell  sarcoma  of  leg  metastasizing 
e  mediastinum;    (e)  osteosarcoma  with  calcified  areas  and  cartilage. 

who  prefer,  as  it  seems  to  me  correctly,  to  call  them  malignant  myomata 
and  malignant  gliomata,  reserving  the  term  sarcoma  for  malignant  tumors 
clearly  of  connective-tissue  nature.  Such  names  can  be  used,  however,  to 
indicate  a  sarcoma  in  which  the  type  of  connective  tissue  from  which  it 
originated  is  still  evident,  as  osteosarcoma,  chondrosarcoma.  Recently,  too, 


SARCOMATA 


971 


there  has  been  a  tendency  to  treat  separately,  on  account  of  their  peculiar 
character,  tumors  thought  to  be  derived  from  endothelium,  and  that  group 
of  pigmented  tumors  long  known  and  still  generally  spoken  of  as  melanosar- 
comata.  In  addition  to  these  there  are  numerous  tumors  which  arise  from 
somewhat  specialized  cells  belonging  to  the  blood-forming  apparatus  and 


c    P 


Fig.  494. — Several  types  of  sarcoma:  a,  Mixed-cell  sarcoma;  6,  coarse  spindle-cell 
sarcoma;  c,  metastatic  round-cell  sarcoma;  d,  sarcoma  of  thyroid  with  giant-cells;  e, 
sarcoma  of  ovary. 


which,  under  various  names  (lymphosarcoma,  leucosarcoma,  myeloma,  etc.), 
have,  rightly  or  wrongly,  been  considered  in  connection  with  the  diseases  of 
that  apparatus,  since  it  is  by  no  means  quite  clear  that  they  are  tumors  at 
all.  Finally,  there  are  tumors,  usually  of  rather  complicated  structure  and 
often  occurring  at  birth,  or  in  the  very  young,  which  have  long  been  desig- 


972 


TEXT-BOOK   OF   PATHOLOGY 


nated  sarcomata,  but  which  appear  to  be  rather  of  the  nature  of  the  so- 
called  mixed  tumors,  which  are  referable  to  the  aberrant  growth  of  tissue 
displaced  in  the  course  of  embryonic  development.  In  this  group  there 
may  be  mentioned  especially  many  of  the  malignant  tumors  of  the  testicle 
and  the  sarcomata  of  the  kidney  which  grow  during  infancy  and  childhood. 
Nevertheless,  in  spite  of  the  nebulous  state  of  our  knowledge  as  to  the 
real  relations  of  these  questionable  growths,  there  remain  many  well- 


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^Y^fe     ,;-,  f«  ::.V<«  -  •• :.'.  '-v  y-O;^::.; 

^^^^^^W^i?^ 

^Kx/fe^C:^^ 


^cW^^S^ 


Fig.  495.— Sarcoma  of  tissues  of  the  axillary  plexus.     The  cells  of  the  tumor  are  long 
and  fusiform,  and  there  are  many  wandering  cells. 

defined  sarcomata  which,  in  any  series  of  cases,  stand  out  sharply  as  easily 
recognized  representatives  of  certain  groups.  They  are  distinguished  from 
one  another  chiefly  by  the  form  of  their  cells  and  by  the  character  of  their 
intercellular  substance,  as  well  as  their  energy  of  growth,  but  there  are  so 
many  transitional  forms  and  combinations  that  I  do  not  wish  to  draw  very 
sharp  lines  between  them  (Fig.  494). 
Of  these,  the  commonest  are  the  spindle-cell  sarcomata,  which  originate 


SARCOMATA 


973 


in  almost  any  situation.  In  the  series  which  I  have  for  study  spindle-cell 
sarcomata  arose  in  the  breast,  hand,  mesosalpinx,  vulva,  wall  of  ovarian 
cyst,  leg,  liver,  etc.,  but  any  connective  tissue,  such  as  fasciae,  subcutaneous 
tissue,  or  the  framework  of  organs,  may  be  their  starting-point.  They  are 
white  or  gray-white,  rather  firm,  shining,  and  somewhat  circumscribed 
masses  which  have  perhaps  less  tendency  to  metastasize  widely  than  some 
of  the  other  forms.  Microscopically,  they  are  found  to  be  composed  of 
smoothly  arranged,  elongated  or  spindle-shaped  cells,  very  uniform  in  size 
and  general  appearance, 
and  supported  in  bundles 
or  whorls  by  the  most 
delicate  stroma,  with  wide 
and  very  thin-walled 
blood-vessels.  The  inter- 
cellular substance  of  the 
tumor  itself  is  usually  ex- 
tremely scanty,  so  that 
the  cells  lie  close  together. 
In  some  cases,  however, 
there  is  a  good  deal  of  fib- 
rillar  intercellular  sub- 
stance, the  cells  are  less 
uniformly  arranged  and 
tend  rather  to  a  branched 
form  (Fig.  495).  To  such 
tumors  the  name  fibrosar- 
coma  may  be  fittingly 
applied.  The  secondary 
growths  or  metastases  may 
occur  in  the  lymph-glands, 
which  drain  the  area  of 
the  tumor,  but  they  are 
more  frequently  found  in 
the  lungs  (Fig.  496)  and 
later  in  other  internal  or- 
gans which  would  indicate 

that  the  cells  of  the  tumor  were  transported  by  way  of  the  venous  blood- 
stream (cf.  Fig.  28).  Borst  emphasizes  the  idea  that  such  spindle-cells 
are  especially  immature,  approaching  in  this  respect  embryonic  cells.  It 
seems  to  me,  however,  that  this  is  based  merely  upon  the  general  resem- 
blance in  form  to  the  cells  of  embryonic  connective  tissue.  Their  biolog- 
ical characters,  which  should  be  of  greater  weight  in  deciding  such  a 
question,  are  totally  abnormal,  and  they  have  acquired  powers  which 
might  distinguish  them  very  sharply  from  even  the  most  immature  of 
embryonic  cells,  since  they  are  such  as  to  enable  them  to  grow  indefinitely 


Fig.  496. — Metastatic  sarcoma  in  the  lung.  Nod- 
ules are  found  in  various  parts  of  the  pleura,  but 
especially  along  the  margins  of  the  lobes. 


TEXT-BOOK    OF    PATHOLOGY 

without  at  any  time  differentiating  themselves  into  any  finite  tissue  which 
obeys  the  normal  laws  of  growth.  The  resemblance  to  embryonic  tissue  is, 
therefore,  most  superficial,  and  they  are  rather  cells  which  have  no  true 
analogue  in  the  body  at  any  stage  of  its  development. 

Nearly  as  common  as  the  spindle-cell  sarcomata  are  those  in  which  cells 
of  many  forms  and  sizes  occur,  with  many  bizarre  modifications  of  their 
nuclei.  For  want  of  any  better  term,  these  may  be  called  mixed-cell  sarco- 
mata (Fig.  494,  a) .  They  arise  anywhere,  too,  but  perhaps  most  commonly 
in  connection  with  the  internal  organs.  I  have  seen  them  especially  in  the 
retroperitoneal  region,  apparently  springing  from  the  lymph-glands  there, 
and  forming  huge  masses,  but  there  are  before  me  examples  from  the  thy- 
roid, from  the  ovary,  periosteum,  etc.  The  cells  are  in  general  fusiform, 
but  are  somewhat  irregularly  arranged  and  form  by  no  means  so  compact 
and  orderly  a  tissue  as  in  the  pure  spindle-cell  type.  Among  these  are 
many  of  much  larger  size,  with  several  nuclei  or  one  very  large  and  deeply 
stained  nuclear  mass. 

Round-cell  sarcomata  are  in  our  experience  relatively  rare  as  long  as  we 
separate  from  them  the  lymphosarcomata  and  leucosarcomata,  which  have 
distinctive  features,  as  already  mentioned.  They  are  tumors  composed  of 
small  round  cells  held  in  a  most  delicate  vascular  stroma  which  in  any  single 
microscopical  preparation  might  be  difficult  to  distinguish  from  lymphosar- 
comata. They  arise,  however,  as  single,  rather  circumscribed  masses  spring- 
ing from  the  connective  tissue  of  the  skin  or  fasciae  or  intermuscular  septa 
or  elsewhere,  and,  aside  from  their  local  invasion  and  destructive  growth 
spread,  not  in  a  regional  way,  as  lymphosarcomata  do,  but  exactly  as  other 
sarcomata,  by  the  transportation  of  their  cells,  usually  by  the  blood-stream 
to  the  distant  lungs,  where  they  form  once  more  circumscribed  and  solid 
nodules  (Fig.  497).  When  a  regional  lymph-gland  is  involved,  it  usually 
presents  a  more  or  less  definitely  outlined  tumor  mass  embedded  in  its  sub- 
stance, and  is  not  itself  at  first  completely  replaced  by  the  new  tissue.  These 
round-cell  sarcomata  are  extremely  malignant,  and  give  rise  to  wide-spread 
metastases,  often  passing  through  the  lungs  into  the  general  circulation. 
There  are  some  with  small  and  some  with  relatively  large  cells. 

Other  distinctly  sarcomatous  tumors  of  equally  cosmopolitan  origin  are 
composed  of  cells  uniform  in  type,  but  not  definitely  round  nor  spindle- 
shaped.  They  are  rather  polygonal  or  plump  cells,  which  form  a  compact 
tissue  with  abundant  ramifying  blood-vessels. 

In  these  especially,  but  also  in  the  other  forms  already  described,  there 
often  occurs  what  seems  to  me  to  be  a  local  necrosis  of  the  tumor  cells  from 
lack  of  sufficient  blood  supply.  This  leads  to  a  curious  condition  in  which 
only  those  cells  which  are  close  to  the  blood-vessels  remain  alive  and  the 
rest  fade  into  a  pale-pink  staining  debris  (Fig.  498).  Consequently  the 
tumor  appears  to  be  made  up  of  blood-vessels  each  with  a  thick  mantle  of 
cells,  and  such  tumors  have  been  described  as  a  separate  type  under  the 
name  angiosarcoma.  The  cells  about  the  blood-vessels  have  been  regarded 


SARCOMATA  975 

as  arising  from  a  hypothetical  tissue  spoken  of  as  perithelium,  and  the  tu- 
mor, therefore,  called  a  perithelial  angiosarcoma.  It  is  possible  that  tumors 
with  this  structure  really  exist,  to  which  the  explanation  just  given  will  not 
apply,  but  I  have  not  seen  them.  The  appearance  is  common  enough, 
but  in  itself  does  not  seem  sufficient  to  warrant  the  use  of  a  special  name. 
Alveolar  sarcomata  are  those  in  which  the  tumor-cells  are  rounded  or 
polygonal,  rarely  fusiform,  and  grow  in  groups  or  strands  which  lie  in  the 


*  St^iam    W>      «*  A  £*  *  ~*  • 

%&Xv^«*,**  *H6.-.  *  *&*  ®  *• 

^%i£;®«?*&  ty&  *  +*  ?•  *  *&$.*>  i^ 


F'ig.  497. — Round-cell  sarcoma  primary  in  the  testicle.     There  are  several  large  cells 
which  show  irregular  mitotic  figures. 


meshes  of  a  fairly  dense  stroma  (Fig.  493,  c  ).  In  a  single  section  the  cells 
appear  to  be  inclosed  in  alveolar  spaces  and  indeed  they  then  resemble  very 
closely  some  kinds  of  carcinoma.  At  times  it  is  difficult  if  not  impossible  to 
distinguish  between  them  from  a  single  section,  although  the  distribution  of 
the  tumors  and  the  history  of  the  case  will  usually  decide.  Efforts  have 
been  made  to  state  histological  criteria,  by  which  it  is  made  to  appear  that 
the  cells  of  the  sarcoma  are  in  more  intimate  relation  with  the  stroma  and 


976  TEXT-BOOK    OF    PATHOLOGY 

often  pervaded  by  fine  fibrillse  of  stroma,  while  the  carcinoma  cells  lie 
isolated  in  spaces  lined  by  endothelium.  I  am  sure  that  this  is  all  based  on 
hypothesis  made  to  suit  the  case  for  the  relation  of  the  epithelial  cells  of  the 
cancer  to  the  connective  tissue  may  in  point  of  space  be  just  as  close  as  that 
of  the  sarcoma  cells;  moreover,  the  fibrillaB  of  stroma  are  not  evident,  and 
the  cancer  cells  do  not  restrict  themselves  to  endothelial-lined  channels,  but 
push  into  any  cranny  or  crevice  of  the  fibrous  tissue.  The  form  of  the 


Fig.  498.— Sarcoma  springing  from  the  pelvis  and  showing  disintegration  of  the  cells, 
except  in  the  neighborhood  of  the  blood-vessels. 

tumor  cells  is  of  no  help  because  sarcoma  cells  and  epithelial  cells  may  look 
exactly  alike.  But  an  epithelial  origin  is  soon  found  for  the  cancer  in  one 
or  other  characteristic  site,  whereas  the  alveolar  sarcoma  begins  its 
growth,  not  in  an  epithelial  organ,  but  in  some  such  place  as  the  dermis 
or  the  fascia  or  the  skeletal  tissues.  It  is  quite  common  to  find  very 
numerous  subcutaneous  or  intracutaneous  nodules  scattered  over  the  body 
which  reveal  themselves  as  alveolar  sarcomata,  and  appear  to  grow  simul- 


SARCOMATA 


977 


taneously.  They  are  usually  secondary  to  some  original  growth  of  earlier 
formation. 

Giant- cell  Sarcomata. — Although  large  irregular  protoplasmic  masses 
with  several  nuclei  occur  at  times  in  many  of  the  mixed  cell  sarcomata,  there 
is  a  group  of  tumors  in  which  typical  multinucleated  giant-cells  form  so 
constant  and  characteristic  a  feature  that  they  are  classed  by  themselves 
under  this  name. 

They  arise  usually  in  connection  with  bone,  and  although  many  of  them 


Fig.  499. — Giant-cell  sarcoma  springing  from  a  bone. 

are  otherwise  composed  of  spindle-shaped  cells  showing  no  tendency  to 
cartilage  or  bone  formation  (Fig.  499),  there  are  also  tumors  containing 
such  giant-cells  which  definitely  belong  to  the  group  of  osteosarcomata. 
For  this  reason,  the  idea  has  been  suggested  that  the  giant- cells  may  be 
identical  with  the  osteoclasts  of  the  bone  which  are  endosteal  or  periosteal 
cells  modified  by  their  phagocytic  function.  Others  have  thought  that 
since  giant-cell  sarcomata  occur  also  in  other  places,  such  as  the  breast,  far 
from  any  connection  with  bone,  the  giant-cells  might  be  regarded  as  com- 
63 


978 


TEXT-BOOK   OF   PATHOLOGY 


parable  to  the  ordinary  foreign  body  giant-cells.  There  is  perhaps  no 
fundamental  difference  between  the  giant-cell  character  of  osteoblasts  and 
that  of  foreign-body  giant-cells,  and  in  both  cases  it  seems  to  be  a  morpho- 
logical modification  dependent  upon  the  function  of  the  cells  and  perhaps 
only  temporary.  It  is,  therefore,  difficult  to  decide  upon  the  relation  of  the 
cells  of  the  tumor  to  such  cells  and  probably  dangerous  to  assume  that  any 
of  these  types  of  giant-cells  could  transmit  their  giant-cell  character  to 
their  offspring. 


^t^^^^l^K^^^^-^v^^::^^^ 


500.  —  Giant-cell  sarcoma  (epulis)  from  the  jaw. 


The  most  common  giant-cell  sarcomata  are  those  which  grow  from  the 

alveolar  process  of  the  jaw  and  hang  as  pedunculated  tumors  in  the  cavity 

the  mouth.     These  growths,  which  are  known  by  the  name  epulis,  are 

covered  for  a  time  with  the  mucosa  of  the  mouth,  but  tend  to  become 

ulcerated.     They  are  usually  rather  small,  but  occasionally,  as  in  one  case 

icfa  I  saw,  reach  such  a  size  as  practically  to  fill  the  mouth.     When 

loved,  they  show  little  tendency  to  recur  and  there  are  no  metastases. 


SARCOMATA 


979 


Microscopically  the  dense,  hard  tumor  is  found  to  be  composed  of  inter- 
laced spindle-cells  with  numerous  large  multinucleated  giant-cells  (Fig.  500). 
Other  giant-cell  sarcomata,  closely  related  to  these,  spring  from  the  peri- 
osteum of  long  bones,  or,  still  more  commonly,  from  their  endosteal  lining. 
Expanding  and  eroding  the  cortex  of  the  bone,  they  form  large  masses  which 
are  kept  covered  by  a  constantly  new  formed  shell  of  periosteal  bone.  The 
central  part  may,  through  haemorrhage  or  other  disturbances  of  circulation, 


Fig.  501. — Periosteal  osteosarcoma  of  the  humerus.    The  marrow  cavity  is  not  invaded. 

become  necrotic  and  softened,  and  there  may  be  formed  a  cyst-like  swelling 
in  or  about  the  bone,  in  the  walls  of  which  little  or  no  tumor  tissue  is  left. 
Osteosarcoma,  Osteochondrosarcoma.  —  There  are  other  sarcomata, 
usually  forming  large  nodular  masses  about  the  bones,  which  are  developed 
from  the  periosteum  or  from  the  endosteum.  These,  while  showing  to  some 
degree  the  capacity  of  sarcomata  to  metastasize,  have  retained  the  power  of 
the  bone-forming  cells  to  elaborate  all  the  types  of  connective  tissue  con- 


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TEXT-BOOK    OF    PATHOLOGY 


cerned  in  the  formation  of  bone.  Hence  the  tumors  are  found  to  contain 
cartilage,  osteoid  tissue,  and  definite  bone,  as  well  as  the  less  specialized 
cellular  or  fibrous  tissue. 

Those  which  arise  from  the  periosteum  form  spindle-shaped  or  irregular 
nodular  masses  around  the  bone  (Fig.  501),  often  with  beautiful,  glistening, 
radially  arranged  spicules  of  bone  which  give  the  tumor  great  rigidity. 

Those  which  start  in  the  endos- 
teum  fill  the  marrow  cavity,  erode 
through  the  cortex  of  the  shaft  of 
the  bone,  and  finally  spread  out- 
side as  expanding  nodular  tumors 
(Fig.  502).  In  either  case  there 
may  be  great  irregularity  in  the 
form  of  the  growth  and  in  the 
character  of  the  tissue  of  which  it 
is  composed.  In  all  these  tumors 
which  arise  from  bone-forming 
cells  the  new-formed  tissue  usu- 
ally presents  a  ground-substance 
of  irregular  or  spindle-shaped 
cells,  among  which  certain  groups 
give  rise  to  areas  of  cartilage  or 
cartilage  -  like  tissue.  This  be- 
comes calcified,  and,  by  a  proc- 
ess resembling  that  of  normal 
ossification,  lamellae  of  bone  are 
formed,  usually  in  the  most  ir- 
regular arrangement.  In  other 
cases,  or  even  in  the  same  tumors, 
osteoid  tissue  is  usually  formed 
without  the  intervention  of  carti- 
lage, and  later  becomes  calcified 
into  true  bone.  Many  tumors, 
however,  remain  as  osteoid  sar- 


Fig.  502. — Osteosarcoma  involving  the 
marrow  of  the  humerus,  piercing  the  cortex 
in  many  places,  and  growing  out  radially 
under  the  periosteum. 


comata,  composed  largely  of  os- 
teoid tissue  with  relatively  little 
bone  formation.  The  cortex  of 
the  original  bone  may  remain  vis- 
ible in  the  midst  of  such  tumors, 

but  usually  shows  much  erosion  and  one  or  more  fractures.  In  other  cases, 
with  the  growth  from  inside,  the  dense  cortex  is  eroded  away  and  replaced 
on  the  outer  surface  of  the  advancing  tumor.  Since  the  replacement  is  less 
rapid  than  the  erosion,  a  thin-walled  dilatation  of  the  cortex  is  produced 
and  finally  broken  through. 

Osteosarcomata  and  the  allied  chondrosarcomata  form  metastases  in 


MYXOMATA  981 

distant  organs,  such  as  the  lungs,  and,  in  those  new  situations,  the  secondary 
nodules  usually  show  the  same  atypical  cartilage  and  bone  formation.  They 
are,  in  general,  less  malignant  than  other  sarcomata,  but  are  by  no  means 
entirely  innocent. 

Sarcomata  of  other  types  may  also  arise  in  the  interior  of  the  bones,  and, 
having  eroded  their  way  through  the  cortex  and  spread  outside  into  a  large 
tumor,  metastasize  extensively  elsewhere.  These  appear  not  to  grow  from 
the  active  bone-forming  endosteum,  since  they  form  little  or  no  bone  or 
cartilage,  but  are  composed  of  soft  cellular  tissue.  In  one  which  we  studied 
recently  there  had  been  a  tumor  springing  from  the  femur  for  which  the  leg 
had  been  amputated  several  months  before  death.  At  autopsy  enormous, 
soft,  partly  necrotic  tumor  masses  were  found  in  the  lungs  and  mediasti- 
num. These  were  composed  of  variegated  cells  without  the  least  evidence 
of  any  tendency  to  bone  formation  (Fig.  493,  d). 

LITERATURE 

Sarcoma. — Borst:  XV.  Cong.  Internat.  di  Med.,  Lisbonne,  1906,  Section  iii. 
Ackermann:  Volkmann's  kl.  Vortrage,  1883,  Nr.  233,  234. 
Coenen:  Beit.  z.  kl.  Chir.,  1909,  Ixiii,  337. 
Monckeberg:  Ergebn.  d.  allg.  Path.,  1906,  x,  730. 

MYXOMATA 

This  term  is  used  to  indicate  tumors  which  are  composed  of  a  loose  connec- 
tive tissue  with  branched  cells  widely  separated  by  a  viscid,  opalescent, 
mucoid  fluid,  which  actually  contains  mucin.  While  such  tissue  is  not 
found  in  the  adult  body,  it  does  exist  in  the  Wharton's  jelly  of  the  umbilical 
cord,  which  tissue,  therefore,  stands  as  the  prototype  of  the  myxoma. 

These  tumors  are  found  in  various  situations  in  the  subcutaneous  and 
intermuscular  tissues  in  connection  with  tendons,  periosteum,  and  joints, 
and  especially  in  the  heart. 

Ribbert  makes  a  point  of  declaring  that  in  those  frequent  cases  in  which 
a  complex  or  teratomatous  tumor  presents  patches  of  mucoid  tissue  here 
and  there,  the  myxomatous  part  is  not  to  be  regarded  as  a  secondary  degen- 
eration of  some  other  part  of  the  tumor.  In  other  words,  he  maintains  the 
independence  of  the  myxoma  as  a  distinct  tumor  which  may  be  combined 
with  cartilage  or  with  bone,  etc.,  to  form  a  myxochondroma  or  myxo- 
osteoma. 

In  the  heart  the  soft  tumor  is  in  most  cases  found  to  hang  in  polypoid 
form  from  the  wall  of  the  left  auricle,  more  rarely  arising  from  the  septum 
or  other  situation.  It  is  covered  with  endothelium  and  composed,  as  in 
other  cases,  of  the  mucin-containing  loose  tissue. 

In  most  instances  myxomata  are  benign  and  well-outlined  tumors,  but 
occasionally  they  evince  signs  of  malignancy  and  invade  widely  and  metas- 
tasize to  other  organs.  On  the  whole,  they  are  rare  tumors. 

There  is  a  form  of  myxomatous  tumor  which  grows  in  great  nodular  masses 
in  the  -retroperitoneal  region  at  the  root  of  the  mesentery,  and  pushes  aside 


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the  abdominal  organs,  although  it  does  not  become  closely  adherent  to 
them.  The  nodules  are  encapsulated,  and  may  be  as  large  as  a  cocoanut. 
On  removal  they  tend  to  recur,  and  even  to  produce  metastases  in  the  liver 
and  other  organs.  Such  tumors  are  not  rare,  and  we  have  had  an  oppor- 
tunity to  study  one  of  them  from  the  Mount  Sinai  Hospital  material,  where 
Dr.  Mandlebaum  has  seen  four.  In  this  case  there  were  five  large  masses, 
one  of  which  seemed  almost  entirely  composed  of  fat.  The  others  were 
elastic,  translucent,  and  gelatinous,  with  little  admixture  of  fat.  Micro- 
scopically the  lipoma-like  tumor  showed  some  areas  of  the  same  translucent 


5    ^f^ST"* 


Fig.  503. — Myxoma  from  retroperitoneal  region. 

tissue.  The  larger  gelatinous  tumors  were  composed  of  an  extremely  loose 
vascular  tissue  in  which  the  cells  were  rather  small,  provided  with  a  rounded 
or  oval  vesicular  nucleus,  and  long  branching  protoplasmic  processes  by 
which  they  held  together  (Fig.  503).  The  intercellular  fluid  was  extremely 
abundant,  and  it  was  necessary  to  examine  frozen  sections,  since  any 
attempt  to  make  a  paraffin  section  resulted  in  great  shriveling  of  the  tissue. 
With  hsematoxylin  the  fluid  assumes  a  bluish  stain. 

LITERATURE 
Ribbert:  Frankfurter  Ztschr.  f.  Path,  1910,  iv,  30. 


CHAPTER  L 
TUMORS  (Continued) 

Pigmented  tumors:  Ncevi.  Their  relation  to  epithelium  and  connective  tissue.  Melano- 
mata  or  melanotic  sarcomata.  Tumors  of  adrenal  origin:  Hypernephromata.  Rela- 
tion to  aberrant  adrenal  tissue.  Endotheliomata:  difficulty  of  establishing  their  relation 
to  endothelium.  Endotheliomata  from  lymphatic  endothelium;  cylindromata.  Pleural 
and  peritoneal  tumors.  Endotheliomata  of  the  meninges.  Tumors  derived  from  endothelium 
of  the  blood-vessels.  "  Perithelial  "  tumors. 

TUMORS  which  show  the  presence  of  brown  or  black  pigment,  and  which  in 
some  cases  develop  an  extreme  malignancy,  form  a  group  whose  position  in 
the  general  scheme  of  tumors  is  still  extremely  debatable,  because  it  is 
impossible  to  decide  as  to  the  nature  of  the  cells  from  which  they  arise. 
Since  they  behave  more  in  the  manner  of  sarcomata  than  in  that  of  other 
tumors,  they  may  be  described  here,  although  it  must  be  borne  in  mind  that 
there  is  no  good  proof  of  their  right  to  this  place. 


The  simplest  of  these  are  the  pigmented  moles  or  nsevi,  which  are  flat  or 
slightly  elevated,  gray  or  brown  or  almost  black  patches  in  the  skin.  Some- 
times they  are  quite  prominent,  roughened,  and  irregular,  and  may  be  marked 
by  the  growth  of  coarse  hairs  (Fig.  504)  .  There  are  many  varieties  in  so  far  as 
the  intensity  of  pigmentation  and  the  bulk  of  the  tumor  tissue  are  concerned, 
but  the  structure  is,  in  its  essentials,  similar  in  all.  Occasionally,  however, 
the  tumors  are  exceedingly  rich  in  blood-vessels,  so  that  they  have  then  the 
character  of  superficial  angioma:  a.  The  overlying  skin  is  slightly  irregular  in 
thickness  and  sends  down  quite  long  interpapillary  processes  of  epithelium. 
The  papillae  of  the  corium  are  enlarged  by  the  presence  of  compact  or  loose 
masses  of  cells,  commonly  called  nsevus  cells,  which  are  sometimes  quite 
colorless  (Fig.  505)  and  sometimes  deeply  pigmented.  It  is  with  regard  to 
the  nature  of  these  cells  that  discussion  has  been  carried  on  for  years,  since 
it  is  most  desirable  that  we  should  know  whether  they  are  derived  from  the 
epithelium  or  not.  The  following  table  from  Dalla  Favera  shows  fairly  well 
the  position  taken  by  various  authors  on  this  point. 

1.  They   arise   from  the   epidermis    (Unna,   Kromayer,    Marchand, 
Gilchrist,  and  many  others). 

2.  They  are  of  mesodermal  origin,  and  are  — 

(or)  Young  connective-tissue  cells  (Simon,  Virchow,  Riecke). 

983 


gg4  TEXT-BOOK   OF   PATHOLOGY 

(6)  They  arise  from  proliferation  of  the  lymphatics  (v.  Reckling- 
hausen,  Lubarsch,  Herxheimer,  and  others). 

(c)  They  spring  from  the  endothelium  and  penthelmm  of  blood- 

vessels (Pick,  Jadassohn). 

(d)  They  originate  in  the  sheaths  of  nerve-fibres  (boldan). 

3.  They  are  specially  characterized  cells  of  mesodermal  origin— ehro- 
matophores  (Ribbert). 

From  this  it  will  be  seen  what  divergent  views  have  been  held  by  the  best 
observers.  Dalla  Favera,  in  a  paper  from  Marchand's  institute,  presents 
the  study  of  30  najvi,  and  brings  very  convincing  histological  pictures  to 


Fig.  504. — Small  pedunculated  nsevus  of  skin  showing  the  relation  of  the  nsevus  cell 

strands  to  the  epidermis. 


prove  that  naevus  cells  originate  in  direct  continuity  with  the  epithelial 
cells,  forming  in  little  nests  in  cavities  among  those  cells,  and  later  becoming 
loosened  and  separated.  Ribbert  is  quite  as  emphatic  in  his  claim  that 
these  cells  are  not  epithelial  cells,  since  the  character  of  their  nuclei  and 
protoplasm,  and  especially  the  possession  of  numerous  long  processes,  makes 
that  practically  impossible.  As  chromatophores  they  are  mesodermal  cells 
whose  duty  it  is  to  carry  pigment.  Similar  cells  are  found  in  many  lower 
animals,  where  they  lie  in  the  skin,  and  by  changes  in  their  form  are  instru- 
mental in  producing  changes  in  its  color. 


MELANOTIC   SARCOMA 


98^ 


Such  pigmented  and  colorless  nsevi  may  remain  for  many  years  without 
much  increase  in  size  and  without  producing  any  ill  effects.  Through  trau- 
matism  or  for  some  other  more  obscure  reason  they  may,  however,  begin  to 
grow  and  produce  a  definite  tumor.  The  pigmented  tumor  thus  formed  is  a 
melanoma  or  melanotic  sarcoma. 


Fig.  505. — Non-pigmented  nsevus  of  skin  of  the  shoulder.    The  papillae  of  the  coriuna 
are  hypertrophied.    Large  masses  of  "nsevus  cells"  lie  in  its  deeper  parts. 


MELANOTIC  SARCOMATA 

These  tumors  cannot  always  be  shown  to  have  originated  in  a  well-defined 
mole,  and  there  are  many  cases  in  which  the  cutaneous  manifestations 
remain  inconspicuous  while  large  internal  metastases  develop.  Doubtless 
it  could  be  said  that  the  origin  was  really  from  some  small  mole  in  such 
cases,  but  in  one  which  was  seen  in  the  Presbyterian  Hospital  recently  there 
was  only  a  bluish  stain  above  the  knee  which  could  not  be  felt  with  the 
finger,  and  yet  the  adjacent  inguinal  lymph-nodes  were  greatly  enlarged 
and  the  man  actually  coughed  or  spat  up  a  piece  of  tissue,  which  on  section 
showed  the  typical  structure  of  a  melanosarcoma.  No  autopsy  was  obtain- 
able to  reveal  the  position  of  the  growth  from  which  that  piece  came. 
Another  case  may  be  recalled  in  which  a  melanosarcoma  apparently  arose 


TEXT-BOOK   OF    PATHOLOGY 

in  a  healing  hsematoma  under  the  thumb-nail  and  caused  death  from  nu- 
merous metastases  some  months  after  the  first  injury. 

Usually  it  is  possible  to  trace  the  black  tumor-mass  which  develops  in  the 
skin  to  a  preexisting  nsevus  at  the  same  spot.  That  nsevi  are  not  essential 
is  shown,  however,  by  the  growth  of  quite  similar  tumors  from  the  choroid 
of  the  eye,  from  the  brain  and  meninges,  from  the  conjunctiva,  the  nasal 
mucosa,  the  adrenal,  ovary,  intestine  (ampulla  of  Vater),  the  rectum, 

urethra,  etc. 

For  those  who  hold  to  the  ectodermal  or  epithelial  origin  of  the  tumors, 


Fig.  506. — Primary  melanoma  of  the  choroid.  There  was  relatively  little  pigment  in 
this  tumor.  The  retina  is  dislodged  and  stretches  through  the  middle  of  the  vitreous 
humor  at  6.  The  outer  layer  of  the  retina  passes  over  the  tumor  at  a. 

it  would  seem  that  some  of  these  sites  could  hardly  be  explained.  Never- 
theless, the  invasion  of  ectodermal  sympathetic  cells  in  the  adrenal  is  ad- 
duced to  explain  the  tumors  of  adrenal  origin,  while  in  other  cases  the  par- 
ticipation of  displaced  embryonic  remains  in  the  form  of  teratomata  may 
afford  a  source  of  epithelial  cells.  It  is  not  possible  to  form  a  definite  opinion 
as  to  the  true  nature  of  the  pigmented  cells  from  the  evidence  now  available. 
Naturally,  there  is  no  fundamental  reason  why  mesodermal  cells  should  not 
form  pigment  from  materials  supplied  by  the  blood,  although  in  general  we 
are  more  accustomed  to  find  the  pigments  of  the  body  produced  by  cells  of 
epithelial  origin.  Whatever  is  ultimately  determined  to  be  their  true  rela- 


MELANOTIC   SARCOMA 


987 


tion,  it  is  clear  that  these  cells  do  not  merely  receive  pigment  transferred  to 
them  from  other  cells,  but  maintain  throughout  their  existence  the  ability 
to  form  pigment  and  transmit  that  ability  to  their  offspring. 

The  melanosarcomata  of  the  skin  are  composed  of  compact  masses  of 
cells  which  in  section  have  an  irregular  polygonal  form  or  are  more  often  fusi- 
form (cf.  Fig.  49),  although  Ribbert  shows  that  in  fresh  teased  specimens 
they  possess  numerous  long  processes  which  are  pigmented  to  their  ends. 
The  pigment  is  in  fine  granules  and  clumps  and  is  yellowish  brown  or  dark 
brown  in  color.  Much  of  it  is  scattered  free  in  the  crevices  of  the  tissue 
and  is  taken  up  by  various  phagocytic  cells.  The  stroma  is  sometimes  very 


Fig.  507. — Melanoma.     Multiple  small  metastatic  nodules  in  the  liver.    The  primary 
tumor  was  in  the  choroid  of  the  eye. 

delicate,  but  often  coarse  enough  to  divide  the  tumor  into  an  alveolar 
arrangement. 

In  the  eye  these  tumors  spring  from  the  choroid  either  as  a  flat,  lamellar 
plate,  or  as  a  nodule  which  may  be  distinctly  pedunculated.  They  grow  up 
into  the  vitreous  humor,  pushing  the  layers  of  the  retina  before  them,  and 
finally  filling  the  whole  eye  or  bursting  outward  to  invade  the  orbit  (Fig 
506). 

In  the  other  sites  in  which  primary  melanomata  occur  their  mode  of 
growth  and  histological  structure  are  similar.  Melanomata  grow  with  great 
rapidity  and  spread  their  metastases  by  way  of  the  blood-stream  with 
extraordinary  effect,  producing  secondary  growths  in  great  numbers  in  all 
the  organs  (cf.  Fig.  48).  These  vary  in  size  from  minute  groups  of  cells  so 
small  as  to  be  visible  only  when  they  stand  out  by  their  black  color  against 


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such  a  tissue  as  the  white  matter  of  the  brain,  up  to  enormous  masses  which 
occupy  a  great  part  of  the  liver.  There  are  usually  many  nodules  scattered 
in  each  organ,  and  in  the  case  of  the  liver  it  is  common  to  find  hundreds 
of  rounded  tumors  which  are  embedded  everywhere  in  the  tissue  (Fig.  507). 
Most  of  these  are  very  deeply  colored,  but  some  of  them  may  be  perfectly 
unpigmented.  Frequently  a  single  nodule  shows  both  black  and  white 
portions.  In  the  heart-wall  one  may  find  several  coal-black  nodules  or  a 
whole  sprinkling  of  small  black  points. 

In  all  these  positions  necrosis  and  disintegration  of  the  tumor  occur,  and 
much  of  the  pigment  thus  released  is  taken  up  by  the  endothelial  cells  and 
wandering  phagocytes  or  remains  scattered  free  in  the  crevices  of  the  tissue. 
It  seems  to  be  carried  in  the  blood-stream  to  the  kidneys,  and  is  decolorized 
in  this  transit,  but  appears  again  in  its  black  form  in  the  urine,  especially 
after  exposure  to  air.  The  pigment  itself  is  one  of  the  melanins,  and  con- 
tains sulphur,  but  no  iron. 

LITERATURE 

Dalla  Favera:  Ziegler's  Beitrage,  1903,  xliii,  43. 

T.  C.  Gilchrist:  Jour.  Cutaneous  and  Genito-Urinary  Diseases,  1899,  xvii,  117. 
Ribbert:  Ziegler's  Beitrage,  1897,  xxi,  471. 
Geschwulstlehre,  Bonn,  1904,  255. 

Wolfrum:  Ergebn.  d.  allg.  Path.,  1914,  xvi,  Ergnzbd.,  660. 
Kyrle:  Arch.  f.  Dermatol.  u.  Syphilis,  1913,  cxviii,  319. 
Pinkus:   Dermatol.  Ztsehr.,  1908,  xvi,  483. 
Maclachlan:  Jour.  Med.  Research,  1914,  xxix,  433. 
Winternitz:  Johns  Hopkins  Hosp.  Bull.,  1909,  xx,  314. 

TUMORS  OF  ADRENAL  ORIGIN  (HYPERNEPHROMATA) 

This  is  a  group  of  tumors  of  such  common  occurrence  as  to  be  familiar  to  all 
pathologists,  but  yet  so  peculiar  in  their  histological  characters  and  location 
as  to  have  given  rise  to  differences  of  opinion  with  regard  to  their  origin, 
which  are  even  yet  unsettled. 

They  are  nodules  of  soft,  opaque,  yellow  tissue,  sometimes  very  small, 
sometimes  growing  to  a  great  size,  and  situated  in  the  adrenal  gland,  in  the 
kidney,  or  just  beneath  its  capsule,  or  in  any  one  of  many  other  positions,  such 
as  the  liver,  pancreas,  retroperitoneal  tissue,  spermatic  cord,  epididymis, 
etc.  The  tumors  may  be  multiple,  and  while  the  small  multiple  nodules 
appear  to  remain  localized,  the  larger  ones  may  exhibit  an  extreme  malig- 
nancy, forming  metastases  in  the  lung,  bones,  and  other  distant  organs. 

Attention  was  directed  to  the  probability  of  their  origin  from  the  adrenal 
by  Grawitz,  who  referred  those  occurring  in  the  kidney  to  the  overgrowth  of 
small  misplaced  masses  of  adrenal  tissue  embedded  in  the  substance  of  that 
organ.  It  is  found  that  accessory  nodules  of  adrenal  tissue  are  actually 
distributed  quite  widely  in  the  body,  and  are  found  not  only  in  the  immedi- 
ate neighborhood  of  the  adrenal  itself,  or  embedded  in  its  cortex,  but  also  in 
the  liver,  kidney,  and  in  the  other  situations  mentioned,  broad  ligament, 
spermatic  cord,  epididymis,  etc.  These  are  often  of  microscopic  dimen- 


TUMORS    OF   ADRENAL   ORIGIN    (HYPERNEPHROMATA) 


989 


sions,  may  be  present  in  considerable  numbers,  and  are  usually  composed  of 
tissue  identical  with  that  of  the  cortex  of  the  adrenal.  There  are  found 
occasionally  accessory  adrenals  which  contain  medullary  elements  also,  and 
a  few  have  been  described  which  were  said  to  be  composed  entirely  of 
medullary  tissue.  The  most  common  are  those  in  which  cortical  cells  are 
arranged  radially  to  form  a  small  rounded  nodule. 

Such  nodules  appear  not  to  grow  to  any  great  size.     They  contain  the 
same  abundant  lipoids  as  the  adrenal  cortex,  but  do  not  produce  adrenaline, 
since  that  is,  of  course,  a  function 
of  the  medulla. 

The  larger  tumors  are  most  com- 
monly found  embedded  in  the  kid- 
ney, the  tissue  of  which  they  push 
aside  or  destroy  (Fig.  508).  They 
usually  grow  in  the  cortex,  bulging 
under  the  capsule,  which  they  may 
perforate,  but  in  many  cases  they 
extend  through  the  pyramidal  re- 
gion so  as  to  approach  the  pelvis. 
The  best  preserved  part  of  the  tu- 
mor is  yellow  or  reddish -yellow, 
often  interspersed  with  gray,  trans- 
lucent areas,  but  in  practically  every 
case  there  are  found  extensive  areas 
of  necrosis  with  wide-spread  haemor- 
rhage, which  gives  the  cut  surface 
an  extremely  variegated  appearance. 

In  the  further  course  of  their  de- 
velopment these  tumors  metastasize 
sometimes  by  way  of  the  lymphatic 
channels,  but  more  often  through 
the  venous  blood-stream.  I  have 
seen  one  case  in  which  the  lymph- 
atics in  the  walls  of  the  blood-vessels 
in  the  lungs  were  filled  with  the 


Fig.  508. — Hypernephroma  embedded  in 
the  substance  of  the  kidney. 


yellow  tumor  mass,  in  such  a  way 
that  all  these  vessels  stood  out 
prominently  as  thick-walled  tubes 

composed  of  a  soft  yellow  material.  In  this  case  the  primary  transpor- 
tation may  well  have  taken  place  by  way  of  the  circulating  blood,  the 
filling  of  the  pulmonary  lymphatics  being  a  secondary  phenomenon.  On 
the  other  hand,  Oberndorfer,  Ribbert,  and  others  describe  extraordinary 
invasions-ef  the  branches  of  the  renal  vein,  with  continuous  extension  of  the 
tumor  through  the  vena  cava  into  the  heart.  We  saw  such  a  case  at 
autopsy  in  which  the  main  tumor  was  situated  in  the  left  kidney.  The 


990 


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veins  draining  it  were  completely  occluded  by  moulds  of  tumor  tissue  which 
extended  to  fill  the  left  renal  vein,  and  reached  across  to  ramify  in  the  right 
renal  vein  far  into  the  right  kidney.  In  the  vena  cava  it  proceeded  upward, 
forming  a  cylindrical  mass  3  cm.  in  diameter,  which  completely  blocked  and 
distended  the  vein  up  to  a  point  just  below  the  entrance  of  the  hepatic  veins. 
On  looking  down  into  the  vena  cava  it  could  be  seen  as  a  rounded  mass  partly 
covered  with  fresh  thrombi.  Metastases  were  found  in  the  lungs  and  in 
various  bones,  those  in  the  skull  being  especially  striking  since  their  growth 


Fig.  509. — Hypernephroma  showing  characteristic  large  clear  cells. 

from  the  diploe  was  accompanied  by  the  formation  of  sharp  spicules  of  bone 
which  projected  about  each  nodule. 

When  studied  microscopically,  these  tumors  are  found  to  present  a  great 
variation  in  structure,  but  those  arising  from  the  kidney  resemble  closely 
those  derived  from  the  adrenal  itself.  The  most  common  microscopical 
picture  is  that  in  which  wide  strands  of  cells  anastomose  freely  with  one 
another  and  are  cut  at  various  angles  (Fig.  509) .  These  are  supported  by  a 
delicate  stroma  with  thin-walled  blood-vessels.  The  cells  are  large,  cylindri- 


TUMORS    OF   ADRENAL    ORIGIN    (HYPERNEPHROMATA)  991 

cal,  or  cubical,  and  extremely  pale  and  transparent,  recalling  in  their  appear- 
ance the  cells  of  a  growing  plant  tissue.  Glycogen  is  found  in  these  cells, 
together  with  abundant  droplets  of  cholesterine  esters  and  other  lipoids, 
such  as  are  normally  found  in  the  adrenal  cortex.  The  resemblance  of  the 
tumor-cells  to  those  of  the  adrenal  cortex  has  always  been  emphasized,  but 
it  must  be  admitted  that  they  are  far  more  transparent  than  the  cells  of  the 
gland.  In  many  cases  the  tumor-cells  are  arranged  not  in  strands,  but  as 
the  lining  elements  of  tubular  spaces.  These  canals  may  anastomose 
widely  or  become  distended  into  spaces  of  considerable  size.  Frequently 
they  are  filled  with  blood,  which  appears  to  be  in  a  good  state  of  preservation, 
so  that  the  idea  has  arisen  that  these  may  be  tumors  in  which  the  typical 
cells  are  really  endothelial  cells  lining  blood-channels,  and  that  they  should 
be  regarded  rather  as  endotheliomata.  In  other  cases  still  the  necrosis  of 
the  tumor  tissue  leaves  nothing  but  mantles  of  cells  about  the  blood-vessels, 
and  these  have  been  looked  upon  by  some  authors  as  peritheliomata.  This 
peculiar  condition  has  been  mentioned  elsewhere  in  connection  with  other 
tumors,  and  it  was  said  that  it  seems  quite  wrong  to  assign  to  these  rem- 
nants of  tissue  a  name  which  suggests  that  they,  as  "perithelial"  cells,  had 
given  rise  to  the  tumor. 

Not  all  these  tumors  are  even  as  simple  as  this,  for  there  are  some  in  which 
large  cavities  occur  and  others  in  which  the  epithelial  cells  are  thrown  up 
into  most  complicated  papillary  folds  which  may  almost  fill  the  cavities.  In 
these  cases  the  cells  are  usually  more  granular  and  less  like  vegetable  cells. 

Since  the  assertion  of  Grawitz  that  such  tumors,  even  when  they  occur  in 
the  kidney,  arise  from  misplaced  bits  of  adrenal  tissue,  there  has  been  a 
great  deal  of  discussion  of  their  origin  and  true  relations.  Sudeck,  Stoerck, 
and  others  contest  their  relation  to  the  adrenal,  and  claim  that  there  is  strong 
evidence  that  they  are  really  derived  from  the  tissue  of  the  kidney,  and  that 
they  are  renal  rather  than  adrenal  tumors.  In  the  lack  of  any  perfectly 
decisive  proof  it  seems  to  me  that  their  arguments  are  weak,  and  that  the 
evidence  which  Grawitz  himself  brought  forward  to  show  their  relation  to 
the  adrenals  is  stronger.  These  arguments,  which  deal  with  the  lipoid  and 
glycogen  content,  with  the  formation  of  spaces  or  lumina  in  the  tumors,  etc., 
may  be  read  in  the  papers  of  Stoerk,  Sisson,  Sabolotnow,  and  others. 

Wells  has  analyzed  the  lipoid  content,  and  has  found  that  it  approaches 
that  of  the  normal  adrenal  cortex  and  far  exceeds  that  of  other  tumors.  He 
could  demonstrate  no  adrenaline-like  substance  in  any  of  the  tumors. 

LITERATURE 

Stoerk:  Verb.  d.  Dtsch.  Path.  Gesell.,  1908,  xii,  123. 
Grawitz:  Arch.  f.  kl.  Chir.,  1884,  xxx. 
Sabolotnow:  Ziegler's  Beitrage,  1907,  xli,  1. 

Wells:  Arch.  Int.  Med.,  1909,  iv,  291;  Jour.  Med.  Research,  1908,  xvii,  461. 
Sisson:  Ziegler's  Beitrage,  1910,  xlix,  476. 
Davis:  Arch.  Int.  Med.,  1911,  viii,  60. 
Kostenko:   Dtsch.  Ztschr.  f.  Chir.,  1911,  cxii,  284. 
Rosenfeld:  Frankfurter  Ztschr.  f.  Path.,  1913,  xiv,  151. 


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ENDOTHELIOMATA 

The  tumors  so  far  discussed  have  been  described  as  though  they  were  com- 
posed of  elements  whose  relationship  to  some  tissue  which  gave  them  origin 
is  so  readily  recognizable  as  to  rouse  no  doubts.  Further,  they  have  been 
spoken  of  as  though  in  every  part  they  presented  the  same  characteristic 
appearance.  In  many  cases  these  things  are  true,  and  we  have  no  hesita- 
tion in  assigning  a  definite  source  for  a  tumor  which  is  quite  uniform  in 
structure  throughout,  and  whose  cells  are,  as  in  the  case  of  a  fibroma  or 
chondroma,  obviously  of  the  same  general  character  as  those  of  the  tissue 
in  which  they  develop.  More  emphasis  should  have  been  laid,  however, 
upon  the  frequent  admixture  of  other  tissues,  and  especially  upon  the  modi- 
fications which  the  essential  tissue  of  the  tumor  undergoes.  Thus  nothing 
is  commoner  than  to  find,  instead  of  a  pure  chondroma,  an  osteochondroma 
or  a  myxochondroma  or  a  myxochondrosarcoma.  In  these  cases  it  must  be 
decided  whether  the  tissues  are  of  equal  dignity  in  the  tumor  growth,  or 
whether  one  or  two  of  them  represent  metaplasia  or  degenerative  changes  in 
the  other.  In  most  of  the  cases  already  considered  we  have  dealt  with 
tissues  so  closely  related  that,  as  in  the  case  of  cartilage,  bone,  and  connec- 
tive tissue,  we  are  not  surprised  to  find  one  assuming  the  character  of  the 
other  or  giving  rise  to  the  other  in  its  further  growth.  We  realize  that  many 
of  these  changes  are  due  to  the  infiltration  of  fluid  or  of  mucin  or  to  some 
other  mechanical  or  chemical  change  which  can  produce  an  alteration  in  the 
appearance  of  the  interstitial  substance  or  of  the  cells  themselves. 

In  spite  of  some  difficult  feats  of  tracing  the  cells  to  unfamiliar  stages  in 
the  embryonic  development  of  their  parent  cells,  we  have  found  it  possible 
to  feel  pretty  sure  of  the  point  of  departure  of  the  tumor  elements.  Of 
course,  a  rigid  criticism  might  show  that  we  are  by  no  means  possessed  of 
proofs  of  these  histogenetic  relations,  but,  on  the  whole,  there  is  so  much 
evidence  that  the  tracing  seems  safe  enough. 

There  are,  however,  many  tumors  whose  origin  and  histogenetic  relations 
are  difficult,  if  not  impossible,  to  trace.  They  are  never  the  familiar  tumors 
which  occur  in  dozens  of  cases  in  practically  the  same  form  and  situation, 
but  odd  growths  which  appear  in  some  unusual  site  or  in  tissues  where  any 
one  of  several  origins  might  be  assigned  to  them.  In  structure  they  are 
unlike  any  known  tissue,  and  offer  no  suggestion  as  to  their  nature  from  the 
non-committal  arrangement  of  their  cells.  Of  course,  it  must  occur  to 
every  one  that  in  time  these  tumors  will  be  recognized  in  spite  of  their  lack 
of  resemblance  to  known  mature  tissues,  just  as  the  neuroblastomata  were 
finally  recognized,  although  they  had  long  been  contemplated  without 
understanding.  But  the  stumbling-block  is  that  a  name  has  been  dis- 
covered under  which  all  these  difficult  tumors  can  be  conveniently  classed, 
and  thus  pigeonholed  and  withdrawn  from  further  study.  Every  unusual 
tumor  which  lacks  characters  that  will  permit  its  ready  recognition  stands 
an  excellent  chance  of  being  labeled  endothelioma  and  relegated  to  oblivion. 


ENDOTHELIOMATA  993 

Still  more  disturbing  is  the  fact  that  certain  well-known  groups  of  tumors, 
such  as  the  mixed  tumors  of  the  salivary  glands,  have  been  declared  by 
some  one  to  be  endotheliomata,  and  have,  therefore,  been  classed  in  that 
capacious  group  by  every  one.  Happily,  in  that  particular  type  of  tumor 
there  has  been  sufficient  interest  to  bring  forth  further  study  with  more 
accurate  results. 

In  practically  no  case  has  the  origin  of  a  tumor  from  endothelium  been 
proven.  As  Ribbert  points  out,  the  mere  continuity  of  the  tumor-cells  with 
endothelium  at  the  margin  of  the  tumor  is  no  proof  of  their  identity.  Borst 
has  shown  that  tumor-cells  may  grow  into  lymphatic  channels  and  cause  the 
endothelial  cells  to  proliferate,  but  that  even  when  the  proliferation  is  suffi- 
cient to  close  the  channel,  it  is  only  a  normal  reaction  to  the  presence  of  a 
foreign  tissue  and  not  a  participation  by  the  endothelial  cells  in  the  tumor 
growth.  Ribbert  thinks  that  proof  of  the  endothelial  nature  of  a  tumor 
will  require  the  study  of  that  tumor  at  its  inception,  which  is  impossible. 

Much  confusion  has  arisen  because  of  the  uncertainty  as  to  what  should 
be  called  endothelium,  and  many  different  standpoints  have  been  taken. 
All  agree  that  the  lining  cells  of  blood-  and  lymph-vessels  and  the  lining 
of  the  cerebrospinal  spaces  must  be  accepted  as  endothelium.  Disputed 
tissues  are  the  lining-cell  layers  of  pleura,  peritoneum,  etc.  According  to 
the  coelom  theory,  these  cells  must  be  epithelial  (hypoblastic  and  epiblastic) 
in  origin.  Some  other  characteristics,  such  as  the  possession  of  cilia,  etc. 
make  them  seem  more  allied  to  epithelium,  and  indeed  there  are  many  now, 
including  Ribbert,  who  regard  the  serosa  cells  as  epithelial  in  nature  and  the 
tumors  derived  from  them  as  epithelial  tumors. 

Even  yet,  in  spite  of  all  the  work  on  the  relation  of  the  lymphatics  to  the 
connective  tissue,  much  is  written  of  the  endothelial  cells  which  line  or 
partly  line  the  indefinite  lymph-spaces  or  crevices  in  the  tissue,  and  what  is 
written  is  used  as  a  complete  explanation  of  the  origin  of  certain  obscure 
tumors.  Since  it  appears  that  the  lymphatics  are  complete  blind-ending 
tubes  lined  with  endothelium,  such  tumors  would  have  to  be  derived  from 
their  walls. 

There  is  no  reason  that  endothelial  tumors  should  not  arise  from  the 
endothelium  of  the  lymphatics  or  blood-capillaries.  No  doubt  they  do  and 
possibly  some  of  the  tumors  described  as  endotheliomata  really  have  this 
origin,  but  it  is  far  from  proven  or  even  plausible  in  most  cases,  and  in  many 
the  essential  cells  of  the  tumor,  though  flattened  and  stretched  out,  are 
easily  shown  to  be  epithelial  cells.  Indeed,  in  most  of  these  tumors  which 
arise  in  the  skin,  in  the  mouth,  or  nasal  sinuses,  in  connection  with  bones, 
or  in  less  characteristic  situations,  it  is  found  that  the  tumor-cells  are  flat- 
tened, rather  deeply  staining  cells,  arranged  in  strands  which  anastomose 
and  give  off  long-pointed  processes  which  extend  into  crevices  of  the  con- 
nective tissue.  The  cells  do  not  resemble  any  normal  type  closely,  and 
since  no  primary  growth  is  found  in  any  of  the  usual  epithelial  organs,  and 
since  further  the  cells  stand  out  too  distinctly  from  the  stroma  to  be  accepted 
64 


TEXT-BOOK    OF    PATHOLOGY 

as  connective-tissue  cells,  it  is  rather  feebly  assumed  that  they  must  be 
endothelial  cells.  The  proof  is  not  much  stronger  than  that,  and  is  rather  a 
process  of  exclusion  than  a  positive  tracing  of  a  relation  to  endothelium. 
Even  though  every  one  must  admit  the  possibility  and  even  the  probability 
of  the  existence  of  tumors  derived  from  endothelium  of  the  lymphatics,  this 
kind  of  reasoning  is  most  unsatisfactory. 

In  the  following,  the  types  of  tumors  which  have  been  looked  upon  as 
derived  from  endothelium  may  be  given  briefly  and  discussed.  It  will  be 
found  that  the  evidence  of  their  relation  to  endothelium  is  thought  to  be 
satisfactory  in  the  cases  of  endothelioma  of  the  dura,  and  in  a  very  small 
number  of  tumors  derived  from  capillary  blood-vessels,  but  that  in  the 
others  it  is  either  disproven  or  very  doubtful.  New  tumors  are  constantly 
being  described  in  which  an  attempt  is  made  to  establish  an  endothelial 
origin,  and  the  matter  may  soon  reach  a  state  of  greater  clearness. 

Endotheliomata  Derived  from  Lymphatic  Endothelium. — Tumors  of  the 
skin  are  described  by  Borst  and  others  as  composed  of  nodular  masses  of 
rather  dense  tissue  in  which  anastomosing  strands  of  flattened  smooth  cells, 
sending  off  pointed  processes,  are  embedded  in  connective  tissue.  Similar 
tissues  are  found  elsewhere,  and  may  be  really  endotheliomata  or  derived 
from  much  altered  epithelium. 

Cylindromata  or  tumors  in  which  hyaline  cylindrical  strands  or  balls  are 
interspersed  with  strands  of  flattened  cells  were  described  by  Billroth,  and 
have  been  much  discussed  in  later  years.  They  are  usually  tumors  which 
occur  in  the  mouth,  near  the  salivary  glands,  or  in  the  nasal  sinuses,  but 
may  be  found  elsewhere.  They  are  generally  benign,  but  may  metastasize. 
Histologically  the  cylindrical  hyaline  structures  (which  are  not  peculiar  to 
these  tumors,  but  may  occur  in  sarcomata  and  carcinomata)  are  seen  to  be 
formed  by  modification  of  the  connective-tissue  stroma  or  of  the  walls  of 
the  blood-vessels  (Fig.  510),  although  in  some  cases  such  hyaline  masses 
appear  to  be  formed  in  the  middle  of  a  strand  of  tumor-cells.  The  name  is 
given  on  account  of  this  anatomical  peculiarity,  and  should  not  distinguish 
a  special  type  of  tumor.  While  it  is  difficult  to  decide  upon  the  actual  origin 
of  the  tumor-cells,  Ribbert  has  brought  strong  evidence  that  they  are 
epithelial  and  that  they  arise  from  the  glands  or  surface  epithelium  of  the 
mouth  and  nasopharynx. 

Pleural  or  peritoneal  tumors  have  given  rise  to  much  difference  of  opinion. 
They  are  apparently  primary  in  the  lining  cells  of  the  pleura  or  peritoneum, 
and  can  be  distinguished  from  those  which  occur  as  metastases  from  pri- 
mary tumors  situated  elsewhere.  The  latter  are  usually  in  the  form  of 
small  lenticular  or  rounded  nodules,  which  extend  into  the  underlying 
lymphatic  channels,  while  the  primary  tumors  of  the  pleura  are  most  com- 
monly seen  as  thick  white  layers  of  dense  tissue  covering  the  lung  and 
containing  in  the  meshes  of  the  connective  tissue  simple  or  very  complicated 
arrangements  of  cells  whose  nature  cannot  be  positively  stated  from  a  study 
of  their  morphology.  There  are  some  investigators  who  insist  that  they  are 


ENDOTHELIOMATA 


995 


derived  from  the  endothelium  of  the  underlying  lymphatic  channels,  but 
the  majority,  including  Ribbert,  refer  them  to  the  serosa  cella  and  consider 
them  epithelial  tumors.  They  may  metastasize  to  lymph-glands  or  extend 
into  the  lung.  Those  arising  in  the  peritoneal  cavity  are  more  likely  to 
occur  in  nodular  form.  They  too  may  invade,  and,  penetrating  the  dia- 
phragm, spread  over  the  pleura. 


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Fig.  510. — Cylindromatous  tumor. 

Endotheliomata  of  the  Dura  Mater. — There  seems  to  be  a  general  agree- 
ment of  opinion  as  to  the  endothelial  character  of  the  lining  of  the  dura. 
The  cells  of  this  lining  are  often  thrown  up  into  minute  solid  masses  which 
can  be  recognized  with  the  naked  eye  and  which  seem  to  foreshadow  the 
possibility  of  tumor  formation.  Tumors  attached  to  the  dura  and  pressing 
into  the  surface  of  the  brain  are  quite  common.  They  may  reach  such  a 
size  as  to  compress  the  brain  seriously  and  to  cause  death  by  occupying  the 
limited  space  of  the  cranium.  In  one  case  we  observed  a  tumor  of  the  size 
of  an  egg  lying  on  the  convex  surface  of  the  cerebrum,  in  which  it  had 


996 


TEXT-BOOK   OF   PATHOLOGY 


pressed  a  deep  groove  for  its  own  accommodation.  This  was  a  stalked  growth 
hanging  from  the  dura  along  the  median  longitudinal  sinus.  Others  (as  in 
Fig.  511)  embed  themselves  deeply  in  the  cerebral  substance  and  may 
appear  as  though  derived  from  the  brain.  They  are  sharply  limited,  how- 
ever, and  readily  fall  out  of  the  depression  in  which  they  lie.  Most  of  them 
appear  in  the  neighborhood  of  the  cerebellum  and  pons,  and  are  sometimes 
called  cerebellopontine  tumors.  They  are  not  malignant  and  do  not  recur 
when  removed.  In  section  they  are  firm  tumors  which  show  a  peculiar 
whorled  arrangement,  somewhat  like  that  of  a  uterine  myoma.  This 
appearance  is  seen  under  the  microscope  to  be  due  to  the  arrangement  of 


Fig.  511.— Endothelioma  of  the  meninges  lying  in  a  deep  depression  in  the  surface  of 

the  cerebral  hemisphere. 

the  flattened  cells  in  strands  which  interlace,  or  in  concentric  arrangements 
(Fig.  512).  Occasionally  the  flattened  cells  are  closely  wrapped  around  a 
central  grain  of  calcified  material,  and  this  arrangement  may  be  repeated 
throughout  the  tumor,  giving  rise  to  the  so-called  psammoma.  Connective 
tissue  may  be  associated  with  the  "  endothelial "  cells  and  contributes  a 
greater  firmness  to  the  tumor. 

The  term  psammoma  is  another  descriptive  name,  and  is  applied  to  any  tumor  which 
contains  many  tiny  concretions  or  rounded  grains  of  calcined  material  enwrapped  in 
concentric  layers  of  cells.  Such  tumors  occur  in  the  choroid  plexus,  in  the  hypophysis, 
m  the  pineal  gland,  and  elsewhere  in  the  body,  as  well  as  in  the  endotheliomata  of  the 
dura. 


ENDOTHELIOMATA 


997 


Tumors  Derived  from  the  Endothelium  of  the  Blood-vessels. — A  few 

tumors  have  been  described  which  appear  to  represent  this  group,  but  they 
seem  to  be  very  rare.  Borrman,  for  example,  has  described  two  tumors 
composed  of  long  strands  and  channels  composed  entirely  of  endothelium 
and  connected  with  the  blood-capillaries.  These  he  calls  tubular  capillary 
endotheliomata,  and  in  so  far  as  the  relation  to  the  capillary  endothelium 
can  be  proved,  the  name  is  well  chosen.  Colmers  has  also  described  a  tumor 
of  the  penis,  metastasizing  into  the  internal  organs,  which  was  composed  of 
blood-channels  lined  by  tumor-cells,  which  he  regarded  as  endothelial  cells. 


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Fig.  512. — Meningeal  endothelioma.     The  tumor  is  made  up  of  long,  fusiform  cells 

arranged  in  whorls. 

The  endothelial  cells  were  much  changed  in  form,  and  greatly  enlarged,  and 
sometimes  occluded  the  wide  blood-channels  of  the  corpora  cavernosa  into 
which  they  grew.  B.  Fischer  describes  another  peculiar  tumor  situated 
in  the  liver,  most  of  which  it  occupied.  In  the  outlying  parts  of  the  many 
nodules  this  was  seen  to  be  a  mere  widening  of  the  capillaries  with  thick- 
ening of  the  endothelium,  but  in  the  centre  of  each  nodule  the  change  in 
the  endothelium  became  more  striking,  producing  great  widening  of  the 
capillary,  often  with  occlusion  and  disappearance  of  the  liver-cells.  Most 
active  blood  formation  was  found  to  be  going  on  in  the  capillaries  of  these 


ggg  TEXT-BOOK   OF   PATHOLOGY 

areas,  and  one  is  led  to  speculate  as  to  whether  this  may  have  been  an 
exaggerated  myeloid  alteration  rather  than  a  tumor. 

One  tumor  which  I  studied  microscopically  seemed  to  fall  into  this  group. 
It  was  a  pulsating  mass  in  the  region  of  the  left  scapula  in  a  boy,  and  was 
incompletely  removed  at  an  operation,  which  had  to  be  stopped  because  of 
the  excessive  hemorrhage  from  the  tumor.  There  was  a  recurrence  which 
grew  rapidly  until  the  boy's  death,  when  metastases  were  found  in  the  lungs. 
In  the  metastases,  as  well  as  in  the  primary  growth,  the  whole  tumor  was 
composed  of  delicate  canals  lined  with  high  swollen  cubical  cells  with  very 
clear  protoplasm,  quite  like  those  in  a  hypernephroma.  Each  canal  was 
filled  with  blood,  which  seems  to  have  been  in  circulation  and  to  have  given 
rise  to  the  extensive  haemorrhages  at  operation.  This  tumor  reminded  us 
of  a  hypernephroma,  and  it  is  possible  that  it  may  have  been  a  secondary 
growth,  although  no  tumor  was  found  in  the  adrenals  or  kidneys  or  else- 
where, except  the  pulmonary  nodules,  which  were  numerous  and  all  about 
the  size  of  peas. 

"Perithelial"  Tumors. — Many  tumors  have  been  described  as  composed 
of  matted  strands  of  blood-vessels,  each  of  which  is  surrounded  by  a  mantle 
of  tumor-cells  supposed  to  be  derived  from  certain  adventitial  cells  of  the 
vessel-wall,  the  so-called  perit helium.  Such  tumors  have  been  named 
peritheliomata  or  perithelial  angiosarcomata,  and  are  said  to  be  malignant 
growths  metastasizing  rapidly.  It  seems  that  the  conception  of  perithelium 
is  accepted  passively  by  every  writer  and  transferred  from  text-book  to 
text-book.  I  have  searched  in  vain  for  perithelium,  or  even  for  any  clear 
description  of  it,  and  do  not  believe  such  cells  exist.  Of  course,  there  are 
accompanying  lymphatics  in  the  walls  of  the  blood-vessels,  and  there  are 
the  vasa  vasorum,  and  it  is  conceivable  that  a  tumor  might  arise  from  either 
of  these.  The  cells  described  in  such  tumors  have  no  resemblance  to  endo- 
thelium,  but  nothing  can  be  concluded  from  that.  In  all  the  descriptions 
some  mention  is  made  of  hyaline  and  necrotic  changes  in  the  stroma  between 
the  vascular  strands,  and  this,  it  seems,  affords  the  explanation  of  the  ap- 
pearance. Only  those  parts  of  a  sarcoma  remain  alive  which  immediately 
inclose  the  blood-vessels,  and  hence  become  isolated  in  necrotic  ground 
substance  as  mantles  of  cells  around  blood-vessels.  There  may  be  real 
peritheliomata,  but  it  seems  improbable,  and  I  have  not  been  able  to  find 
them. 

LITERATURE 
Borrmann:  Ergebn.  d.  allg.  Path.,  1902,  vii,  870;  Virch.  Arch.,  1898,  cli,  Suppl.,  151; 

ibid.,  1899,  civil,  297. 

Monckeberg:  Ergebn.  d.  allg.  Path.,  1906,  x,  789. 
Volkmann:   Dtsch.  Ztschr.  f.  Chir.,  1895,  xli,  1. 
Hinsburg:  Dtsch.  Ztschr.  f .  Chir.,  1899,  li,  281. 
Lubarsch:   Ergebn.  d.  allg.  Path.,  1897,  ii,  592. 
Colmers:   Ziegler's  Beitrage,  1903,  xxxiv,  295. 
B.  Fischer:  Frankfurter  Ztschr.  f.  Path.,  1913,  xii,  399. 


CHAPTER  LI 
TUMORS  OF  EPITHELIAL  ORIGIN 

Relation  of  epithelium  to  stroma.  Papillomata:  Origin  from  skin  and  mucosce.  Papil- 
lomata  of  bladder  and  ovary.  Adenomata:  Origin  from  skin,  salivary  glands,  gastric  and 
intestinal  mucosce,  kidney,  liver,  adrenal,  hypophysis,  and  prostate.  Adenomata  of  the 
breast.  Intracanalicular  forms.  Cystadenomata  of  ovary:  Their  origin  and  form; 
papillomatous  types.  Adenomata  of  the  uterus. 

IN  the  tumors  hitherto  discussed  cells  evidently  derived  from  the  connec- 
tive tissue  or  some  other  mesoblastic  structure  have  in  most  cases  formed 
the  essential  feature  of  the  growth,  although  in  every  instance  these  have 
been  supported  and  supplied  with  nutrition  by  a  vascular  connective-tissue 
stroma.  It  has  been  made  clear  that  in  these  tumors,  as  in  the  growth  of 
organs  in  the  embryo  or  in  the  new  formation  of  tissue  in  the  healing  of  a 
wound,  the  supporting  framework  and  the  vascular  supply  are  called  for 
and  made  to  serve  the  ends  of  the  more  important  specific  tissue.  This 
becomes  even  more  apparent  in  the  case  of  the  great  group  of  tumors  in 
which  epithelial  cells  play  the  leading  part  in  the  constitution  of  the  growth. 
Although  there  are  some  authors,  such  as  Ribbert,  who  hold  to  the  idea, 
expressed  by  Virchow,  that  the  new-growth  of  epithelium  is  initiated  by  an 
atypical  growth  of  the  underlying  connective  tissue,  the  opposite  view  is 
maintained  by  the  majority,  and  seems  to  me  to  be  supported  by  far  greater 
weight  of  evidence.  Nevertheless  it  will  be  necessary  to  weigh  this  matter 
in  each  case,  and  in  some  it  may  be  found  difficult  to  decide. 

Very  convincing  proof  of  the  mastery  of  the  epithelium  seems  to  be  furnished  by  those 
papillary  epithelial  tumors  of  the  ovary  which  grow  both  from  the  inside  and  the  outside 
of  cysts  in  that  organ.  If  minute  clusters  of  the  epithelial  cells  which  cover  the  branches 
of  these  growths  as  they  project  into  the  peritoneal  cavity  are  broken  off  and  scattered 
over  the  loops  of  the  intestine  and  on  the  surface  of  the  other  abdominal  organs,  they 
take  root  and  grow,  not  merely  into  masses  of  epithelium,  but  into  new  branched  forma- 
tions which  are  supported  by  connective  tissue  springing  from  the  peritoneal  tissue,  and 
supplied  by  branches  of  the  blood-vessels  of  the  organ  on  which  they  grow.  Even  if  a 
bit  of  connective  tissue  be  implanted  with  the  group  of  epithelial  cells,  we  must  admit 
that  the  new  blood-vessels  and  probably  the  new  stroma  are  commandeered  from  the 
underlying  tissues. 

Although  we  may  agree  that  epithelium  growing  so  abundantly  on  a  surface 
as  to  be  forced  up  into  folds  demands  a  vascular  stroma  for  each  fold,  and 
that  epithelium  growing  in  the  form  of  a  gland  demands  the  formation  of 
vascular  connective  tissue  enough  to  surround  it,  there  are  instances  in 
which  the  epithelium  assumes  a  growth  so  rapid  that  it  far  outstrips  the 

999 


1000  TEXT-BOOK   OF    PATHOLOGY 

connective-tissue  formation,  and  abandons  the  ordinary  relation  which  it 
regularly  bears  to  that  tissue,  in  the  formation  of  an  organ  or  in  the  normal 
covering  of  a  surface.  Then  the  epithelial  cells  in  solid  strands  push  their 
way  lawlessly  into  any  crevice  in  the  tissue.  Even  then,  however,  when 
muscle,  organ  tissue,  or  bone  is  destroyed  by  the  advance  of  these  cells,  there 
is  never  formed  any  considerable  mass  of  epithelium  alone,  but  the  connec- 
tive tissue  follows  with  its  blood-vessels,  though  often  in  an  irregular  and 
inadequate  way,  and  forms  a  support  for  the  epithelium  in  its  new  position. 
Should  the  epithelial  cells  be  set  free  in  the  lymph-  or  blood-stream  and 
lodge  in  the  capillaries  of  a  distant  organ,  their  multiplication  in  that  new 
site  is  at  once  assisted  by  the  ingrowth  of  fibroblasts  and  capillaries  which 
quickly  organize  a  stroma.  These  are  the  malignant  epithelial  tumors,  and 
it  is  seen  that  the  difference  which  exists  between  their  structure  and  the 
more  orderly  form  of  the  benign  ones  depends  upon  the  headlong  irregular- 
ity of  their  growth,  with  which  the  stroma  can  scarcely  keep  pace. 

We  may  consider  first  the  benign  epithelial  tumors,  in  which  the  relation 
between  the  epithelium  and  its  stroma  or  supporting  framework  is  main- 
tained nearly  as  it  is  in  normal  tissues,  and  afterward  the  malignant  or 
cancerous  form,  in  which  this  relation  is  disturbed.  It  must  be  remembered, 
however,  that  the  difference  between  a  malignant  and  a  benign  tumor  con- 
sists not  merely  in  this  morphological  manifestation,  but  in  the  overwhelm- 
ing energy  of  growth  of  the  epithelial  cells  of  the  cancer  against  which  the 
normal  tissues  can  set  up  no  effective  barrier. 

Benign  Epithelial  Tumors. — Those  epithelial  growths  which  maintain,  at 
least  in  principle,  the  normal  relations  between  epithelium  and  stroma  fall 
into  several  groups,  according  to  their  general  form,  although  these  groups 
overlap  in  the  sense  that  combinations  or  transitions  from  one  form  to 
another  are  found.  The  types  are  as  follows : 

A  papilloma  is  a  tumor  of  lobulated,  branched,  or  papillary  form,  in  which 
each  fold  or  offshoot  of  the  epithelial  layer  has  a  central  core  of  connective 
tissue  with  blood-vessels. 

An  adenoma  is  a  tumor  composed  of  glands  of  tubular,  acinous,  or  other 
form,  embedded  in  a  vascular  stroma.  Such  a  tumor  may  exist  as  a  nodule 
in  the  substance  of  a  solid  organ,  or  it  may  project  as  a  polypoid  growth  on  a 
mucous  surface.  Since  the  glands  are  often  without  connection  with  the 
efferent  ducts,  many  of  them  may  become  cyst-like.  Indeed,  there  is  no 
sharp  line  between  these  tumors  and  cysts,  which  may  be  multilocular  or 
unilocular.  Within  such  cysts  the  epithelium  may  be  thrown  up  into  papil- 
lary growths,  so  that  a  combination  of  cystoma  or  cystadenoma  with  papil- 
loma occurs. 

PAPILLOMATA 

The  term  is  applied  on  the  basis  of  their  form  to  tumors  composed  of 
branching,  cauliflower-like,  or  finely  lobulated  growths  of  epithelium,  with  a 
stroma  which  branches  to  carry  blood-vessels  into  each  prolongation.  Some- 
times these  branches  are  so  small  that  only  single  capillary  loops  suppljr 


PAPILLOMA 


1001 


them  with  blood.  Although  this  general  principle  of  formation  is  carried 
out  throughout  the  group,  there  are  great  differences  in  their  form  and  con- 
sistence, which  depend  upon  the  character  of  the  epithelium  from  which 
they  rise,  since  those  which  occur  upon  the  skin  are  usually  rough  and  hard, 
while  those  growing  from  the  mucous  membranes  in  the  interior  of  the  body 
are  more  commonly  very  soft,  with  loose,  cedematous  stroma.  In  the  skin, 
papillomata  may  appear  anywhere  on  the  surface  of  the  body,  but  are  some- 
what more  common  on  the  face  and  in  the  anal  and  genital  region,  than 
elsewhere.  They  are  often  mulberry  shaped  on  a  short  stalk,  and  rather 
soft,  often  more  deeply  indented,  rough,  and  horny.  These,  especially  in 
some  cases  in  which  they  are  situated  on  the  penis  or  labia,  may  grow  to  a 


Fig.  513. — Papilloma  of  cheek. 


considerable  size.  Being  exposed  to  constant  traumatism,  they  are  fre- 
quently inflamed  or  ulcerated.  Fig.  513  shows  the  structure  of  such  a 
tumor  which  was  found  growing  on  the  cheek,  and  corresponds  almost 
exactly  with  the  appearance  of  others  found  on  the  lips,  margin  of  the  anus, 
and  elsewhere. 

Less  complex  are  the  common  warts,  which  are  small  papillomata,  most 
frequently  seen  on  the  hands  and  composed  of  elongated  papillae  covered 
with  thick  epithelium.  In  many  of  them  the  skin  is  merely  thickened  and 
deformed,  although  continuous,  while  in  others  the  main  mass  of  the  wart 
seems  to  break  through  the  surrounding  skin,  to  protrude  as  a  brush  of  fine, 
stiff,  epithelium-covered  papillae.  Section  shows  the  continuity  of  the 


1002  TEXT-BOOK    OF    PATHOLOGY 

deeper  layers  of  the  epidermis  with  this  papillary  growth.  Wile  states  that 
these  warts  are  infectious  in  character  and  may  be  produced  by  inoculation 
of  a  cell-free  extract  from  other  warts.  In  other  cases  the  keratinization 
of  the  thick  epithelial  covering  is  so  extensive  that  an  actual  horn-like 
outgrowth  may  be  formed,  and  such  horns,  growing  usually  on  the  face 
or  scalp,  may  reach  a  length  of  several  centimetres. 

Many  pedunculated  papillary  tumors  are  pigmented  or  bear  long  hairs, 
and  these  on  section  are  found  to  be  made  up  largely  of  the  peculiar  cells 
described  as  characteristic  of  pigmented  moles.  They  are,  in  fact,  nsevi 
which  have  assumed  a  papillary  form,  and  although  to  this  degree  they  are 
papillomata,  the  fact  that  they  are  only  thinly  covered  with  stretched-out 
epidermis  and  that  the  cells  which  take  the  initiative  are  na3vus  cells,  and 
not  epithelium  proper,  justifies  the  distinction.  They  are  extremely  com- 
mon, and  when  not  deeply  pigmented,  may  resemble  the  ordinary  papil- 
lomata very  closely. 

Besides  these,  there  are  many  small,  pedunculated  fibromata  which  im- 
pose themselves  as  tumors  resembling  papillomata.  They  have  been  referred 
to  in  an  earlier  section,  where  their  relation  to  the  nerves  was  discussed. 
The  fact  that  they  are  essentially  new  growths  of  connective  tissue  with 
only  a  thin  covering  of  normal  epidermis  serves  to  distinguish  them  from 
the  present  group. 

In  the  stratified  epithelium  which  lines  the  mouth  and  nasopharynx 
papillomata  spring  up  from  the  tongue,  the  nose,  and  elsewhere,  which 
resemble  those  of  the  skin.  Irritation  and  trauma  may  cause  modification 
in  the  epithelium,  so  that  the  more  exposed  parts  are  denuded.  Similar 
tumors  are  found  in  the  larynx  and  trachea,  often  attached  by  stalks  to  the 
vocal  cords,  where,  of  course,  they  interfere  greatly  with  phonation.  These 
are  fairly  hard,  and  although  in  the  trachea  rising  from  cylindrical  epithe- 
lium, may  be  covered  with  stratified  epithelium. 

In  the  urethra,  vulva,  and  vagina  similar  growths  occur.  In  these  regions 
care  must  be  taken  to  distinguish  from  true  papillomata  the  flat  and  pointed 
condylomata,  which  are  not  tumors,  but  peculiar  hyperplastic  growths  of 
epithelium  caused  by  infection,  with  inflammatory  reaction.  The  flat 
condylomata  are  of  syphilitic  origin,  while  the  pointed  or  irregular  ones  are 
formed  in  the  course  of  chronic  gonorrhoea,  chancroids,  or  other  long-stand- 
ing infectious  processes  about  the  genitalia.  They  even  occur  in  pregnancy, 
and  disappear  after  childbirth,  although  here  the  participation  of  an  infec- 
tion is  not  to  be  excluded.  Apparently  the  gonococcus  is  not  directly 
responsible  for  them.  Such  condylomata  show  on  section  (Fig.  514)  an 
intensely  inflamed  tissue  with  distinct  papillary  new-formation  of  epithe- 
lium, so  that  without  the  clinical  history  it  might  be  rather  difficult  to  draw 
a  sharp  line  between  them  and  papillomata. 

In  the  stomach  and  intestine  papillomata  occur,  but  they  are  by  no  means 
so  frequent  as  the  more  polypoid  glandular  tumors,  which  will  be  referred  to 
under  Adenomata.  This  is  probably  because  of  the  tendency  of  the  cylin- 
drical epithelium  of  the  digestive  tract  to  f9rm  tubular  glands,  rather  than 


PAPILLOMA  1003 

to  throw  itself  up  into  papillary  processes.  Nevertheless,  there  are  some 
such  tumors  which  hang  like  great  tassels  in  the  cavity  of  the  stomach,  or 
less  commonly  in  the  colon.  Those  which  I  have  seen  in  the  stomach  were 
associated  with  other  tumors  of  a  cancerous  nature,  but  this  is  probably  a 
coincidence.  They  are  so  soft  and  fragile  that  losses  of  substance  fre- 
quently occur  with  haemorrhage  from  the  remaining  surface. 

The  papillomata  of  the  bladder  are  very  similar  in  appearance,  being 
extremely  soft,  tassel-like,  stalked  masses  of  thread-like  papillae  which  float 
about  in  water.  They  show  in  section  a  delicate  stroma  covered  by  thick, 
stratified  epithelium,  the  surface  layers  of  which  are  usually  lost.  From 
being  caught  in  the  urethral  orifice  in  the  contraction  of  the  bladder  the 
papillae  are  often  torn  and  portions  are  discharged  in  the  urine,  together  with 
blood.  These  tumors  tend  to  recur  when  they  have  been  removed  by 

r  .  -  - 


Fig.  514. — Acuminate  condyloma  from  a  case  of  chronic  gonorrhoea. 

operation,  and  in  most  cases,  whether  interfered  with  by  operation  or  not, 
they  finally  invade  and  destroy  the  bladder-wall,  revealing  themselves  as 
carcinomata.  They  should  doubtless  be  regarded  from  the  first  as  papillary 
carcinomata  of  the  bladder. 

From  the  surface  of  the  ovary,  and  usually  simultaneously  from  both 
ovaries,  richly  branching  papillomatous  tumors  are  found  to  grow,  extending 
into  the  peritoneal  cavity.  They  appear  to  arise  from  the  epithelial  cover- 
ing of  the  organ,  and  are  supported  by  the  usual  vascular  stroma  derived 
from  the  ovary.  In  their  biological  characters  they  resemble  those  which 
occur  in  the  walls  of  ovarian  cystadenomata. 

In  all  these  tumors  the  extensive  growth  of  the  epithelium,  which  casts 
it  into  folds  and  projecting  papillae,  is,  nevertheless,  governed  by  a  certain 


1004  TEXT-BOOK   OF    PATHOLOGY 

obedience  to  the  normal  laws  of  growth,  which  maintains  a  smooth  line  of 
demarcation  between  the  epithelium  and  the  underlying  stroma.  The 
whole  tumor  may  become  infiltrated  with  leucocytes  during  inflammation, 
and  these  cells  wander  readily  from  the  stroma  into  the  epithelium,  but  it 
is  possible  to  trace  round  every  projection  and  into  each  bay  and  indenta- 
tion the  distinct,  regular  line  of  separation  between  epithelium  and  stroma. 
The  usefulness  of  a  recognition  of  this  line  in  diagnosis  is  realized  daily. 
In  a  case  observed  recently  there  was  a  mass  extending  from  the  tonsil  and 
pillars  of  the  fauces  downward  on  the  epiglottis,  in  a  man  of  middle  age. 
Sections  of  an  excised  portion  showed  everywhere  a  typical  papilloma  with 
perfectly  even,  thick,  stratified  epithelial  covering,  uniformly  marked  off 
from  the  stroma.  Doubts  as  to  the  nature  of  a  tumor  in  that  situation 
prompted  the  excision  of  another  fragment,  which  in  general  showed  the 
same  structure,  but  at  several  points  it  was  possible  to  see  that  an  excessive 
and  lawless  growth  of  epithelium  had  burst  the  barrier,  and  had  invaded 
the  stroma  in  the  form  of  long  strands  of  cells.  The  malignant  nature  of 
the  tumor  was  at  once  clear,  and  the  diagnosis  is  being  substantiated  by  the 
clinical  course  of  the  growth. 

ADENOMATA 

Epithelial  tumors  of  glandular  origin  and  retaining  in  general  a  gland-like 
structure  are  extremely  common,  and  occur  in  practically  every  situation 
where  there  are  glands.  They  may  present  themselves  as  nodules  embedded 
in  the  substance  of  solid  glandular  organs,  or  as  polypoid  masses  projecting 
on  the  surface  of  a  mucosa.  The  stroma  is  sometimes  dense  and  hard, 
often  soft  and  gelatinous,  so  as  to  give  the  tumor  a  polypoid  character.  The 
epithelium-lined  spaces  may  become  enlarged  to  form  cysts,  and  these  may 
be  partly  occupied  by  papillary  ingrowths  of  the  same  epithelium.  It  is  as 
well  to  consider  the  cysts  with  the  adenomata,  since  those  cysts  which  are 
not  modifications  of  these  tumors  are  of  a  quite  different  nature,  and  are 
due  either  to  obstruction  and  dilatation  of  the  ducts  of  glands  or  to  the 
congenital  misplacement  of  embryonic  tissues,  under  which  headings  they 
may  be  discussed. 

Adenomata  of  the  skin  may  arise  from  the  sweat-glands  or  from  the 
sebaceous  glands.  Such  tumors  are  rare  and  must  be  distinguished  from 
the  vesicles  which  result  from  obstruction  of  the  ducts  of  the  sweat-glands 
and  the  so-called  milia  or  comedones,  which  are  due  to  the  accumulation  of 
sebaceous  material  in  obstructed  sebaceous  glands. 

In  the  digestive  tract  small  adenomata  may  spring  from  the  mucus- 
secreting  glands,  or  occasionally  appear  in  the  salivary  glands.  The  so- 
called  ranula  is  a  cystic  tumor  which  forms  in  the  frenulum  of  the  tongue, 
and  is  derived  from  the  sublingual  ducts,  especially  from  Nuhn's  glands. 
In  the  salivary  glands  themselves  there  occurs  not  only  a  form  of  "cylin- 
droma,"  but  also  and  more  frequently  composite  tumors  containing  several 
types  of  tissue.  These  may  be  discussed  later. 


ADENOMA 


1005 


In  the  stomach  and  intestine  adenomata  usually  project  or  hang  by  a 
stalk  as  soft,  polypoid  tumors  made  up  of  abundant,  irregular,  and  partly 
cystic  glands,  of  much  greater  length  than  the  normal  glands,  and  embedded 


-.^   .•...•-—...-..•;._.      >— •  Y     AV.^-;   -.:.-    .^;   •>-. IV 
^^"^/^^C^A^W^^  *»    ^^';£2<        V;? 

iU|te|aH^ 


^^-^-^ 


-,^, :';;  ^i!i|IIIft^i^-^^ 


:  "( ^:®l®^6e/^ 


Fig.  515. — Tip  of  polypoid  adenoma  of  the  intestine. 

in  a  loose  stroma  which,  on  account  of  the  traumatism  to  which  it  is  exposed, 
is  constantly  inflamed.  Sometimes  these  polyps  reach  a  considerable  size, 
and  may  offer  a  certain  obstruction,  or  be  seized  by  the  intestinal  wall  in  its 


1006 


TEXT-BOOK   OF   PATHOLOGY 


peristaltic  contraction  and  dragged  on  into  a  lower  part  of  the  gut.  In  this 
process  the  wall  of  the  intestine  may  be  invaginated  by  the  tension  on  the 
stalk  of  the  tumor,  and  an  intussusception  started. 

Microscopically,  such  adenomata  are  in  continuity  with  the  rest  of  the 
mucosa,  but  there  is  a  sudden  transition  from  the  normal  into  the  largo 
distorted  glands,  lined  with  cylindrical  epithelium,  which  may  stain  more 
deeply  than  the  normal  cells.  The  muscularis  is  not  affected,  but  the  sub- 
mucosa  is  greatly  thickened  at  this  point  and  extends  upward  into  the 
tumor  (Fig.  515). 

Polypoid  adenomata  are  often  multiple,  and  sometimes  so  numerous  and 
so  small  as  to  give  the  intestinal  mucosa  a  shaggy  appearance.  When  they 
are  larger  (Fig.  516),  they  project  into  its  lumen  at  every  level  as  rounded, 
soft,  velvety  masses,  varying  in  diameter  up  to  one  centimetre  or  more. 


Figs.  516. — Multiple  polypoid  adenomata  of  the  mucosa  of  the  colon. 

They  must  be  distinguished  from  the  irregular,  polypoid  masses  of  mucosa 
which  are  often  formed  at  the  margins  of  ulcers  in  the  process  of  healing,  or 
by  the  undermining  of  part  of  the  mucosa  in  old  dysentery.  In  the  latter 
case  the  isolated  mucosa  breaks  free  at  one  end  and  hangs  in  the  intestine 
as  a  polypoid  mass. 

Adenomata  in  the  kidney  are  grayish-red  nodules  lodged  in  the  cortex, 
usually  small,  but  sometimes  attaining  a  great  size.  They  are  composed  of 
ramifying  or  twisted  glandular  or  tubular  epithelial  structures  in  which  the 
cells  are  much  smaller  than  those  of  the  convoluted  tubules  (Fig.  517).  It 
seems  probable  that  the  tumor-cells  are  the  offspring  of  cells  destined  to 
form  kidney  substance,  but  diverted  to  the  formation  of  a  tumor  at  a  rela- 
tively early  stage  of  development. 

In  the  liver,  as  in  other  solid  glandular  organs,  it  is  sometimes  difficult  to 


ADENOMA  1007 

determine  whether  the  nodular  growths  of  the  parenchyma  of  the  organ 
should  be  looked  upon  as  tumor  formations,  or  as  the  result  of  a  compensa- 
tory hyperplasia.  It  has  been  made  clear  in  discussing  cirrhosis  of  the  liver 
that  the  destruction  of  a  portion  of  the  liver  tissue  causes  the  great  over- 
growth of  the  remaining  fragments,  so  that  the  organ  assumes  a  rough, 
nodular  arrangement,  in  which  the  nodules  are  sometimes  quite  large. 


Fig.  517. — Adenoma  of  the  kidney. 

Microscopical  study  shows,  however,  that  the  strands  of  cells  which  make 
up  these  nodules,  though  disarranged  from  the  normal  order,  are  still  in  con- 
nection with  the  bile-ducts  and  actively  functioning.  It  is  probable  that 
this  is  the  nature  of  the  circumscribed  and  irregularly  arranged  nodules  of 
liver  tissue  which  are  sometimes  found  embedded  in  a  liver  which  is  other- 
wise almost  normal  looking.  At  least  this  explanation  seems  safest  so  long 
as  the  cells  of  the  nodule  closely  resemble  the  normal  liver-cells.  Occasion- 


1008  TEXT-BOOK   OF   PATHOLOGY 

ally,  however,  there  are  seen  nodules  composed  of  irregular  strands  or 
tubules  of  cells  which  no  longer  stain  as  do  the  normal  cells,  and  these  must 
be  regarded  as  adenomata  representing  less  highly  differentiated  liver-cells 
or  derivatives  of  the  bile-duct  epithelium. 

The  adenoma-like  nodules  of  the  cortex  of  the  adrenal  have  been  des- 
cribed elsewhere,  and  mention  has  been  made  of  those  of  the  thyroid.  The 
thyroid  adenomata  are  extremely  common,  and  here  again  it  is  sometimes 
difficult  to  feel  sure  that  we  are  dealing  with  actual  tumors,  and  not  with 
hyperplasia  of  the  functioning  gland.  This  is  especially  the  case  in  the 
rather  indistinctly  outlined  nodules  of  thyroid  tissue  in  which  the  alveoli 
are  distended  with  clear  colloid  and  lined  with  thin,  flat  epithelium.  In 
these  cases  the  rest  of  the  thyroid  is  frequently  distended  with  colloid,  in 
the  same  way,  evidently,  as  the  result  of  some  abnormality  in  its  function. 


Fig.  518. — Adenomatous  nodules  in  the  thyroid.     Some  of  these  contain  abundant 

colloid. 

It  is  much  easier  to  feel  sure  of  the  tumor  character  of  the  more  common 
nodules  which  make  up  the  bulk  of  the  adenomatous  or  nodular  goitres 
(Fig.  518),  since  they  are  sharply  outlined  and  are  composed  of  a  quite 
abnormal  tissue,  in  which  the  alveoli  are  often  extremely  small  and  lined  with 
relatively  large  cuboidal  cells.  These  cells  occupy  so  much  of  the  whole 
diameter  of  each  alveolus  that  the  lumen  is  often  lost,  and  the  tumor  is 
found  to  be  made  up  of  narrow  anastomosing  strands  or  clusters  of  cells. 
Occasionally  the  larger  alveoli  contain  distinct  colloid  secretion,  but  often 
there  is  none  to  be  seen.  The  stroma  is  very  abundant  and  becomes  more 
conspicuous  with  the  degeneration  and  disappearance  of  the  alveoli,  after 
which  haemorrhages  and  wide-spread  necroses  occur,  followed  by  liquefac- 
tion of  the  tissue,  with  the  formation  of  cyst-like  cavities  full  of  bloody  or 
brown  turbid  fluid.  Extensive  calcification  may  occur  in  the  walls  of  the 
cysts  or  in  the  substance  of  such  adenomata. 


ADENOMA 


1009 


Tumors  of  the  hypophysis,  composed  of  a  gland-like  growth  of  one  or 
other  of  the  elements  of  the  organ,  have  been  much  studied  of  late,  and  have 
been  mentioned  in  connection  with  acromegaly.  They  are  most  commonly 
composed  of  the  chromophobe  cells,  which  are  arranged  in  solid  strands  or 
alveoli.  Adenomata  of  the  eosinophile  cells  have  also  been  observed. 

The  adenomata  of  the  prostate  have  been  discussed  elsewhere. 


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Fig.  519.  —  Adenofibroma  of  breast.    The  acini  are  very  uniform  in  size,  and  are  often 
lined  with  two  layers  of  epithelial  cells. 


There  remain  the  most  common  and  important  adenomatous  growths, 
namely,  those  of  the  breast  and  the  ovary. 

The  adenomata  of  the  breast,  often  called  adenofibromata  on  account  of 

their  dense  stroma,  are  very  common,  and  assume  a  great  many  different 

forms.     They  are  benign  tumors,  limited  in  their  outline,  and  growing 

expansively  so  that  they  can  sometimes  be  shelled  out  of  the  remaining 

65 


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TEXT-BOOK   OF   PATHOLOGY 


breast  tissue.  This  is  not  always  the  case,  and  if  they  are  examined  in  a 
section  through  the  breast,  they  are  found  to  appear  as  grayish-white,, 
rather  translucent  nodules,  or  indistinctly  localized  areas  of  dense  consis- 
tence. There  is  one  group  which  in  such  a  cut  surface  shows  a  peculiar 
structure,  as  though  many  small  papillary  or  cauliflower-like  masses  were 
inclosed  in  cysts.  These  can  indeed  be  partly  turned  out  of  such  cavities,  but 
are  attached  at  some  point  by  a  stalk.  They  are  the  intracanalicular 


Fig.  520.— Adenofibroma  of  the  breast.     The  epithelial  structures  resemble  ducts  in 

many  places. 

fibroadenomata,  and  their  peculiar  appearance  will  be  recognized  by  the 
description  of  their  microscopical  structure. 

The  more  homogeneous  adenomata  of  the  breast  show  on  section  many 
epithelial  structures  in  the  form  of  acini,  canals,  or  small  cysts  surrounded 
by  an  abundant  stroma  which  is  usually  rather  lax  immediately  about  the 
glands  and  denser  in  the  broad  intervening  strands  (Fig.  519).  In  some 
cases  the  whole  stroma  is  cellular  and  rather  cedematous,  without  any  dense 
bands  or  areas  of  fibrous  tissue.  This  is  so,  especially  in  the  cases  in  which 


ADENOMA 


1011 


the  epithelium-lined  spaces  have  the  character  of  long  tubules  (Fig.  520). 
In  every  case,  whether  the  epithelial  structures  have  the  arrangement  of 
acini  or  tubules  or  are  in  the  form  of  cysts,  the  lining  epithelium,  which 
may  be  in  two  layers,  is  sharply  bounded  by  a  hyaline  basement  membrane. 
In  some  tumors  this  membrane  is  very  broad  and  thick.  When  the  cells 
are  able  to  disregard  the  barrier  and  burst  through  to  grow  at  large  in  the 


»<  •.•: 

'  I 

' 


Fig.  521.  —  Adenoma  of  breast.    Some  of  the  acini  are  lined  with  high  cubical  or  cylin- 
drical epithelium,  and  such  acini  are  sometimes  dilated  into  cysts. 


crevices  of  the  stroma,  the  tumor  must  be  recognized  as  a  cancer.  While 
it  is  not  easy  to  show  histologically  that  an  adenoma  can  change  its  charac- 
ter and  assume  that  of  a  carcinoma,  the  clinical  history  of  these  tumors 
gives  much  support  to  the  idea  that  this  change  may  occur. 

The  formation  of  cysts  is  of  very  frequent  occurrence  (Fig.  521),  and 
although  in  most  instances  they  never  reach  any  great  size,  there  are  occa- 


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TEXT-BOOK   OF   PATHOLOGY 


sionally  seen  adenomata  in  which  nearly  the  whole  tumor  is  occupied  by  a 
cyst.  Distinction  must  be  drawn  between  the  cyst  formation  in  actual 
adenomata  and  the  development  of  many  minute  cysts  scattered  diffusely 
through  the  breast  in  the  so-called  chronic  mastitis,  which  will  be  described 
later.  In  the  adenomata  the  cysts  are  found  to  contain  clear  fluid,  or  fluid 
rendered  turbid  by  the  presence  of  many  desquamated  cells,  or  blood- 
stained fluid  which  may  become  thick  and  deeply  pigmented  with  blood- 
pigments.  In  some  cases  the  cysts  contain  a  butter-like  material  produced 


Fig.  522. — Intracanalicular  adenofibroma  of  breast,  showing  numerous  apparently  free 
epithelium-covered  masses  packed  together. 

by  the  epithelium.  The  epithelium  may  be  reduced  to  a  thin  layer  of 
flattened  cells,  or  it  may  be  lost  entirely.  On  the  other  hand,  it  is  frequently 
proliferated  and  thrown  up  into  folds  and  papilla?  (cf.  Fig.  521).  Distinct 
papillomatous  outgrowths  may  press  into  the  cyst  so  as  to  fill  it  completely. 
Such  intracystic  papillomata  are  of  quite  frequent  occurrence. 

Intracanalicular  Adenomata.— Closely  related  to  these  are  the  intracanal- 
icular  forms  described  above.  In  microscopic  sections  even  the  smaller 
epithelial  structures  may  show  the  curious  appearance  in  which  isolated 
masses  of  connective  tissue  covered  with  epithelium  lie  packed  together 


ADENOMA  1013 

inside  an  irregular,  epithelium-lined  cavity  or  canal  as  though  they  were 
really  free  within  the  canal.  The  canal  itself  is  thus  reduced  to  a  series  of 
branching  slits  (Fig.  522).  In  truth  these  are  sections  of  polypoid  in- 
growths which  press  into  the  cyst  or  canal  and  are  cut  at  a  point  away  from 
their  stalks.  Sections  in  another  direction  would  show  them  as  stalked 
polypoid  masses.  The  question  once  more  arises  as  to  whether  they  are 
initiated  by  the  growth  of  epithelium  or  by  an  excessive  growth  of  connec- 
tive tissue  which  pushes  the  epithelium  into  the  cavity.  In  all  probability 
it  must  be  answered,  as  in  the  case  of  the  papillomata,  that  the  evidence  is 
in  favor  of  the  primary  activity  of  the  epithelium.  Such  intracanalicular 
growths  have  a  stroma  which  is  loose  and  mucoid  in  the  neighborhood  of 
the  glands;  dense  and  firm  in  the  intervening  areas.  The  denser  fibrous 
tissue  stains  red  with  eosin,  while  the  mucoid  tissue  assumes  a  blue  stain. 
On  this  account  they  are  often  called  intracanalicular  myxofibromata. 
Cystadenomata  of  the  Ovary. — In  the  ovary  the  epithelial  growths  are 
very  commonly  cystic.  It  is  true  that  there  are  rare  instances  in  which  a 
papillomatous  tumor  springs  from  the  surface  of  the  ovary,  and  we  shall  see 
later  that  there  are  other  solid  ovarian  tumors  of  a  malignant  character. 
The  common  adenomatous  ovarian  tumors  are,  however,  cystic  and  are 
spoken  of  as  cystadenomata.  There  are  several  varieties : 

1.  Simple  ovarian  cysts — the  so-called  hydrops  folliculi. 

2.  Pseudomucinous  cystadenomata. 

3.  Serous  cystadenomata. 

The  division  is  not  important  since  it  is  evident  that  it  is  based  on  no  essential 
difference.  The  first  type  has  long  been  supposed  to  arise  from  the  Graaf- 
ian  follicles  through  mere  accumulation  of  fluid  in  their  cavities,  and  this 
view  was  supported  by  the  finding  of  ova  in  the  walls  of  the  cysts  (Roki- 
tansky  and  others).  Although  rigorously  upheld  by  Pfannenstiel,  it  has 
been  practically  abandoned  by  most  writers  since  the  work  of  Nagel,  v. 
Kahlden,  and  others,  who  have  shown  that  these  cysts  are  not  derived  from 
Graafian  follicles,  but  from  ingrowths  of  the  germinal  epithelium  of  the 
surface  of  the  ovary,  v.  Kahlden  traced  this  clearly  in  many  cases  and 
showed  that  the  ova  seen  by  several  investigators  were  really  protoplasmic 
masses  somewhat  resembling  ova,  but  produced  by  the  epithelial  cells,  per- 
haps as  a  futile  effort  on  the  part  of  those  cells  to  carry  out  the  function  for 
which  they  were  originally  intended. 

The  cystadenomata  are  also  derived  from  solid  or  tubular  ingrowths  of 
the  superficial  germinal  epithelium,  and  not  from  the  Graafian  follicles  nor 
from  the  so-called  Pfliiger's  cords,  which  are  groups  of  ova  and  epithelial 
cells.  They  are  frequently  single,  but  often  arise  from  both  ovaries  simul- 
taneously and  are  formed  of  one  large  cyst  or  of  a  great  number  of  smaller 
ones  (simple  and  multilocular  cystomata).  At  one  time  much  attention  was 
devoted  to  the  chemical  study  of  the  contents  of  these  cysts,  and  they  were 
grouped  on  this  basis  although  it  is  not  a  distinction  of  great  importance. 
There  are  some  which  contain  pseudomucin,  a  substance  allied  to  mucin  but 


1014  TEXT-BOOK    OF    PATHOLOGY 

easily  split  by  boiling  with  acids  so  as  to  produce  a  carbohydrate  which  will 
reduce  copper.  This  fluid  may  be  slightly  viscid  or  thick  and  gelatinous, 
sometimes  dense  enough  to  cut.  I  remember  well  one  such  cyst  of 
enormous  size  from  which,  at  operation,  a  whole  tubful  of  yellowish  brown, 
gelatinous,  semifluid  material  was  evacuated.  The  others,  which  may  be 
called  serous  cysts,  contain  a  fluid  rich  in  albumin  but  not  gelatinous  and 
containing  no  glycoproteid. 

The  cystadenomata  are  sometimes  quite  small,  and  may  at  times  push 
their  way  into  the  substance  of  the  ovarian  and  broad  ligament.  Usually 
they  occupy  most  of  the  substance  of  the  ovary,  which  is  spread  out  on  the 


^  • 


Fig.   523.— Large  multilocular  cystadenoma  of  the  ovary.    The  Fallopian  tube  on 
that  side  is  greatly  elongated  and  stretched  out  over  the  tumor. 

surface,  and  press  up  into  the  peritoneal  cavity  attached  only  by  the  stalk 
which  contains  the  ovarian  blood-vessels.  In  this  way  they  may  reach  the 
most  enormous  size,  producing  a  colossal  distension  of  the  abdomen  where 
they  are  carried  like  a  tremendous  burden  held  in  front.  Their  operative 
removal  after  the  fluid  is  withdrawn  through  a  cannula  is  often  an  extremely 
easy  feat,  since  it  consists  merely  in  cutting  through  the  stalk  of  the  vessels. 
The  pseudomucinous  cysts  frequently  develop  many  daughter  cysts  in 
their  walls,  or  they  may  be  definitely  multilocular  or  composed  of  a  great 
mass  of  small  cysts  (Fig.  523).  These  are  lined  with  columnar  or  high 
cuboidal  epithelium,  which  produces  the  fluid  contents.  Thev  are  by  far 
the  commonest  of  the  cystadenomata  (Fig.  524). 


ADENOMA 


1015 


The  serous  cysts  are  also  usually  unilateral,  but  are  very  often  multiloc- 
ular,  each  small  cyst  being  lined  with  high  columnar  epithelium  which  is 
often  ciliated.  We  have  recently  observed,  in  two  cases,  bilateral  multi- 
locular  ovarian  cystadenomata  composed  of  such  small  cysts  that  the  very 
large  tumors  appeared  to  be  almost  solid.  In  such  cases  there  is  frequently 
a  great  accumulation  of  fluid  in  the  peritoneal  cavity. 


Fig.   524.  —  Multilocular  cystadenoma  of  the  ovary.     The  cysts  are  lined  with  high 

columnar  epithelium. 


Both  pseudomucinous  and  serous  cystadenomata  may  thus  be  multiloc- 
ular,  or  in  the  form  of  a  single  cyst,  although  even  then  the  remnants  of 
broken  partitions  are  usually  evident.  Both  types  show,  as  a  rule,  some 
infolding  or  papillary  growth  of  their  epithelium,  and  this  may  proceed  to 
the  formation  of  highly  complex  papillomatous  ingrowths  (Fig.  525).  These 
are  sometimes  small  and  uniformly  scattered  over  the  wall;  more  often 
they  arise  from  the  wall  in  branching  masses,  leaving  much  of  the  lining 


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TEXT-BOOK   OF   PATHOLOGY 


smooth.  Such  masses  may  completely  fill  the  cyst.  The  papillomatous 
growths  may  also  appear  on  the  outside  of  the  cyst,  so  as  to  hang  in  the 
peritoneal  cavity,  and  then  they  resemble  the  papillomaof  the  ovary  already 
described.  Fragments  are  broken  off  and  swept  into  all  parts  of  the  peri- 
toneum, where  they  adhere  and  grow,  forming  new  papillomata  wherever 
they  lodge.  This  may  take  place,  also,  in  the  edges  of  an  operative  wound 
in  the  abdomen.  In  this  sense  the  papillomatous  cystoma  partakes  of  the 


Fig.  525.— Portion  of  a  papillomatous  growth  springing  from  the  wall  of  an  ovarian 

cystadenoma. 

character  of  malignancy,  but  it  goes  no  further  and  there  are  no  metastases 
outside  of  the  peritoneal  cavity  nor  is  there  any  destructive  invasion  of  the 
underlying  tissue.  A  somewhat  analogous  process  follows  the  rupture  of  a 
pseudomucinous  cyst,  with  extravasation  of  the  contents  into  the  peri- 
toneum. The  gelatinous  material  is  spread  everywhere  over  the  wall  and 
>comes  partly  organized  by  the  upgrowth  of  granulation  tissue.  Some 
writers  have  thought  that  epithelial  cells  are  implanted  and  continue  the 


ADENOMA  1017 

production  of  the  pseudomucin,  but  the  evidence  for  this  is  insufficient. 
The  result  is  that  the  whole  peritoneal  cavity  is  lined  with  a  thick,  translu- 
cent layer,  often  spoken  of  as  pseudomyxoma  peritonei.  A  similar  process 
may  take  place  in  connection  with  certain  epithelial  tumor  growths  of  the 
appendix  vermiformis. 

Cysts  of  the  parovarium  are  generally  unilocular,  thin  walled,  and  filled 
with  clear  fluid.  They  are  derived  from  the  parovarian  remnants  which 
lie  in  the  mesosalpinx  and  the  cyst  is  found  in  that  situation. 

Adenomata  of  the  Uterus. — From  the  uterine  mucosa  there  are  formed 
polypoid  adenomatous  growths  comparable  to  those  of  the  intestine.  They 
are  soft,  broad  masses,  sessile  on  the  mucosa  of  the  uterus,  and  usually  sit- 
uated in  or  near  one  of  the  cornua,  although  they  sometimes  occur  in  the 
cervix  and  may  contain  small  cysts.  On  section  they  are  found  to  be  com- 
posed of  enlarged  and  distorted  glands  embedded  in  a  cellular  stroma. 

LITERATURE 

Aschoff :  Ergebn.  d.  allg.  Path.,  1897,  ii,  456. 
Simpson:  Jour.  Med.  Research,  1913,  xxvii,  269. 
Lincoln  Davis:  Annals  of  Surgery,  1906,  xliii,  556. 
Pfannenstiel:  Veit's  Handb.  d.  Gynakologie,  1908,  iv,  107. 
Olshausen:  Billroth-Liicke,  Handb.  d.  Frauenkr.,  ii,  308. 
Waldeyer:  Arch.  f.  Gynak.,  1870,  i,  252. 
Seydel:  Ergebn.  d.  allg.  Path.,  1901,  vi,  805. 
Williams:   Johns  Hopkins  Hosp.  Rep.,  1892,  iii,  1 
v.  Kahlden:  Ziegler's  Beitrage,  1900,  xxvii,  1. 


CHAPTER  LII 
CARCINOMATA 

General  characters,  grouping.  Flat-cell  carcinomata.  Epitheliomata  of  Up,  skin,  etc. 
Mode  of  growth  and  metastasis.  Epitheliomata  of  tongue,  tonsils,  bronchi,  oesophagus, 
gall-bladder,  urinary  bladder.  Epitheliomata  of  the  vaginal  portion  of  the  cervix  uteri. 
Their  frequency  and  importance.  Adamantinomata.  Basal-cell  carcinomata.  Their 
relatively  benign  character.  Distribution,  peculiar  morphology.  Relation  to  ncevi.  Other 
tumor  assigned  to  this  group.  Analogous  tumors  of  intestine  and  appendix. 

General  .Characters. — The  carcinomata  or  cancers  are  tumors  composed 
essentially  of  epithelium,  although  they,  like  other  tumors,  are  supported 
or  surrounded  by  a  vascular  stroma,  which  they  exact  from  the  neighboring 
tissue.  They  are  quite  analogous  to  the  papillomata  and  adenomata  except 
in  the  fact  that  their  epithelial  cells  are  possessed  of  the  enormous  vigor  of 
growth,  which  breaks  through  every  barrier,  and  enables  them  to  grow  into 
new  colonies  when  they  are  transported  by  the  lymph-  and  blood-streams 
and  lodged  in  distant  organs.  It  is  this  character  of  malignancy  which 
marks  them  out  from  other  epithelial  tumors,  and  even  in  the  earliest  stages 
gives  them  an  anatomical  form  different  from  that  of  the  benign  growths. 
It  is  not  possible  with  the  means  now  at  our  command  to  distinguish  with 
certainty  a  cell  of  the  epithelium  which  has  this  exaggerated  power  of 
growth  from  a  cell  of  the  epithelium  of  a  benign  tumor  or  even  a  normal  cell. 
But  it  is  quite  possible  to  distinguish  these  cells  by  their  behavior,  not  only 
in  the  distribution  of  the  tumor  throughout  the  body,  but  in  the  minuter 
relations  which,  in  microscopical  section,  the  epithelial  cells  are  seen  to  bear 
to  the  surrounding  tissues.  It  is  true  that  the  cells  themselves  are  usually 
different  from  normal  cells,  and  in  some  cases  extremely  different.  No 
doubt,  in  time  we  shall  have  a  reliable  morphological  criterion  by  which 
we  may  say  definitely  that  an  isolated  cell  is  a  cancer-cell  or  a  normal  cell, 
but  at  present  no  such  criterion  exists,  and  we  rely  upon  the  arrangement 
of  the  cells  and  their  relation,  in  their  growth,  to  the  surrounding  tissues, 
because  there  are  many  instances  in  which  the  individual  tumor  cells  look 
so  precisely  like  the  normal  cells. 

..Practically  the  same  distribution  and  architectural  plan  found  in  the 
papillomata  and  adenomata  is  repeated  in  distorted  fashion  in  the  carcino- 
mata. We  may,  therefore,  expect  to  find  a  great  variety  of  cancerous 
tumors;  nevertheless,  by  divergence  from  the  original  form,  epithelial  cells 
from  the  most  widely  different  sources  often  approach  a  common  nonde- 
script type  so  that  the  tumors  which  they  produce  finally  resemble  each 
other. 

1018 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA  1019 

We  may  distinguish  the  following  groups  of  carcinomata : 

1.  Squamous  or  Flat  Cell  Cancers.— These  arise  in  the  skin,  oesophagus, 
etc.,  or  wherever  there  is  stratified  epithelium,  and  are  commonly  known  as 
epitheliomata. 

2.  Basal-cell  Cancers. — These  arise  chiefly  in  the  skin,  but  analogous 
tumors  are  found  elsewhere.     They  are  relatively  non-malignant  and  are 
the  basis  of  the  so-called  rodent  ulcers. 

3.  Cylindrical-cell  Cancers. — These  are  analogous  to  the  polyps  or  poly- 
poid adenomata  of  mucosaB  which  have  glands  lined  with  columnar  epithe- 
lium.    They  retain  the  tendency  to  form  gland-like  structures  lined  with 
cylindrical  epithelium  and  are  hence  called  adenocarcinomata. 

4.  Cancers  Derived  from  Acinous  Glands. — These  are  analogous  to  the 
solid  adenomata  and  are  the  commonest  cancers,  since  they  include  the  can- 
cers of  the  breast.     In  them  the  epithelium  usually  grows  in  solid  strands. 
No  very  appropriate  name  has  been  given  them  and  none  is  in  common  use. 
They  are  gland-cell  cancers  so  non-committal  in  appearance  as  not  to  sug- 
gest a  definite  morphologically  descriptive  name.     The  term  carcinoma 
simplex  which  was  at  one  time  applied  to  them  is  misleading  and  useless 
since  they  are  in  no  sense  more  simple  than  the  others.     Of  the  various 
metamorphoses  of  these  tumors  which  change  their  consistence  or  give 
them  peculiar  characters,  almost  constant  enough  to  stamp  some  of  them 
as  another  type  of  carcinoma,  we  shall  speak  later.     The  most  striking  of 
these  is  the  formation  of  a  gelatinous  or  colloid  material  either  in  the 
cells  themselves,  in  cystic  spaces  lined  by  columnar  cells,  or  in  the  stroma. 
Such  colloid  cancers  fall  readily  enough  into  the  different  groups  already 
given,  but  on  account  of  this  common  peculiarity  it  might  be  tempting  to 
class  them  together  as  a  distinct  type. 

FLAT  OR   SQUAMOUS  CELL  CARCINOMATA 

There  is  extraordinary  similarity  among  these  tumors  from  whatever  point 
in  stratified  epithelium  they  arise.  Those  which  spring  from  the  skin  show 
as  a  rule  a  greater  tendency  to  keratinization  than  those  derived  from  such 
epithelium  as  that  of  the  oesophagus,  but  this  is  not  invariably  so  and  does 
not  constitute  a  reliable  distinction  between  the  two. 

Epitheliomata  of  the  lip  (Fig.  526)  begin  in  persons  of  rather  advanced 
age,  most  commonly  in  men,  in  the  form  of  a  slight  scaly  roughness  with 
little  or  no  underlying  induration.  After  some  slight  traumatism  which 
may  cause  the  place  to  bleed,  a  crust  forms,  but  there  is  no  healing,  and  if  it 
is  pulled  off,  an  ulcer  is  left  upon  which  another  crust  forms.  By  this  time 
thickening  of  the  skin  in  that  area  is  palpable.  The  growth  of  this  thick- 
ened area  proceeds  until  there  is  a  considerable  mass,  which  extends  quite 
far  into  the  substance  of  the  lip.  Usually  there  is  repeated  uncovering  of  a 
superficial  ulceration,  which  quickly  becomes  overlaid  with  a  dry  crust,  but 
it  sometimes  happens  that  this  destruction  of  the  surface  is  very  slight 
indeed.  On  the  other  hand,  the  ulceration  may  go  very  deep  and  cause 


1020 


TEXT-BOOK   OF    PATHOLOGY 


great  distortion  of  the  lip,  hollowing  out  a  great  cavity  which  exposes  the 
teeth.  A  firm  nodule  may  be  felt  by  this  time  in  the  position  of  the  sub- 
mental  lymph-gland,  and  there  may  even  be  similar  firm  masses  replacing 
the  cervical  lymph-glands.  If  operative  extirpation  of  the  primary  tumor, 
together  with  the  glands  which  may  be  involved,  be  delayed  beyond  the 
early  stages,  death  follows  after  long  delay,  from  the  development  of 
metastases  in  more  distant  organs,  among  which  the  liver  is  most  promi- 
nent. As  a  rule,  however,  in  all  such  neglected  cancers  which  are  allowed 
to  metastasize,  death  is  actually  the  immediate  result  of  lobular  pneu- 
monia or  other  similar  terminal  in- 
fection. 

When  cut  through,  the  tumor  and 
its  metastatic  growths  appear  as 
grayish,  translucent  masses  of  tissue 
closely  flecked  with  opaque  yellow 
spots.  These  become  more  conspicu- 
ous as  the  tumor  grows  older  and 
are  scarcely  to  be  found  in  the  per- 
fectly fresh  margins  where  growth  is 
proceeding.  Slight  pressure  will  ex- 
press little  masses  or  cylinders  from 
the  cut  surface,  and  these  are  found 
to  be  composed  of  necrotic  and  kera- 
tinized  cells. 

Microscopical  study  of  a  section 
through  an  epithelioma  of  the  skin 
(Fig.  527)  reveals  the  existence  of  a 
mass  of  growing  strands  of  epithe- 
lium which  extend  far  down  into  the 
thickened  dermis  and  subcutaneous 
tissue.  These  are  solid  columns  of 
epithelial  cells  which  frequently  anas- 
tomose with  one  another  and  branch. 
They  are  several  cells  broad  or  may 

expand  into  much  wider  or  bulbous  masses  in  which  there  is  evident  a 
tendency  to  a  concentric  arrangement  of  the  cells,  which  become  more 
and  more  keratinized  toward  the  centre.  Sometimes  these  concentric 
horny  masses  are  relatively  large,  and  are  often  spoken  of  as  cancroid 
pearls,  cancroid  being  an  old  name  for  this  type  of  epithelioma.  All  the 
stages  in  keratinization  are  seen  plainly  in  passing  from  the  outer  layer 
of  cells  which  lies  next  the  connective  tissue  in  toward  the  centre  of  such 
a  pearl.  The  cells  become  thickly  studded  with  black  staining  droplets  of 
eleidin,  which  in  turn  fade  as  the  nucleus  and '  cell-body  shrink  into  the 
horny  scale  of  the  innermost  layers.  The  most  extraordinary  enlargement 
and  deformities  of  the  epithelial  cells  appear  in  such  areas  and  all  sem- 


Fig.  526.— Epithelioma  of  lip  with  begin- 
ning ulceration. 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA 


1021 


blance  of  the  regularity  with  which  the  process  goes  on  in  the  normal  skin 
may  be  lost. 

The  margin  of  the  tumor  is  usually  continuous  with  the  normal  skin- 
occasionally  there  is  a  break  between  the  epithelial  masses  of  the  tumor  and 
the  edge  of  the  normal  epidermis,  as  though  the  tumor  had  burst  up  through 
the  skin.  When  the  two  are  continuous,  there  is  not  a  perfectly  abrupt 
transition,  for  the  epidermis  becomes  thickened  and  sends'down  some  rather 
irregular  prolongations  just  before  it  joins  the  tumor.  Even  then  it  is  quite 
possible  that  the  epithelium  of  the  tumor  has  healed  to  the  epidermis  after 
having  burst  up  through  it.  It  is  not  believed  that  the  epidermis  is  con- 
verted into  tumor  tissue  as  the  tumor  spreads,  but  that  all  tumor  epithelium 
arises  from  that  which  first  began  to  grow.  Therefore,  the  epidermis  must 


Fig.  527. — Epithelioma  of  penis  showing  atypical  hyperplasia  of  adjacent  epithelium 
and  downgrowth  of  the  tumor-cell  strands. 

be  pushed  aside  or  burst  through  in  order  to  allow  the  tumor  to  grow.  In 
the  first  case  it  might  retain  its  continuity  with  the  tumor  throughout; 
in  the  second  there  must  be  a  secondary  healing  together. 

The  stroma  runs  everywhere  among  the  strands  of  cells,  carrying  blood- 
vessels. It  is  new  tissue,  of  course,  different  in  arrangement  from  the 
surrounding  dermis  and  subcutaneous  tissue,  but  in  itself  there  is  nothing 
peculiar  to  be  seen.  It  has  no  recognizable  tumor  character,  but  is  rather 
thickly  infiltrated  with  polynuclears  and  especially  mononuclear  leucocytes 
or  lymphocytes.  It  is  encroached  upon  by  the  epithelial  cells  at  every 
point,  and  if  we  follow  the  coarse  strands  downward,  we  find  that  at  their 
termination  they  frequently  narrow  themselves  to  single  rows  of  cells  or 
even  isolated  groups  of  cells  with  advancing  prolongations  which  are 


1022 


TEXT-BOOK   OF   PATHOLOGY 


obviously  insinuating  themselves  into  crevices  of  the  tissue  (Fig.  528). 
In  this  way  they  invade  not  only  the  stroma,  whose  formation  they  have 
enforced,  but  also  the  deeper  connective  tissue  and  muscle.  Any  crevice 
or  intercellular  space  is  seized  upon  for  their  invasion,  and  they  are  by  no 
means  limited  to  the  endothelium-lined  lymphatic  channels,  although  they 
also  enter  these.  At  the  surface,  where  ulceration  has  taken  place,  the  epi- 


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Fig.  528.— Portion  from  tumor  (Fig.  527)  more  highly  magnified,  showing  extensive 
keratinization,  invasive  growth  of  epithelium,  and  inflammatory  reaction. 

thelial  strands  are  interrupted,  and  their  broken  ends  exposed  in  the  base 
of  the  ulcer  or  covered  by  an  ordinary  granulation  tissue.  Where  the 
strands  are  intact,  there  may  be  excessively  thick  layers  of  keratinized  or 
horny  cells.  In  the  deeper  strands,  too,  instead  of  compact  pearls,  there 
are  often  found  cavities  lined  with  keratinized  cells  and  filled  with  a  soft 
de*bris  of  desquamated  scales  (Fig.  527). 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA  1Q23 

The  living  cells  of  these  strands  are  obviously  unlike  the  cells  of  the 
normal  epidermis  in  many  respects,  although  since  other  conditions  may 
produce  similar  morphological  alterations,  it  is  not  possible  to  recognize 
them  by  these  abnormalities  as  definitely  cancerous  cells.  They  are 
usually  rather  enlarged  and  polygonal,  or  irregular  in  outline,  and  are  ir- 
regularly arranged  with  regard  to  one  another.  Their  protoplasm  takes  a 
rather  deep  pink  stain  with  eosin  in  many  cases,  and  their  nuclei  seem 
especially  rich  in  chromatin  and  consequently  deep  stained.  There  may 
be  two  or  more  nuclei  in  a  single  cell  and  the  mitotic  figures  which  are 
abundant  may  be  irregular  or  multipolar.  The  cell  strands  are  often 
invaded  by  leucocytes,  and  fragments  of  these  cells  may  even  be  found 
embedded  within  the  cancer  cells.  Other  cell  inclusions  of  various  forms 
occur,  and  have  been  studied  with  great  care,  because  it  was  thought 
that  they  might  be  parasites  causing  the  growth  of  the  tumor.  These  must 
be  discussed  later. 

The  most  important  point  for  consideration,  however,  is  the  relation  of  the 
tumor-cells  to  the  adjacent  tissue.  They  are  not  definitely  and  smoothly 
bounded  by  a  line  of  demarcation  from  the  connective  tissue.  Instead,  it 
is  constantly  to  be  observed  that  the  cells  grow  out  irregularly  at  any 
point  in  the  course  of  the  strand,  and  push  their  way  into  that  tissue  in  a 
way  totally  foreign  to  the  normal  epidermis.  This  process,  which,  as  we 
have  said,  is  most  striking  along  the  advancing  margin  of  the  tumor  where 
it  encroaches  upon  the  underlying  tissue,  is  the  visible  sign  of  the  malig- 
nancy of  growth  which  gives  the  tumor  its  peculiar  character. 

It  has  been  said  that  the  tumor-cells  sometimes  push  their  way  into 
the  lymph-channels,  and  it  is  probable  that  in  doing  this  they  are  aided 
by  a  certain  degree  of  amoeboid  activity,  which  they  have  been  shown  to 
possess  in  tissue  cultures  (Hanes  and  Lambert).  In  those  channels  they 
are  swept  along  with  the  stream  whenever  they  break  loose,  and  lodge  in 
the  next  lymph-gland,  which  acts  as  a  sieve.  There,  instead  of  disinte- 
grating and  being  devoured  by  phagocytes  as  other  cells  would  be,  they 
are  often  able  to  establish  themselves  in  the  lymph-sinus  and  grow  rapidly, 
filling  up  all  the  sinuses  between  the  lymph-cords  and  beneath  the  capsule 
of  the  gland  with  a  solid  injection  of  epithelial  cells,  or  else  spreading  from 
the  sinus  in  which  they  lodge  to  produce  a  nodule  of  tumor  tissue  which 
extends  radially  to  occupy  a  large  part  of  the  gland.  In  this  process  the 
epithelium  at  once  causes  the  formation  of  a  new  vascular  stroma  for  its 
cells  at  the  expense  of  the  gland,  and  in  its  growth  separates  and  destroys 
the  normal  tissue  of  the  gland  which  it  replaces.  The  structure  of  this  new 
nodule  is  finally  in  every  respect  similar  to  that  of  the  original  tumor  and 
all  the  processes  of  keratinization  and  other  changes  described  for  that 
situation  are  repeated  here.  This  is  true,  too,  for  further  metastases  even 
when  the  renewed  transportation  of  cells  from  the  first  metastasis  gives  rise 
to  secondary  or  tertiary  colonies  in  distant  organs. 

Epitheliomata  may  occur  in  many  situations  in  the  skin,  although  it 


1024  TEXT-BOOK   OF   PATHOLOGY 

seems  that  places  at  which  two  types  of  epithelium  come  together  are  rather 
predisposed  to  the  development  of  these  tumors.  The  lip,  the  edges  of  the 
nostrils,  the  eyelid,  the  penis  and  vulva,  the  margin  of  the  anus  are  places 
where  they  most  frequently  occur.  In  the  margins  of  old  varicose  ulcers 
they  may  develop,  apparently  stimulated  or  possibly  even  caused  to  grow 
by  the  long-continued  irritation  to  which  the  skin  in  exposed  in  a  site 
where  it  is  continually  endeavoring  to  grow  and  being  as  constantly  frus- 
trated. 

Epitheliomata  are  by  no  means  limited  to  the  skin,  but  occur  very  fre- 
quently in  mucosse  which  are  covered  with  stratified  epithelium. 

Thus  such  tumors  may  originate  at  almost  any  point  in  the  interior  of 
the  mouth.  Although  they  sometimes  occur  in  the  cheek  or  gums,  epi- 
theliomata  of  the  tongue  are  far  more  common.  They  may  occupy  any 
situation  from  the  tip  to  the  extreme  base  of  the  tongue,  and  grow  in  such  a 


Fig.  529.— Epithelioma  of  tongue  with  ragged  ulceration. 

way  as  to  form  a  dense  mass  extending  far  into  its  substance  and  becoming 
deeply  ulcerated  (Fig.  529).  There  is  little  or  no  keratinization,  and  the 
superficial  layers  readily  become  macerated.  Metastases  may  appear  in 
the  regional  lymph-glands  and  internal  organs.  In  one  case  in  which  we 
found  a  great  solid  mass  embedded  in  the  root  of  the  tongue,  with  only  slight 
superficial  ulceration,  there  were  enormous  nodular  masses  in  the  cervical 
lymph-glands  throughout  the  whole  chain,  and  other  nodules  in  the  liver. 
In  another  case  in  which  the  deeply  ulcerated  tumor  had  extended  so  as  to 
approach  the  internal  carotid  artery,  it  finally  eroded  that  vessel  some 
weeks  after  a  partial  extirpation  of  the  tumor  tissue.  A  formidable  haem- 
orrhage was  stopped  by  ligature  of  the  artery,  but  the  man  died  ten  days 
later.  There  were  no  metastases,  but  there  was  a  large  abscess  in  the 
cerebral  hemisphere  of  that  side.  This  case  is  cited  merely  as  an  example 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA  1025 

of  the  unexpected  sequelae  which  may  complicate  the  course  of  a  tumor  of 
this  kind,  developed  in  the  immediate  neighborhood  of  important  structures. 

Epitheliomata  may  develop  from  the  surface  epithelium  or  crypts  of 
the  tonsils,  and  are  often  particularly  destructive.  Laryngologists  meet 
with  similar  tumors  involving  the  vocal  cords,  the  arytenoid  folds,  or  the 
epiglottis.  They  are  quickly  ulcerated,  and  lay  bare  the  cartilages  of  the 
larynx  after  having  destroyed  the  soft  tissues.  One  case  has  already  been 
mentioned  in  which  a  tumor  assumed  the  form  of  a  papilloma,  although 
spreading  over  the  arytenoid  folds  and  epiglottis  on  both  sides  and  extend- 
ing to  the  pillars  of  the  fauces.  In  most  cases,  however,  the  tumors  are  not 
elevated,  but  appear  as  flattened,  rough  thickenings  of  the  tissue,  soon 
hollowed  out  into  ragged  ulcers. 

Tumors  of  the  trachea  and  large  bronchi  are  rare,  and  not  ordinarily  of 
the  type  of  flat-cell  epithelioma,  as  is  natural  from  the  fact  that  those 
canals  are  lined  with  cylindrical  ciliated  epithelium.  Nevertheless  in  the 
substance  of  the  lung  tumors,  which  are  definitely  squamous,  epitheliomata 
do  arise  from  the  branches  of  the  bronchi.  We  have  recently  observed 
a  whole  series  of  these  tumors  of  the  lung,  among  which  there  were  several 
instances  in  which  a  great  cavity  in  the  upper  part  of  the  lung  was  found  on 
incision  to  be  lined  with  opaque,  yellowish-white,  friable,  crumbling  tissue. 
In  some  of  these  the  bronchus  could  be  traced  directly  into  the  cavity, 
its  walls  becoming  thickened  by  a  great  new-growth  of  the  mucosa,  which 
became  continuous  with  the  margins  of  the  lining  of  the  cavity.  Micro- 
scopical sections  show  in  these  cases  that  most  of  the  tumor  is  made  up  of 
strands  of  atypical  stratified  epithelium  showing  all  the  characters  of  those 
seen  in  the  cutaneous  cancers.  The  cells  are  held  together  by  very  distinct 
intercellular  bridges  (prickle  cells)  and  undergo  keratinization.  In  the 
bronchus  one  may  trace  the  transition  of  cylindrical  into  squamous  epi- 
thelium. It  is  perhaps  an  example  of  metaplasia  which  converts  one  kind 
of  epithelium  into  another,  although  it  is  conceivable  that  some  other 
explanation,  depending  rather  upon  embryonic  displacement  of  cells 
destined  to  become  squamous  epithelium,  might  be  offered  instead.  Dr. 
Adler  has  reviewed  these  tumors  of  the  lung,  and  in  his  book  it  may  be 
learned  that  there  are  many  other  types  in  which  cylindrical  cells  play  the 
important  role.  There  are  also  some  derived  from  the  flattened  alveolar 
epithelium,  although  their  cells  scarcely  retain  that  form. 

To  return  to  the  digestive  tract,  epitheliomata  are  common  in  the 
oesophagus,  where  they  occur  at  almost  any  level,  but  most  frequently 
opposite  the  cricoid  cartilage,  the  bifurcation  of  the  bronchi,  and  at  the 
cardiac  orifice  of  the  stomach.  Whether  the  explanations  given  for  these 
traditional  sites  are  satisfactory,  must  be  left  to  the  future  to  determine. 
It  has  been  thought  that  the  cesophageal  mucosa  at  these  points  is  irritated 
by  passing  food,  since  a  certain  projection  into  the  lumen  is  caused  by  the 
firm  structures  which  touch  the  outside. 

The  epitheliomata  are  usually  broad,  flattened  masses  which  nearly 

66 


1026  TEXT-BOOK    OF    PATHOLOGY 

encircle  the  oesophagus,  and,  by  encroaching  upon  its  lumen,  obstruct  it 
greatly.  The  starvation  caused  by  this  obstruction  hastens  the  decline 
in  health  of  the  affected  person.  We  have  been  repeatedly  struck  by  the 
fact  that  the  tumor  may  not  extend  all  the  way  around  the  wall  of  the 
oesophagus,  but  leaves  intact  a  narrow  band  of  normal  mucosa  which  joins 
the  unaffected  mucosa  above  and  below  the  tumor.  On  section,  the  cut 
surface  of  the  tumor  is  quite  like  that  of  other  epitheliomata,  except  that  it 
is  perhaps  less  closely  flecked  with  necroses.  Nevertheless,  ulceration 
does  occur  rapidly  and  at  the  same  time  the  tumor  extends  through  the 
muscular  and  connective-tissue  coats.  Usually  adhesions  of  dense  fibrous 
tissue  form  between  the  diseased  oesophagus  and  neighboring  structures, 
so  that  further  growth  of  the  tumor  extends  through  the  adhesions  into 
those  organs.  Thus  a  main  bronchus  or  the  trachea  may  be  invaded  and 
perforated  so  that  there  is  formed  a  definite  fistula  between  the  bronchus 
and  oesophagus.  In  that  case  bronchopneumonia  rapidly  follows  the 
leakage  of  cesophageal  contents  into  the  bronchus.  The  lung  may  be 
invaded  directly,  or  an  opening  be  formed  into  the  pleural  cavity.  In 
rare  cases  the  aorta  or  inferior  vena  cava  are  eroded  and  death  may  follow 
from  haemorrhage.  Occasionally  the  tumor  recedes  in  its  growth  and  under- 
goes a  partial  healing,  with  the  formation  of  scar  tissue  which  contracts 
about  the  oesophagus,  forming  a  narrow  stricture.  Metastases  are  found 
in  the  pericesophageal  lymph-glands,  in  the  lungs,  in  the  liver,  or  in  other 
more  distant  situations.  I  saw  a  case  in  which  the  tumor  had  invaded 
a  pulmonary  vein,  producing  infarcts  in  the  kidneys  and  intestines  and 
emboli  surrounded  by  haemorrhages  in  the  liver  and  meninges.  Another 
projected  in  the  form  of  nodules  into  the  lumen  of  the  trachea,  while  there 
were  secondary  nodular  growths  in  the  parietal  pleura.  Microscopically 
these  tumors,  like  those  of  the  skin,  grow  in  the  form  of  solid  branching 
strands  of  cells  which  readily  invade  the  muscularis.  They  are  rather 
less  regular  in  form,  and  in  the  character  of  their  nuclei,  than  the  cells  of 
the  skin  cancers  and  do  not  become  keratinized.  Nevertheless,  the  same 
concentric  arrangements  may  be  found  with  flattening  and  degeneration 
of  the  central  cells. 

The  tumors  of  the  gall-bladder  are  usually  of  the  cylindrical  cell  type, 
but  they  may  sometimes,  as  in  the  case  of  the  lung,  show  themselves  to  be 
composed  of  squamous  epithelium,  a  character  which  is  maintained  in 
all  the  metastatic  nodules. 

In  the  urinary  bladder  there  appear  papillomatous  tumors  which  have 
already  been  described,  and  these,  as  it  was  then  said,  are  probably  from 
the  beginning  malignant  in  character  and  merely  impose  themselves  for  a 
time  as  benign  growths.  At  the  bases  of  the  tassel-like  papillomatous 
growths  the  thick  stratified  epithelium  is  found  to  invade  the  underlying 
tissue  in  the  form  of  solid  strands  (Fig.  530).  Usually  after  a  time  ulcera- 
tion may  destroy  most  of  the  papillomatous  growth,  leaving  only  a  ragged 
area  in  the  bladder-wall  lined  by  rough  masses  of  growing  epithelium. 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA  1027 

Another  type  of  carcinoma  of  the  bladder  does  occur,  however,  in  which  the 
wall  is  infiltrated  and  invaded  widely  without  having  lodged  at  any  time  a 
papi  lomatous  growth.  I  saw  one  case,  however,  in  which  there  were  many 
small  polypoid  tumors  scattered  over  the  bladder-wall  and  concentrated 


f.  $& 

&<  -•/  *  A  ',  •  >!«*  ~E  o°s   «§  ?§5«5£»I»*  ,«;>  r  i  'X0^"*  "-*  t«  • '.  i 

M!/ 


f^;V;^?  i.V.V   yV;  >'!**-=     ';'xf  ^''•'^'v    '?,    /V-'^ 


Fig.  530. — Papillomatous  tumor  of  bladder,  showing  invasive  growth  of  some  strands 

of  epithelial  cells. 

especially  about  one  ureteral  orifice.  That  ureter  was  greatly  dilated  and 
was  lined  with  similar  tiny  papillomata  which  extended  up  into  the  pelvis 
of  the  kidney.  It  was  difficult  to  be  sure  whether  the  primary  growth  was 
in  the  ureter  or  bladder.  Single  carcinomatous  nodules  sometimes  occur 


1028 


TEXT-BOOK   OF    PATHOLOGY 


in  the  ureter,  causing  its  great  obstruction,  and  giving,  rise  to  metastases 
in  neighboring  lymph-glands.  In  these  one  finds  very  delicate  narrow 
strands  of  epithelial  cells  which  no  longer  resemble  closely  the  large  cells 
of  the  typical  epitheliomata. 

The  epitheliomata  of  the  cervix  uteri  and  adjacent  vaginal  wall  are  per- 
haps the  most  important  of  all,  on  account  of  their  extreme  frequency, 
their  malignancy  and  rapid  growth,  and  their  fatal  effects. 


Fig.  531. — Epithelioma  of  vaginal  portion  of  cervix  uteri,  invading  uterine  and  vagi- 
nal wall.  There  is  great  ulceration,  which  approaches  bladder  and  rectum  without  ac- 
tually perforating  them. 

Another  type  of  carcinoma  of  the  uterus  derived  from  the  tubular  glands  of  the  body 
of  the  organ,  and  maintaining  the  character  of  an  adenocarcinoma,  will  be  described 
later,  but  it  is  of  much  less  importance,  since  it  is  relatively  rare  and  by  no  means  so 
malignant. 

These  tumors  (Fig.  531)  develop  in  the  portio  vaginalis  of  the  cervix 
uteri,  near  the  line  of  transition  of  the  stratified  epithelium  into  the 
cylindrical  mucosa,  and  appear  at  first  as  rough  erosions  with  a  surface 
which  bleeds  easily  and  is  almost  papillary  in  form.  Growing  into  the 
substance  of  the  cervix  the  tumor  may  surround  the  external  os  with  a 
dense  ring  of  friable  epithelium.  The  further  growth  is  usually  accom- 


FLAT   OR   SQUAMOUS   CELL   CARCINOMATA  1029 

panied  by  ulceration,  which  hollows  out  a  funnel-shaped  or  irregular 
aperture.  A  longitudinal  section  of  the  uterus  at  this  stage  shows  that 
much  of  the  cervical  wall  is  occupied  by  a  gray,  solid  tissue  with  numerous 
opaque  flecks  of  white.  The  growth  stops  abruptly  above  and  gives  place 
to  the  ordinary  mucosa  which  lines  the  cavity  of  the  uterus.  Extension 
outside  on  the  vaginal  portion  of  the  cervix  and  over  the  vault  of  the 
vagina  is  common,  and  later  more  of  the  vagina  may  be  involved  in  the 


Fig  532.— Epithelioma  of  cervix  uteri  with  many  multinucleated  cells.     In  the  centre 
there  is  an  epithelial  cell  showing  multipolar  mitosis. 

continuous  growth.  Metastases  to  the  inguinal  lymph-glands  and  later 
to  those  of  the  retroperitoneal  region  may  occur  at  this  stage,  and  there 
may  even  be  nodules  in  the  liver  or  lungs.  The  further  growth  of  the  tumor 
extends  into  the  parametrium,  forward  into  the  wall  of  the  bladder,  and 
backward  to  involve  the  wall  of  the  rectum.  Ulceration  takes  place 
rapidly  and  it  is  not  uncommon  to  find  a  great,  ragged  perforation  between 
the  vagina  and  bladder  or  between  vagina  and  rectum.  I  have  seen  one 


1030 


TEXT-BOOK    OF    PATHOLOGY 


case  in  which,  from  such  ulceration,  bladder,  uterus,  and  rectum  all  opened 
in  common  into  a  great  ragged  cavity.  Infection  of  the  bladder  and 
ureters  is  sure  to  follow,  and  death  may  be  immediately  due  to  an  ascending 
suppurative  nephritis.  The  tumor  is  composed  of  thick,  irregular  strands 
of  stratified  epithelium,  which  is  not  keratinized,  but  in  which  the  most 
extreme  irregularities  in  the  form  of  the  cells  may  be  observed.  In  one 
such  case  (Fig.  532)  there  were  cells  of  all  sizes,  even  including  huge  proto- 


H 

„••;••>.-•  '*'••*$ 


Fig.  533.—Adamantinoma.     Each  mass  of  cells  presents  a  central  cavity  filled  with  fluid. 

plasmic  masses  containing  as  many  as  12  nuclei  irregularly  placed  through- 
out the  cell-body.  Multipolar  mitotic  figures  in  which  several  centrosomes 
and  achromatic  spindles  could  be  seen  in  relation  to  a  very  much  branched 
arrangement  of  chromosomes  gave  the  explanation  of  the  formation  of 
these  multinucleated  cells.  Other  tumors  of  this  type  are  less  atypical 
and  merely  present  irregularly  branching  cords  of  cells,  which  ramify  and 
spread  freely  in  any  direction  to  invade  the  uterine  muscle.  Necroses  are 


BASAL-CELL   CARCINOMATA  1031 

frequent  in  such  tissue,  involving  the  broader  bands  of  epithelial  cells. 
The  stroma  which  is  formed  in  association  with  them  is  much  infiltrated 
with  wandering  cells,  and  it  may  happen  that,  at  the  surface  of  the  tumor, 
only  those  epithelial  cells  which  are  immediately  around  the  blood-vessels 
remain  alive  and  project  as  papillary  remnants. 

The  remote  metastases  which  may  be  in  the  peritoneum  or  omentum,  in 
the  liver,  kidneys,  etc.,  as  well  as  in  the  regional  lymph-glands,  often  reach 
a  considerable  size,  although  in  the  cases  which  I  have  seen  they  have  been 
relatively  small.  They  maintain  the  type  of  tumor  tissue  seen  in  the  origi- 
nal growth. 

Tumors  which  belong  in  this  general  class  are  the  cancers  of  aniline 
workers,  of  chimney-sweeps,  of  betel  chewers,  and  of  those  in  whom  z-ray 
burns  have  long  persisted.  It  will  be  more  useful  to  describe  them  in  con- 
nection with  the  general  discussion  of  carcinoma  and  other  tumors. 

Adamantine  Epitheliomata  or  Adamant inoinata. — These  are  rare  tumors 
which  develop  in  the  substance  of  the  jaw  bone  at  the  base  of  the  tooth,  and 
push  their  way  out,  displacing  the  tooth  and  causing  the  wasting  away  of 
the  bone  until  they  emerge  as  nodular,  hard  masses  which  may  reach  the 
size  of  a  grape-fruit.  The  tumors,  which  are  usually  quite  small,  are  de- 
rived, according  to  the  general  opinion,  from  the  enamel  organ,  which  is 
an  epithelial  structure  at  the  base  of  the  tooth  concerned  in  the  formation  of 
enamel.  Malassez  regards  them  as  derived  from  certain  paradental  rem- 
nants of  epithelium,  but  the  evidence  for  the  other  origin  seems  stronger. 

The  tumors  are  really  benign,  and  should  perhaps  be  considered  in 
another  place,  but  their  morphology  is  much  like  that  of  an  epithelioma. 
The  strands  of  epithelium  are  broad  and  anastomose  irregularly  (Fig. 
533).  They  are  hollowed  out  centrally  into  cavities  which  are  seen  to  be 
due  to  the  gradual  separation  of  the  cells  and  the  accumulation  of  fluid. 
The  cells  ramify  somewhat,  and  are  connected  by  very  distinct  intercel- 
lular bridges.  The  most  peripheral  cells  abutting  on  the  connective  tissue 
are  almost  cylindrical  in  form.  A  characteristic  appearance  is  produced 
by  this  arrangement,  and  it  is  very  easy  to  recognize  these  tumors. 
The  stroma  is  dense  and  fibrous  and  sometimes  contains  bone. 

LITERATURE 
Skin.— Oneway:  Ztschr.  f.  Krebsforschung,  1910,  viii,  403. 

Dittrick:  Amer.  Jour.  Med.  Sci.,  1905,  cxxx,  277. 
Penis.— Patterson:  Univ.  Penna.  Med.  Bull.,  1901,  xiv,  157 
(Esophagus.-Szkztz:  Mitth.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1903,  xi,  634 

Cummins:   Proc.  Path.  Soc.  Phila,  1908,  xi,  44. 
Ton^.-Kiittner:  Beitrage  z.  kl.  Chir.,  1898,  xxi,  732 
Atoanfcnoma.-Krompecher:  Ziegler's  Beitrage,  1918,  tav,  165. 

BASAL-CELL  CARCINOMATA 

Krompecher  has  pointed  out  the  fact  that  many  of  the  tumors  which  grow 
in  the  skin  and  are  distinctly  derived  from  the  epithelium  are  quite Different 
in  structure  from  the  epitheliomata  just  described  and  quite  as  different  in 


1032 


TEXT-BOOK   OF   PATHOLOGY 


their  biological  characters.  These  comprise,  in  addition  to  many  flattened 
irregular  nodular  masses,  the  so-called  rodent  ulcers,  which  have  been  long 
known  to  differ  from  the  ordinary  epitheliomata  in  that  they  are  relatively 
benign  and  rarely  show  any  tendency  to  metastasize  rapidly.  Krompecher 
regards  these  tumors  as  growths  derived  from  the  lowermost  or  basal  layers 
of  the  epidermis,  for  which  reason  they  show  no  tendency  to  keratinization 
or  to  pearl  formation.  Indeed,  he  is  willing  to  ascribe  certain  tumors  to  the 
cylindrical  or  Malpighian  layer,  others  to  the  rete  layer  with  cuboidal  cells, 

and  the  highly  malignant  epitheliomata 
to  the  more  superficial  or  spiny  layer. 
This  seems  open  to  question,  and  it  is 
conceivable  that,  while  the  more  inno- 
cent basal-cell  cancers  may,  in  truth,  be 
derived  from  these  lower  layers,  the 
malignant  epitheliomata  may  represent 
a  different  biological  alteration  of  any 
or  all  cells  of  the  epidermis,  so  that  their 
malignancy  is  not  merely  the  effect  of 
their  being  derived  from  a  somewhat 
more  differentiated  layer  of  the  same 
cells. 

The  basal-cell  cancers  appear  most 
frequently  on  the  face,  being  especially 
common  in  the  upper  part,  about  the 
forehead,  the  cheek,  the  nose,  and  the 
eyelids  (Fig.  534).  They  are  also  to  be 
found  on  the  back  or  abdomen,  or  in 
any  other  region  of  the  body,  and  it  is 
to  be  observed  that  they  do  not,  like 
the  ordinary  epitheliomata,  arise  at  the 
margins  of  the  skin  and  mucosae,  where 
complexities  in  development  occur. 
Krompecher  gives  diagrams  which  show 
how  they  grow  from  the  lower  layers  of 
the  epidermis,  forming  masses  of  solid 
strands  or  complicated  formations  of 
ramified  epithelial  structures  in  which 

the  cells  maintain  themselves  in  single  layers.  In  these  cases  the  super- 
ficial layer  of  the  epithelium  persists  as  a  smooth  sheet  of  cells,  although 
occasionally  it  may  dip  down  into  the  middle  of  each  downgrowth  of  the 
basal  epithelium. 

On  section  through  such  tumors  (Fig.  535)  one  is  impressed  with  the  fact 
that,  in  spite  of  the  complexity  of  the  downward-growing  strands,  all  reach 
to  about  the  same  level.  Further,  it  is  seen  that  they  are  very  sharply 
outlined  against  the  stroma,  and  show  little  inclination  to  strew  their  cells 


Fig.  534. — Basal-cell  epithelioma  or 
rodent  ulcer  of  eyelid. 


BASAL-CELL  CARCINOMATA 


1033 


mto  the  irregular  crevices  of  that  tissue.     Doubtless  this  morphological 

character  ,s  an  expression  of  their  benign  type  of  growth.     The  cells  are 

*ter  small  and  compact,  with  deeply  staining  nuclei  and   relatively 

scant  protoplasm,  which  also  takes  a  rather  dark  stain.     There  is  little  or 


Fig.  535. — Basal-cell  epithelioma  of  the  skin,  showing  peculiar  limitation  of  the  down- 
ward growth. 


nothing  of  the  pallor,  the  inflation,  and  the  nuclear  irregularities  which  are 
so  common  in  the  cells  of  the  more  malignant  epitheliomata.  Necrosis  and 
ulceration  are  common,  however,  and  the  tumors  often  present  themselves 
as  advancing  ragged  ulcers  with  only  a  very  thin  wall  of  tumor  tissue. 


1034  TEXT-BOOK   OF   PATHOLOGY 

Upon  extirpation  they  show  little  tendency  to  recur,  but  even  if  there  is  a 
recurrence,  it  is  exceptional  to  find  metastases  in  the  regional  lymph-glands 
or  in  more  distant  situations. 

It  will  at  once  suggest  itself  that  the  nsevi  bear  a  considerable  resemblance 
to  these  tumors,  since  they  are  composed  of  small,  compact  cells  which  lie 
in  the  papillae  of  the  dermis,  and  are  thought  by  many  to  be  connected  with 
the  epidermis  itself.  It  is  true  that,  in  nsevi,  the  connection  of  the  tumor- 
cells  with  the  epithelium  must  be  sought  for  with  great  care,  and  is  fre- 
quently impossible  to  find,  that  the  cells  have  little  histological  resemblance 
to  those  of  the  epithelium,  and  that  their  great  tendency  to  form  or  to 
accumulate  pigment  in  their  cell-body  marks  them  out  from  those  of  the 
basal-cell  tumors.  There  the  tumor-cell  strands  are  everywhere  continu- 
ous with  the  epithelium;  they  are  not  merely  isolated  groups  of  cells  lying 
in  the  substance  of  the  dermal  papillae:  they  are  typically  epithelial  in 
character,  and  seldom  contain  any  considerable  amount  of  pigment.  They 
have  little  energy  of  growth  and  rarely  metastasize,  while  from  the  nsevi 
there  arise  the  most  malignant  of  all  tumors,  the  melanomata,  which  may 
scatter  secondary  nodules  in  thousands  in  every  tissue  of  the  body.  Never- 
theless, there  are  many  who  regard  the  nsevi  and  the  melanomata  as  tumors 
of  epithelial  origin,  and  Krompecher  identifies  them  more  or  less  closely 
with  his  basal-cell  cancers.  A  decision  is  difficult  in  this  matter,  but  it 
seems  that  there  are  sufficient  points  of  distinction  to  warrant  the  separa- 
tion of  the  groups.  The  tumors  which  were  referred  to  as  endotheliomata 
of  the  skin  by  Braun,  and  accepted  as  such  by  Borst,  were  mentioned  under 
that  heading  as  possibly  derived  from  the  endothelium  of  the  lymphatic 
channels  in  the  skin.  Such  tumors  are,  of  course,  possible,  but  Krompecher 
unhesitatingly  ascribes  to  them  an  epithelial  origin  and  regards  them  as 
identical  with  the  basal-cell  cancers.  This  identification  he  pushes  further 
to  include  many  tumors  which  arise  from  the  glands  which  open  upon  sur- 
faces of  stratified  epithelium,  and  even  the  mixed  tumors  of  the  salivary 
glands,  which  we  shall  discuss  in  the  next  chapter.  He  finds  that  basal-cell 
cancers  arise  in  ovarian  tumors,  in  dermoid  cysts,  and  other  tumors  of 
teratomatous  origin.  This  can,  of  course,  never  be  contradicted,  since 
those  tumors  have  such  manifold  possibilities.  Finally,  the  neuroepithelio- 
mata  of  the  retina  described  by  Flexner,  and  later  by  Wintersteiner,  seem 
to  him  to  have  similar  characters. 

In  the  intestine  Krompecher  describes  no  analogues  of  his  tumors,  but 
other  authors  have  found  curious  carcinomata  in  the  small  intestine,  usually 
occurring  as  multiple  nodules,  and  often  causing  stricture  or  obstruction  of 
the  gut,  which,  from  their  structure  and  behavior,  seem  to  resemble  these 
basal-cell  cancers  quite  closely.  They  are  dense  masses  which  partly 
encircle  the  intestine  at  several  points  or  project  into  its  interior  and  are 
made  up  of  rather  narrow  strands  of  cells  in  a  dense  stroma.  One  tumor 
apparently  of  this  character  occurring  in  our  material  was  called  an  intesti- 
nal adenoma.  It  is  composed  of  broad,  solid  strands  of  cells,  with  rounded 


BASAL-CELL   CARCINOMATA  1035 

nuclei,  which  extend  down  into  the  muscularis  and  show  little  connection 
with  the  overlying  mucosa.  The  cells  of  these  strands  are  frequently  col- 
lected into  rosettes  or  interlacing  strands,  which  look  like  tubules,  but  are 
solid  and  closely  packed  together  to  form  the  main  masses.  In  this  respect 
they  remind  one  of  the  neuroepitheliomata.  Similar  tumors  of  relatively 
benign  character  are  found  in  the  appendix.  There,  too,  the  tumor  tissue 
is  composed  of  narrow,  irregular,  solid  strands  of  small  cells,  in  no  place 
reproducing  the  crypts  or  glands  of  the  appendix,  as  would  be  the  case  in  an 
adenocarcinoma.  Implantations  in  the  peritoneum  may  occur,  but  metas- 
tases  are  rare. 

In  spite  of  the  numerous  papers  which  have  appeared  recently  with  regard 
to  these  tumors,  it  seems  that  there  remains  much  to  learn  as  to  their  rela- 
tions. 

LITERATURE 

Krompecher:  Ziegler's  Beitrage,  1900,  xxviii,  1.     Der  Basalzellenkrebs,  Jena,  1903. 
Bunting:  Johns  Hopkins  Hosp.  Bull.,  1904,  xv,  389. 
Oberndorfer:  Frankfurter  Ztschr.  f.  Path.,  1907,  i,  426. 
Burckhardt:    Ibid.,  1912,  xi,  219. 
Dietrich:  Ibid.,  1913,  xiii,  390. 


CHAPTER  LIII 
CARCINOMATA  (Continued) 

Adenocarcinomata:  General  characters  and  distribution.  Carcinomata  of  the  stomach: 
polypoid,  solid,  and  scirrhous  forms.  Their  histology  and  mode  of  growth;  metastasis. 
Colloid  forms,  their  somewhat  different  mode  of  growth.  Carcinomata  of  the  gall-bladder 
and  ducts;  carcinomata  of  the  pancreas,  of  the  colon,  of  the  prostate.  Metastasis  into  bones 
from  prostatic  tumors.  Adenocarcinomata  of  the  uterus  and  of  the  ovary. 

ADENOCARCINOMATA 

FROM  all  mucosse  in  which  the  epithelium  is  cylindrical  in  form,  and  from 
glands  and  ducts  lined  with  cylindrical  epithelium,  there  may  be  derived 
adenocarcinomata  or  cylindrical-celled  cancers.  These  are  malignant  tu- 
mors which  give  rise  to  extensive  metastases,  often  far  larger  than  the 
primary  growth.  They  maintain  in  irregular  fashion  the  arrangement  of 
tubular  glands,  transmitting  this  mode  of  growth  to  the  primary  metas- 
tases, but  sometimes  losing  it  in  secondary  metastases  which  arise  from  the 
transportation  of  cells  from  the  primary  ones.  This  modification  of  the 
architecture  of  tumors  in  secondary  or  tertiary  metastases  is  not  uncom- 
mon, and  will  be  discussed  later  in  a  more  general  way. 

While  adenocarcinomata  may  thus  appear  in  situations  almost  as  numer- 
ous as  those  which  form  the  point  of  origin  of  epitheliomata,  there  are  cer- 
tain sites  which  become  important  from  the  fact  that  they  are  so  frequently 
the  starting-point  of  these  tumors — the  stomach,  the  gall-bladder,  and  bile- 
ducts,  the  pancreas,  the  large  intestine,  the  body  of  the  uterus,  and  to  a  less 
extent  the  prostate  and  the  bronchial  mucosa.  Of  course,  tumor  tissue  of 
this  structure  may  also  occur  in  teratomata,  where  there  are  abundant 
opportunities  for  its  development.  Except  for  the  exaggerated  energy  of 
growth  of  their  cells,  they  are  quite  comparable  to  the  adenomata  and  poly- 
poid glandular  tumors. 

Carcinomata  of  the  Stomach. — The  extreme  prevalence  of  carcinoma- 
tous  tumors  of  the  stomach,  their  disabling  effects,  and  fatal  outcome  cause 
them  to  occupy  a  very  prominent  place  among  tumors.  There  are  many 
varieties,  and  many  situations  in  the  stomach  may  be  occupied,  so  that  the 
symptoms  vary  greatly.  A  cancer  at  the  cardiac  orifice,  by  obstructing  the 
entrance  of  food  into  the  stomach,  may,  like  the  epitheliomata  of  the  cesoph- 
agus,  result  in  starvation  and  extreme  emaciation.  A  cancer  in  the 
fundus  of  the  stomach  or  on  any  part  of  the  wall  away  from  the  orifice  may 
exist  a  long  time  without  causing  any  symptoms,  while  such  a  tumor  at  the 
pylorus  or  encircling  the  pyloric  ring  is  sure  to  cause  stagnation  of  the 
gastric  contents  and  dilatation  of  the  stomach.  Absorption  of  poisonous 

1036 


ADENOCARCINOMATA 


1037 


decomposition  products  must  then  occur,  and  the  gastric  juice  loses  its  anti- 
septic qualities  with  the  loss  of  its  high  content  of  hydrochloric  acid,  in 
place  of  which  lactic  acid  often  appears.  Bacteria  or  moulds  may  thrive 
m  considerable  quantities  in  the  accumulated  material,  particularly  the 
large  Oppler-Boas  bacillus.  Vomiting  is  frequent,  and  as  a  result  of  the 
dram  of  gastric  juice  or  possibly  of  the  absorption  of  toxic  material  gas- 
tric tetany  may  appear  just  as  it  does  when  the  pylorus  is  obstructed  by 
the  scar  of  an  old  ulcer. 

The  following  types  of  cancer  of  the  stomach  are  met  with  and  are 


Fig.  536. — Large  fungus-like  carcinoma  near  fundus  of  stomach. 


sufficiently  different  morphologically  to  fall  into  groups,  although  doubtless 
in  principle  they  are  alike. 

Carcinomata  about  the  cardiac  orifice  may  be  derived  from  the  prolonga- 
tion of  the  stratified  epithelium  of  the  oesophagus  and  may  therefore  have 
the  anatomical  characters  of  the  epitheliomata.  The  others  derived  from 
the  cylindrical  epithelium  usually  maintain  that  type  of  cell,  although  in 
many  instances  in  which  fine  strands  of  cells  are  found  scattered  through  the 
musculature,  the  cylindrical  character  is  lost. 

Polypoid  Carcinomata. — These  occur  anywhere  on  the  stomach-wall  and 
project  into  the  lumen  as  broad,  pedunculated,  fungus-like  masses,  which 
are  rather  soft  and  easily  torn  or  broken  apart.  In  Fig.  536  there  is 


1038  TEXT-BOOK    OF    PATHOLOGY 

shown  an  example  of  this  type,  in  which  the  tumor  is  situated  very  near  the 
cardiac  orifice,  and  doubtless  projected  in  front  of  it,  without,  however, 
causing  any  marked  obstruction.  Quite  similar  tumors  are  found  near  the 
pylorus.  In  this  case  there  were  no  discoverable  metastases,  and  it  is  my 
impression  that  these  tumors  do  not  form  metastases  so  rapidly  as  do  the 
other  types.  The  normal  mucosa  passes  upward  to  the  overhanging  edge 
and  gives  place  to  the  most  complex  arrangement  of  gland-like  structures 
lined  with  cylindrical  epithelium.  In  places  there  appear  to  be  papil- 
lomatous  areas;  in  others  through  the  whole  depth  of  the  tumor  the  tissue 
is  made  up  of  a  delicate  stroma,  supporting  wide  and  narrow  ramifying 
tubular  epithelial  structures.  There  is  surprisingly  little  downgrowth  into 
the  muscular  wall  in  this  case,  but  in  others  of  the  same  type  it  is  far  reach- 
ing and  destructive.  Necrosis  and  sloughing  of  the  exposed  tumor  is  of 
almost  regular  occurrence. 

Solid  cardnomata  of  more  sessile  form  are  much  denser  than  these 
fungating  types.  They,  too,  may  grow  anywhere  in  the  stomach,  but 
appear  most  frequently  about  the  pylorus  and  the  lesser  curvature.  Va- 
rious stages  may  be  found,  from  a  beginning  adenoma-like  growth  of  small 
size  to  the  huge,  crater-like,  excavated  masses  which  occupy  a  great  part 
of  the  wall  of  the  stomach.  I  remember  one  such  tumor  as  large  as  a  child's 
head,  composed  of  dense,  elastic,  yellowish- white  tissue,  which  projected 
into  the  stomach  and  was  hollowed  out  so  that  the  cavity  extended  far  into 
the  liver,  to  which  the  outer  surface  of  the  stomach  had  become  densely 
adherent.  Ordinarily,  such  tumors  are  found  as  rounded  or  irregular  ulcers 
with  thick,  elevated,  rounded  edges  which  can  be  felt  to  project  a  short 
distance  beneath  the  adjacent  mucosa  (Fig.  537).  One  may  pick  up  and 
move  the  mucosa  almost  as  far  upward  on  this  ridge  as  its  crest — beyond 
that,  although  the  mucosa  looks  smooth  and  velvety  for  a  short  distance 
further,  it  is  adherent  and  immovable.  There  follow  a  roughening  and 
irregularity  of  the  surface  which  then  drops  precipitously  into  the  ulcer. 
On  cutting  through  the  margin  of  the  tumor  the  transition  of  the  normal 
mucosa  into  the  greatly  thickened  epithelial  mass  of  the  tumor  can  be  seen. 
Here  as  in  the  epitheliomata  of  the  skin,  the  significance  of  this  continuity 
may  be  questioned  and  it  seems  probable  that  in  spite  of  the  intermediate 
zone  of  modified  mucosa,  the  unbroken  epithelium  may  be  maintained 
by  repeated  healing  together.  It  is,  however,  possible  that  the  normal 
mucosa  is  merely  pushed  back  by  the  increase  in  size  of  the  tumor.  It 
does  not  seem  probable  that  normal  mucosa  is  converted  into  tumor  as  the 
growth  advances. 

It  is  rare  to  see  a  gastric  carcinoma  which  is  not  ulcerated,  although  the 
tumor  itself  may  be  far  larger  than  the  area  occupied  by  the  ulceration. 
The  cut  surface  reveals  a  white  or  grayish-white  or  yellowish  tissue  which 
interrupts  the  muscularis  mucosae,  and  passing  through  the  submucosa, 
interrupts  and  penetrates  the  muscular  coat  of  the  stomach.  At  the 
margin  the  muscular  coat  may  be  traced  for  some  distance  into  the  tumor, 


ADENOCARCINOMATA 


1039 


between  th    fil°U     f   ^  **  tUm°r  ^  grOWn  in  thousands  °f  fine  Brands 
between  the  fibres  of  the  muscle,  leaving  it  otherwise  intact  for  a  long  time. 

In  the  subserous  t.ssue  it  again  becomes  a  solid  mass.     On  the  outer  surface 

ie  h  ie  cancer  1S  readily  made  out  by  the  ri»di1y of  the "»".  a«d 

isually  by  the  appearance  of  whitish,  flattened  nodules  which  cover  the 
peritoneal  surface.  Dense  adhesions  to  surrounding  organs  are  very 
common,  and  the  stomach  is,  in  consequence,  often  kinked  and  distorted 
by  being  drawn  up  against  the  liver  or  pancreas.  Metastatic  nodules  are 
usually  found  m  the  neighboring  lymph-glands,  which  may  be  greatly 


Fig.  537. — Carcinoma  of  stomach  with  ulceration  and  thickened,  elevated  margin. 

enlarged.  On  section,  they  show  a  white  tissue,  usually  with  yellowish 
necrotic  flecks  in  every  way  similar  to  that  in  the  gastric  wall.  The  omen- 
turn  is  studded  thickly,  in  many  cases,  with  minute  nodules  of  the  same 
tissue  and  is  drawn  up  into  a  dense  prismatic  mass  which  lies  transversely 
in  the  abdomen  and  can  be  felt  through  its  wall.  There  may  be  more 
distant  metastatic  nodules  in  the  peritoneum,  but  it  is  more  common  to 
find  them  rather  limited  to  the  region  of  the  stomach.  The  occurrence  of 
metastatic  nodules  in  the  liver  is  extremely  frequent  and  these  may  reach 
a  very  great  size  and  be  very  numerous.  The  most  remarkable  variation 


1040 


TEXT-BOOK   OF    PATHOLOGY 


occurs  in  this  respect,  for  while  some  large  tumors  show  only  a  few  small 
metastases,  others  of  less  extent  are  found  to  have  given  rise  to  enormous 
growths"  in  the  liver  sufficient  in  number  to  occupy  most  of  its  substance. 
The  occurrence  of  metastases  in  other  situations  will  be  referred  to  later. 
It  has  long  been  thought  that  these  tumors  may  develop  in  the  edge  of  a 
round  ulcer  of  the  stomach,  and  there  is  much  clinical  and  pathological  evi- 
dence to  support  this  view.  The  transformation  of  symptoms  of  long- 
standing gastric  ulcer  into  those  of  a  gastric  carcinoma  may  not  be  very 
convincing,  nor  even  the  discovery  of  an  ulceration  in  the  middle  of  the 
tumor,  with  such  induration  of  its  base  as  to  suggest  the  existence  of  a 
primary  chronic  gastric  ulcer.  But  when  the  tumor  develops  on  one  side 
of  a  typical  round  ulcer,  the  conclusion  is  more  difficult  to  escape.  We 


Fig.  538. — Dense  carcinoma  of  stomach  surrounding  the  whole  pyloric  region  and 
narrowing  the  channel.  There  is  diffuse  infiltration  of  the  whole  thickness  of  the  wall 
with  the  tumor-cells. 


have  seen  two  typical  round  ulcers  of  the  stomach,  in  the  margins  of  which 
carcinomatous  growth  of  epithelium  of  unmistakable  character  was  found, 
although  in  neither  case  had  the  tumor  developed  sufficiently  to  disturb 
the  characteristic  appearance  of  the  ulcer. 

Other  solid  gastric  cancers  grow  as  in  Fig.  538,  without  such  extensive 
ulceration  and  produce  a  great  thickening  of  the  mucosa  and  of  the  sub- 
mucosa,  infiltrating  the  muscle  layer  and  the  subserous  tissue.  Such  a 
tumor  does  become  ulcerated,  but  its  earlier  growth  forms  an  extremely 
dense,  resistant  mass,  which  may  completely  surround  the  pyloric  portion 
and  render  it  quite  rigid. 

Occasionally  there  is  found  a  peculiar  thickening  and  induration  of  the 
whole  stomach-wall,  which  causes  it  to  shrink  to  a  small  size.  There  may 


ADENOCARCINOMATA  1Q41 

be  no  prominent  tumor  nodule  and  little  ulceration,  but  the  mucosa  is 
roughened  and  wrinkled,  and  not  readily  movable  upon  the  underlying 
tissue.  A  section  shows  that  the  whole  wall  is  infiltrated  with  a  tumor  in 
which  the  epithelial  cells  are  relatively  sparsely  scattered  in  an  abundant 
and  dense  stroma.  This  is  the  so-called  diffuse  scirrhous  carcinoma  of 
the  stomach  (Fig.  539). 

Microscopically,  various  appearances  are  met  with  in  these  forms  of 
more  solid  carcinomata.  In  most  cases  the  normal  mucosa,  in  approaching 
the  tumor,  becomes  infiltrated  with  lymphocytes  and  other  wandering  cells, 
and  its  glands  are  lengthened  and  become  tortuous,  often  with  dilatation 
of  the  lowermost  part.  Nevertheless,  they  retain  the  smoothness  of  their 


Fig.  539. — Scirrhous  cancer  with  very  slight  ulceration  occupying  whole  wall  of  stomach 
and  causing  its  great  contraction. 


outline.  Suddenly  as  the  surface  layer  of  the  epithelium  reaches  the  crest 
of  the  marginal  ridge  of  the  tumor,  the  whole  arrangement  changes  and 
the  cells  themselves  assume  a  different  character  (Fig.  540).  The  glands 
become  exceedingly  irregular,  with  numerous  branches,  or  are  greatly 
enlarged  and  partly  or  completely  filled  with  epithelial  cells.  It  is  now  very 
difficult  to  determine  just  how  much  of  the  epithelial  mass  belongs  to  each 
gland,  for  their  identity  as  glands  is  lost,  and  instead  there  are  ramifying 
cavities  lined  with  several  rows  of  cells  among  which  are  other  cavities,  or 
there  are  solid  groups  of  cells.  The  cells  lose  their  regular  arrangement 
and  to  a  great  extent  their  uniform  cylindrical  shape.  They  no  longer 
range  themselves  on  a  smooth  basement  membrane,  but  grow  at  will  in 
67 


1042 


TEXT-BOOK   OF   PATHOLOGY 


any  direction  into  the  stroma.  The  sudden  change  from  the  moderately 
infiltrated  and  loose  stroma  of  the  mucosa,  to  the  much  denser  stroma 
of  the  tumor  which  is  thickly  infiltrated  with  leucocytes,  is  very  striking. 
Still,  in  other  cases,  the  disarrangement  of  the  glands  in  passing  over  from 
the  mucosa  into  the  tumor  is  by  no  means  so  great,  and  the  whole  tumor  is 


Fig.  540.— Carcinoma  of  stomach  showing  sudden  transition  of  glands  into  the 

matous  distortion. 


carcino- 


found  to  be  made  up,  even  in  its  distant  extensions  through  the  muscle  and 
into  the  subserous  tissue,  of  long  tubules  which  are  coarse  and  deeply 
stained  and  variable  in  calibre,  but  which  do  not  seem  to  fray  out  into  the 
ssue,  or  to  grow  into  more  solid  masses.  At  these  extreme  ends  there  is 
generally  an  indication  of  the  invasive  freedom  of  their  cells.  Usually 


ADENOCARCINOMATA  1043 

however,  even  in  those  in  which  the  glandular  or  tubular  arrangement  is 
best  Deserved  there  are  parts  of  the  tumor  in  which  the  tubules  appear 
solid  strands  with  numerous  spaces  lined  with  cylindrical  cells,  which 
keep  up  the  glandular  appearance. 

In  the  denser  tumors,  such  as  that  shown  in  Pig.  538,  it  is  common  to 

he  glands  of  the  mucosa,  as  one  passes  into  the  tumor,  changing  into 

extremely  long  narrow  tubules  which  are  lost  in  a  dense  and  greatly 

thickened  submucosa.    Between  these  glands,  the  tissue  is  packed  with 


Fig.  541. — Margin  of  a  secondary  nodule  in  the  liver  derived  from  an  adenocarcinoma 

of  the  stomach. 

cells,  many  of  which  are  clearly  wandering  cells,  while  great  numbers  are 
loose  epithelial  cells.  It  is  difficult  to  trace  the  exact  source  of  these  cells, 
although  they  may  sometimes  be  obviously  derived  from  the  lowermost 
ends  of  the  glands.  Deeper  in  the  submucosa  and  far  into  the  muscle  they 
assemble  themselves  into  more  definite  groups,  which  arrangement  they 
retain  wherever  they  are  found.  This  is  practically  the  character  of  the 
growth  in  the  scirrhus  cancers,  in  which  very  small  solid  groups  of  cells  are 
set  free  from  the  ends  of  the  glands,  and  grow  into  the  submucosa.  The 
extreme  growth  of  connective  tissue  in  response  to  this  causes  the  mucosa, 


1044  TEXT-BOOK   OF   PATHOLOGY 

submucosa,  and  muscularis  to  become  matted  together  into  a  leather-like 
mass,  in  which  tumor-cell  strands  are  sparsely  scattered. 

Occasionally  there  are  observed  several  carcinomatous  nodules  projecting 
from  the  mucosa  of  the  stomach,  and  the  explanation  is  to  be  found  in 


, 

£s£i& 


y  •"..<&•":  '    ^'$^-^,?-^-:^:'^i$?:% 


Fig.  542.—  Metastatic  cancerous  nodule  in  the  liver  from  a  primary  carcinoma  of  the 
stomach.  The  section  shows  the  central  necrosis  and  scarring  of  the  tumor,  with  retrac- 
tion and  dell  formation. 

the  fact  that  in  these  cases  the  network  of  lymphatic  channels  in  the  sub- 
mucosa and  in  the  subserous  tissue  is  filled  solidly  with  tumor-cells,  which 
enter  at  the  primary  growth  and  grow  along  until  they  form  a  sort  of  injec- 
tion of  the  whole  network.  The  accessory  nodules  appear  to  be  eruptions 
of  tumor  growth  from  those  underlying  lymphatics.  This  mode  of  growth 


ADENOCARCINOMATA  JQ45 

was  studied  by  Borrmann,  whose  illustrations  correspond  well  with  the 
condition  found  in  several  of  our  cases. 

With  regard  to  metastasis  from  the  carcinomata  of  the  stomach,  a  brief 

statement  was  made  above.     It  is  true  that  the  adjacent  lymph-nodes 

the  adjacent  peritoneum  are  usually  primarily  involved,  and  also 

that  numerous  nodules   are  frequently  formed   in   the  liver  (Fig.  541). 

These  vary  greatly  in  size  and  evidently  in  age,  and  while  there  are  small 


£*L  — 

/>*< '''*!•  -*#%?  "<-'^'3-?ti^< 


,^^:Slttr:P!?: 


i*?^ 
9^fjf*i\^&f  f  *'.' 


Fig.  543. — Invasion  of  lymphatics  in  the  walls  of  a  bronchus  extending  from  pleural 

metastases. 

translucent,  grayish-white  nodules  of  smooth,  globular  form,  there  are  also 
very  large  masses  of  similar  form,  but  showing  the  well-preserved  tumor  tis- 
sue only  in  their  marginal  portions.  The  whole  central  part  of  such  nodules 
usually  presents  necroses,  which  may  affect  only  small  groups  of  cells  here 
and  there,  so  as  to  produce  the  familiar  yellow  flecks  on  a  gray  surface,  or 
may  be  complete,  so  that  nothing  remains  alive  except  the  connective-tissue 
stroma.  When  the  nodule  lies  at  the  surface  of  the  liver,  it  at  first  presents 


1046 


TEXT-BOOK    OF    PATHOLOGY 


a  convex  or  flattened  face,  but  with  the  liquefaction  and  absorption  of  this 
central  necrotic  part  and  the  contraction  of  the  stroma  which  remains 
behind,  there  comes  a  sinking  of  the  centre.  Every  secondary  cancer 
nodule  of  any  age  which  projects  from  the  surface  of  the  liver  shows  this 
central  depression,  and  on  section  the  reason  is  plainly  seen  (Fig.  542). 
Doubtless  insufficient  blood  supply  is  the  cause  of  such  necrosis.  The 
nodules  press  upon  the  blood-vessels  and  bile-ducts  and  cause  local  areas  of 
anaemia  and  chronic  passive  congestion,  and  also  jaundice.  The  jaundice 
may  be  extreme,  but  it  must  be  remembered  that  there  are  often  opportu- 
nities for  its  production  by 
the  compression  of  the  large 
bile-ducts  outside  the  liver 
by  the  main  tumor  or  by  its 
intraperitoneal  metastases. 
The  metastases  are  not 
confined  to  the  abdominal 
organs,  but  are  found  in  the 
pleural  cavities  on  the  cos- 
tal pleura,  or  on  the  surface 
of  the  lung.  There  one  ob- 
serves peculiar  minute,  len- 
ticular flecks  of  gray,  trans- 
lucent tissue,  which  look 
almost  like  tubercles.  They 
are  larger  and  flatter,  how- 
ever. On  section,  the  lung 
is  air  containing,  but  is 
roughened  by  the  projection 
of  the  interlobular  septa, 
blood-vessels,  and  bronchi, 
all  of  which  stand  up  a  little 
from  the  cut  surface  as  gray, 
translucent,  rough  ridges. 
This  is  due  to  the  filling 
up  of  the  lymphatics  in  the 
walls  of  vessels  and  bronchi 

and  in  the  interlobular  septa  with  an  injection  of  epithelial  cells  (Fig. 
543).  Occasionally  larger  lymphatic  trunks  can  be  seen  branching  over 
the  pleural  surface,  and  made  conspicuous  by  the  grayish-white  injec- 
tion of  tumor-cells.  In  other  cases  the  secondary  growths  are  in  the  form 
of  button-like  nodules  on  the  pleura.  In  the  lung  itself  the  tumor  may 
metastasize,  with  the  formation  of  large,  discrete  nodules  which  push  aside 
the  tissue  or,  as  in  a  case  which  we  saw  recently,  with  the  production  of  a 
pneumonia-like  process.  Each  alveolus  over  a  large  area  of  the  lung  was 
filled  with  tumor-cells,  and  since  the  alveolar  walls  and  vessels  were  intact 


,  ; :    '  ': '*•'  i 

°-      -^  *•     *»-'!b        * 

v  ».;«•/.-» 
c ;  %.*CJ 

**•.  T   a  o       *       * 


•»>  vr- 


-  **> 


,v>. 


<*-„ 


>*-: 


Fig.  544. — Colloid  carcinoma  of  the  stomach. 
Secondary  nodule  in  the  liver,  showing  the  tumor- 
cells  separated  from  one  another,  and  each  contain- 
ing a  globule  of  colloid. 


1Q47 


ADENOCARCINOMATA 

patch  had  almost  exactly  the 

Metastases  in  the  brain,  kidneys,  spleen,  and  other  organs  occur,  but  are 
not  especia  ly  common.  Numerous  metastases  in  the  bones  have  been 

und  and  I  have  seen  one  case  in  which  these  growths  produced  rarefac- 
tion with  fractures  of  the  bones. 

Another  form  of  carcinoma  of  the  stomach  which  is  peculiar  in  many  of 
its  characters  is  the  colloid  cancer.  There  are  at  least  two  types  in  which 
the  accumulation  of  a  gelatinous  colloid  material  is  found:  one  in  which  the 


__*,^*s^^          •;       ,t        , 

w^m.  \ 


Fig.  545. — Colloid  cancer  of  the  stomach  with  large  alveoli  filled  with  colloid  material  and 
only  partly  lined  with  the  remains  of  the  epithelium. 


glands  or  tubules  of  the  tumor  are  made  up  of  spaces  in  which  the  epithelial 
cells  lie  quite  loose,  are  rounded  or  spherical,  and  contain  each  a  large  globule 
of  clear  fluid  (Fig.  544) ;  the  other,  in  which  the  tubules  are  distended  into 
cyst-like  cavities  lined  with  a  single  layer  of  cylindrical  epithelium,  and  filled 
with  glairy  fluid  (Fig.  545) .  The  first  of  these  appears  as  a  diffuse  thicken- 
ing of  the  mucosa  and  of  the  whole  wall  of  the  stomach,  with  a  gelatinous, 
yellowish,  translucent  tissue,  which  accumulates  in  soft  nodules  over  the 
outer  surface  of  the  stomach  and  spreads  quickly  into  adjacent  glands  and 
-over  the  peritoneal  surface.  The  second  usually  causes  a  far  greater  thick- 


1048 


TEXT-BOOK   OF   PATHOLOGY 


ening  of  the  stomach-wall,  with  a  large  ulcerated  area  in  the  mucosa  and 
with  great  layers  of  new  tissue  on  the  outer  surface  (Fig.  546).  The  omen- 
turn  is  converted  into  a  huge  mass  of  friable  gelatinous  material,  and  the 
whole  peritoneum  may  be  lined  with  a  thick  layer  of  it.  On  cutting  through 
any  of  this  tissue  the  cavities  filled  with  fluid  are  quite  visible  to  the  naked 
eye,  so  that  this  type  was  once  called  alveolar  cancer.  It  has  the  appear- 
ance of  sago  pudding,  and 
one  may  scrape  off  a  tena- 
cious glutinous  fluid  from 
the  surface.  In  one  case 
which  I  saw  at  autopsy  all 
the  abdominal  organs  and 
the  parietal  peritoneum 
were  covered  with  a  layer 
more  than  a  centimetre  in 
thickness,  which  was  quite 
brittle,  although  fairly  firm. 
It  was  so  transparent  that 
one  could  see  the  blood- 
vessels in  its  depth.  Metas- 
tases,  if  they  occur,  have 
the  same  structure  (Fig. 
547),  but  while  the  tumor 
easily  penetrates  the  stom- 
ach-wall and  spreads  im- 
plantations throughout  the 
abdominal  cavity,  it  is  not 
strikingly  capable  of  pro- 
ducing metastatic  nodules 
in  other  organs. 

Carcinomata  of  the  Gall- 
bladder and  Ducts. — These 
tumors  may  be  described 
much    more    briefly    since 
Fig.  546.— CoUoid  cancer  of  the  stomach.    There       their   general  behavior  re- 
is  great  thickening  of  the  stomach-wall,  so  that  the        sembles  that  of  the  adeno- 
pylorus  is  almost  occluded.  The  colloid-filled  alveoli       carcinomata   of  the   stom- 
of  the  tumor  are  visible  to  the  naked  eye.  ach       It    hag   been    gtated 

that     epitheliomata     may 

arise  in  the  gall-bladder  especially  when  there  are  incarcerated  gall- 
stones there  which  have  long  caused  irritation.  One  sees  them  sometimes 
accurately  moulded  round  the  gall-stones,  and  extending  only  so  far  as  it 
lies  in  contact  with  the  mucosa.  Adenocarcinomata  may  spring  from  the 
mucosa  of  the  gall-bladder  even  in  the  absence  of  inciting  gall-stones,  and 
usually  metastasize  quickly  to  the  liver.  As  a  rule,  the  primary  tumor  is 


ADENOCARCINOMATA 


1049 


Fig.  547.— Secondary  nodules  in  the  lung  from  a  colloid  cancer  of  the  stomach. 


Fig.  548. — Adenocarcinoma  of  the  fundus  of  the  gall-bladder  with  metastases  in  the  li ver 
compressing  and  obstructing  a  large  bile-duct  and  producing  jaundice. 


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TEXT-BOOK   OF   PATHOLOGY 


found  to  invade  the  liver  in  such  a  way  that  there  is  only  a  remnant  of  the 
gall-bladder  wall  which  stretches  over  a  large,  ulcerated  tumor  mass  em- 
bedded in  the  liver.  Rupture  of  this  into  the  peritoneum  or  into  the  ad- 
herent colon  may  occur.  Metastases  resemble  those  from  the  carcinoma 
of  the  stomach,  and  usually  cause  jaundice,  occasionally,  as  in  Fig.  548,  by 
obstructing  one  of  the  larger  ducts.  Quite  similar  carcinomatous  tumors 
may  spring  from  the  bile-ducts  at  any  point,  from  the  ampulla  of  Vater  to 
the  branches  high  in  the  liver.  They  often  appear  to  be  multiple  in  origin, 
although  that  is  by  no  means  certain.  They  almost  invariably  produce 
jaundice,  which  may  be  very  deep.  These  tumors  form  a  large  proportion 
of  the  primary  cancers  of  the  liver  and  may  grow  to  enormous  masses  in  one 
or  other  lobe  of  the  liver  (Fig.  549). 


Fig.  549.— Primary  carcinoma  of  liver  springing  from  bile-ducts.     Numerous  secondary 

nodules  in  the  liver. 

Adenocarcinomata  of  the  pancreas  are  most  frequently  situated  in  the 
head  of  the  gland,  near  the  duodenum,  and  form  large,  irregular  masses 
invading  and  compressing  the  adjacent  structures  with  various  results. 
One  or  both  of  the  pancreatic  ducts  may  be  compressed,  and  the  pancreatic 
tissue  drained  by  the  obstructed  duct  becomes  atrophic.  The  tumors  have, 
as  a  rule,  a  complex  tubular  arrangement  with  high  cylindrical  epithelium. 
Metastases  have  the  same  distribution  as  in  the  carcinoma  of  the  stomach. 

Adenocarcinomata  of  the  Intestine.— In  the  small  intestine  adenocarci- 
nomata  are  quite  uncommon  if  we  except  the  multiple,  relatively  benign 
tumors  which  were  described  in  connection  with  the  basal-cell  cancers.  On 
the  other  hand,  those  of  the  colon  are  especially  common,  and  therefore 


ADENOCARCINOMATA 


1051 


important.  They  may  occur  at  the  ileocsecal  region  (Fig.  550),  or  anywhere 
in  the  course  of  the  colon  or  in  the  rectum.  In  nearly  all  cases  the  tumor 
springs  up  from  the  mucosa  as  a  projecting  mass  which  encroaches  upon  the 
lumen  of  the  colon  and  usually  encircles  it.  Great  obstruction  may  be 
produced  in  this  way,  not  only  by  the  actual  bulk  of  the  mass,  but  more 
especially  by  the  contraction  of  those  tumors  which,  in  their  late  stages, 
become  extensively  degenerated  and  scarred.  In  these  cases  the  lumen  of 
the  intestine  may  be  reduced  to  the  diameter  of  a  few  millimetres,  so  that 
the  contents  stagnate  above  the 
obstruction,  remain  fluid,  and  es- 
cape continuously  in  small  quan- 
tities. As  stated  in  a  previous 
chapter,  muscular  hypertrophy  ap- 
pears above  the  obstruction,  often 
accompanied  by  ulceration  of  the 
mucosa. 

The  carcinomata  of  the  colon 
are  nearly  always  composed ,  of 
irregular,  tubular  downgrowths  of 
epithelium  lined  with  high  cylin- 
drical cells  (Fig.  551).  In  the 
deeper  portions,  these  may,  of 
course,  become  more  atypical  in 
appearance  and  more  confused  in 
their  order,  and  groups  of  cells, 
with  many  cavities .  about  which 
the  palisade  arrangement  is  held 
to,  alternate  with  others  in  which 
the  cavity  is  lined  by  several  lay- 
ers of  cells  (Fig.  552). 

The  intestinal  wall  is  often  pene- 
trated by  the  growth,  and  exten- 
sive adhesions  and  excavations 

Fig.  550. — Adenocarcmoma  at  the  ileo- 

mto  adjacent  organs  occur.      Re-      C£ECal  valve  causing  aimost  complete  ob- 
gional  metastases  into  neighboring      struction. 
lymph-glands  are  common,  perito- 
neal implantations  occur,  and  there  are  metastatic  nodules  in  the  liver  in 
many  cases,  resembling  closely  those  derived  from  tumors  of  the  stomach. 
I  recall  one  case  in  which  there  was  a  very  small  nodule  of  hard  tumor  tissue 
surrounding  the  colon  and  drawing  it  into  an  extremely  narrow  stricture. 
The  whole  mass  was  not  more  than  3  cm.  in  diameter,  and  yet  there  were 
many  metastatic  nodules  in  the  liver,  one  of  which  reached  the  size  of  a 
man's  head. 

Carcinoma  of  the  prostate  is  most  commonly  of  the  adenocarcinomatous 
type,  although  there  are  some  cases  in  which  the  tumor-cells  present  them- 


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selves  in  broad,  solid  strands.  The  tumors  are  capable  of  penetrating  into 
the  bladder  or  into  the  rectum,  with  resulting  ulceration  and  infection. 
Metastases  are  usually  abundant  in  the  lymph-glands  of  the  pelvis  and 
retroperitoneal  tissue,  in  the  liver,  lungs,  and  other  organs,  but  particularly 
in  the  bones.  In  two  of  our  recent  cases  in  which  the  primary  growth  was 
inconspicuous  and  microscopically  showed  the  complex  glandular  arrange- 
ment of  an  adenocarcinoma,  there  were  a  few  internal  metastases,  but  on 
examining  the  skeleton,  it  was  found  that  practically  every  bone  was  in- 
volved. The  cancellous  marrow  of  such  bones  as  the  vertebra?,  sternum, 


Fig.  551.  —  Margin  of  an  adenocarcinoma  of  the  rectum  showing  a  transition  from 
slightly  modified  mucosa  to  the  tumor  growth,  which  maintains  a  gland-like  arrange- 
ment of  the  epithelium. 


ribs,  and  clavicles  was  completely  replaced  by  the  tumor,  which  had  stimu- 
lated an  excessive  new  formation  of  bone,  which  was  very  dense  and 
hard.  In  the  long  bones  the  marrow  cavity  was  entirely  filled  with  a  yel- 
lowish, opaque,  ivory-hard  tissue,  so  that  the  bone  seemed  to  be  quite  solid. 
It  is  so  evident  that  much  new  bone  is  formed  in  such  cases  that  these 
metastases  are  called  osteoplastic.  Microscopically  it  is  found  that  every 
lamella  of  the  cancellous  bone  is  enormously  thickened,  and  that  the  marrow 
spaces  are  correspondingly  narrowed.  All  these  spaces  are  filled  with  tumor 
tissue  which  completely  excludes  the  marrow.  The  layer  of  osteoblasts  is 
preserved  in  apposition  to  the  bone,  and  it  seems  probable  that  the  tumor 


ADENOCARCINOMATA 


1053 


exerts  its  osteoplastic  effect  by  stimulating  those  cells  to  increased  activity. 
Wide-spread  necrosis,  which  involves  a  great  part  of  such  cancerous  bone, 
seems  to  be  of  very  frequent  occurrence.  The  almost  complete  destruction 
of  the  bone-marrow  leads  to  an  extreme  anaemia,  and  to  efforts  at  blood 
formation  in  other  organs,  which  have  been  referred  to  elsewhere  in  discuss- 
ing osteosclerotic  anaemia.  The  carcinomata  of  the  prostate  are  well 
known  for  this  peculiarity  of  metastasizing  into  the  bones,  a  property  which 


Fig.  552. — Adenocarcinoma  of  the  rectum.     Atypical  gland-like  growth. 

is  shared  to  some  extent  by  the  carcinomata  of  the  breast,  stomach,  and 
thyroid. 

Adenocarcinomata  of  the  Uterus. — These  tumors,  already  referred  to  in 
contrast  with  the  epitheliomata  of  the  cervix,  are  developed  from  the  tub- 
ular glands  of  the  fundus  uteri  or  the  more  complex  glands  of  the  cervix. 
In  some  cases  their  growth  seems  associated  with  the  previous  existence  of 
an  adenoma  of  the  uterus,  but  this  is  by  no  means  a  regular  occurrence. 
Since  they  appear  to  grow  rather  slowly,  many  cases  have  been  observed  in 


1054 


TEXT-BOOK    OF    PATHOLOGY 


Fig.  552 A. — Carcinoma  of  the  prostate  extending  into  the  bladder  so  as  to  overhang 
the  urethra.  The  urethra  is  distorted  and  the  seminal  vesicles  somewhat  encroached 
upon. 


ADENOCARCINOMATA 


1055 


which  extirpation  of  the  uterus  was  performed  at  a  time  when  the  carcinoma 
was  still  small  (Fig.  553).  In  such  a  case  the  mucosa  is  found  thickened  and 
rough,  with  many  papillary  projections.  The  growth  extends  into  the 
musculature,  but  for  some  time  is  fairly  evenly  outlined  against  it.  Never- 
theless, it  is  not  long  before  the  invasion  of  the  musculature  occurs  by  the 
downgrowth  of  some  of  the  glandular  elements  which  may  be  found  deep  in 
the  uterine  wall.  Ulceration  may  occur,  and  the  cavity  of  the  uterus 
becomes  enlarged  by  the  excavation  of  the  tumor  in  its  wall.  Even  then 
the  outer  surface  of  the  uterus  may  show  no  evidence  of  the  presence  of  the 
tumor  other  than  the  enlargement. 

Metastases  are  slow  to  form,  and  appear  in  the  retroperitoneal  lymph- 
glands.     I  have  seen  a  few  cases,  however,  in  which  the  secondary  growths 


Fig.  553. — Adenocarcinoma  of  the  uterus.  The  tumor  is  a  mere  ragged  thickening  of 
the  mucosa  at  the  fundus.  There  is  a  fibromyoma  lodged  in  the  substance  of  the  uterine 
wall. 

were  very  widely  disseminated,  involving  the  peritoneum,  liver,  and  other 
organs.  Microscopically,  the  tumor  is  made  up  of  tubular  epithelial 
growths  resembling  in  all  their  complex  modifications  those  already  des- 
cribed for  other  adenocarcinomata,  although  seldom  showing  any  such 
orderly  columnar  cells  with  globules  of  mucus  as  are  usually  found  in  the 
rectal  carcinomata. 

The  tumor  is  to  be  sharply  distinguished  from  the  squamous  cell  epitheli- 
omata  of  the  cervix,  not  only  through  its  histological  characters,  but  through 
its  original  site,  its  mode  and  rate  of  growth,  and  its  much  slighter  malig- 
nancy. 

Adenocarcinomata  in  general,  similar  in  character  to  these,  develop  in 


1056 


TEXT-BOOK    OF    PATHOLOGY 


many  other  places,  and  mention  may  be  made  of  the  kidney,  breast,  ovary, 
and  thyroid  as  points  of  origin. 

Adenocarcinomata  of  the  ovary  are  quite  common,  and  assume  many 
puzzling  forms,  sometimes  appearing  as  solid  tumors  which  may  occupy 
both  ovaries,  and  metastasizing  widely  into  distant  organs.  The  gland- 
like  spaces  in  such  a  tumor  are  lined  with  cells  which  are  very  unlike  the 
epithelial  cells  derived  from  the  skin  or  mucous  surfaces  (Fig.  554) .  In  other 
cases  the  tumor  develops  in  a  cystadenoma  of  the  ovary  and  causes  great 


Fig.  554.— Adenocarcinoma  of  ovary.     There  are  numerous  mitoses  in  the  epithelial 
cells  and  many  multinucleated  cells. 

thickening  of  the  wall  of  one  or  more  of  the  cysts.     These  tumors  are  fre- 

lently  colloid  cancers,  and  even  in  their  distant  metastases  maintain  the 

>ower  of  forming  blue-staining  colloid  material  (Fig.  555).     In  one  which 

we  studied  recently  there  was  a  huge  cyst  with  thick  walls  which,  on  section, 

lowed  a  sticky,  gelatinous  material  in  the  substance  of  the  walls.    Metas- 

*  in  the  abdominal  and  retroperitoneal  lymph-glands  showed  the  tumor 

composed  of  small  cysts  lined  with  cylindrical  epithelium,  which  was 


ADENOCARCINOMATA 


1057 


frequently  thrown  up  into  folds.  The  content  of  these  cysts  was,  however, 
not  like  the  colloid  material  mentioned  above,  but  resembled  the  pseudo- 
mucinous  content  of  some  adenocystomata. 


-,; :  ,*<*fa*    &  - '  *\ 


ttffif J     J  F*  "v ' 

W^P^?'  *»  ^  /jv,  ^v- 


Fig.  555. — Metastasis  in  lymph-gland  from  colloid  carcinoma  of  ovary.     Many  of  the 
epithelial  cells  are  seen  to  be  isolated  in  the  colloid  material. 

LITERATURE 

Stomach.— Ebstein:   "  Magenkrebs,"  Volkmann's  kl.  Vortrage,  1875,  No.  87. 
Verse:  Arbeiten  a.  d.  Path.  Inst.  Leipzig,  1908,  i,  Heft  5. 
Borrmann:  Mitth.  a.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1901,  Suppl.  Bd.  1. 
Lewis:  Surg.,  Gyn.  &  Obst.,  1914,  xix,  757  (Pseudomyxoma) . 
Hauser:    Cylinder-Epithel  Karzinom  des  Magens,  Jena,  1890. 
Gall-bladder. — Laspeyres:   Centralbl.  f.  d.  Grenzgeb.  d.  Med.  u.  Chir.,  1901,  iv,  10. 
Zenker:  Deut.  Arch.  f.  kl.  Med.,  1889,  xliv,  159. 
Miodowski:   Virch.  Arch.,  1902,  clxix,  117. 
Uterus.— Hitschmann:  Arch.  f.  Gynakologie,  1903,  Ixix,  629. 
Lehman:  Ibid.,  1900,  Ixii,  439. 
Cullen:  Carcinoma  of  the  Uterus,  New  York,  1900. 
Pancreas.— Hulst:  Virch.  Arch.,  1905,  clxxx,  288. 
Rectum. — Harrison  Cripps:  Cancer  of  the  Rectum,  London,  1890. 
68 


CHAPTER  LIV 
CARCINOMATA  (Continued) 

Gland-cell  cardnomata:  Carcinomata  of  the  breast;  epitheliomata,  tumors  derived  from 
the  acini  (general  form,  mode  of  extension  and  metastasis,  histology,  relation  to  adenomata 
and  chronic  cystic  mastitis,  scirrhous  forms),  tumors  derived  from  the  ducts,  colloid  cancers. 
Carcinomata  of  the  ovary;  cardnomata  of  the  thyroid;  primary  cardnomata  of  the  liver 
with  drrhosis.  Chorionic  epitheliomata:  Histogenesis  of  chorionic  epithelium,  its  normal 
invasive  growth.  Hydatidiform  mole.  Chorionic  epithelioma;  gross  appearance,  metastasis, 
histology,  and  histogenesis;  relation  to  corpus  luteum. 

GLAND-CELL  CARCINOMATA 

THERE  is  probably  little  justification  for  the  separation  of  cancers  derived 
from  the  cuboidal  or  polygonal  cells  of  the  solid  glands  from  the  others 
which  have  just  been  described,  because  the  division  is  made  on  a  purely 
morphological  basis,  and  it  is  not  always  easy  to  distinguish  them  in  this 
way.  Nevertheless,  the  division  is  convenient  and  serves  a  useful  purpose. 
Such  tumors  are  extremely  common  in  the  breast.  Elsewhere  they  play 
a  less  important  part,  but  they  are  to  be  found  in  the  thyroid,  the  liver, 
the  ovary,  the  prostate,  and  in  some  other  glands. 

The  Carcinomata  of  the  Breast. — There  is  so  great  a  variety  of  these 
tumors  that  the  experience  of  any  one  is  scarcely  sufficient  to  cover  the 
whole  range.  They  are  extremely  common  and  fatal  in  their  effects,  and 
the  efforts  to  extirpate  them  completely  and  to  understand  and  frustrate 
their  extension  affords  much  work  to  the  surgeon.  It  is  difficult  to  make 
any  short  classification,  but  there  may  be  distinguished  the  following: 

1.  Tumors  of  stratified  epithelium,  which  are  either  those  beginning  in 
an  eczema-like  alteration  of  the  nipple  and  adjacent  skin  (Paget's  disease), 
or  those  which  arise  in  the  substance  of  the  breast  and  are,  nevertheless, 
composed  of  squamous  epithelium  (Troell  and  others). 

2.  Tumors  Derived  From  the  Cells  of  the  Acini  of  the  Gland.— These 
may  be  made  up  of  abundant  ramifying  masses  of  cuboidal  cells,  with 
relatively  little  stroma,  so  that  great,  soft,  cellular  masses  are  formed 
(medullary  cancer),  or  there  may  be  less   abundant  cell  strands,  with 
a  relatively  greater  amount  of  stroma,  so  that  the  tumor  area  is  composed 
of  firm  whitish  tissue,  or  finally  the  epithelial  structures  may  be  greatly 
reduced,  so  that  only  small  groups  and  thin  strands  of  cells  are  formed, 
embedded  in  a  dense,  scar-like  mass  of  fibrous  tissue  (scirrhous  cancer). 

3.  Tumors   Derived   From   the   Ducts   and   Their   Branches.— These 
approach  more  nearly  the  cylindrical  cell  cancer,  and  are  often  in  the  form 
of  tumor  masses  made  up  largely  of  tubular  epithelial  structures.     There 

1058 


GLAND-CELL   CARCINOMA 


1059 


are  usually  cysts  associated  with  this  form,  and  these  may  have  a  thick  lin- 
ing of  several  layers  of  cells.  There  is  another  type,  of  relatively  benign 
character,  in  which  every  section  shows  canals  or  cavities  lined  with  a 
thick  layer  of  many  rows  of  irregular  cells.  These  have  been  called 
adenocarcinomata  by  Halsted,  and  have  also  been  referred  to  as  comedo 
cancers,  on  account  of  the  fact  that  cells  can  be  squeezed  out  like  the 
material  from  a  comedo  or  blackhead  in  the  skin. 

4.  Colloid  Tumors. — Tumors  derived  from  the  epithelium  of  the  acini, 
but  presenting  an  extraordinary  colloid  or  gelatinous  metamorphosis  of  the 
stroma.  Of  these,  the  most  important  by  far  are  those  derived  from  the 
cells  of  the  acini.  The  tumor  appears  as  a  hard  nodule  in  the  substance  of 
the  breast,  and  later  often  forms  adhesions  with  the  skin  or  causes  a  retrac- 


f3^ 


Fig.  556. — Carcinoma  of  the  breast  showing  retraction  of  the  nipple  and  limited  inva- 
sion of  the  fat. 

tion  of  the  nipple  (Fig.  556).  The  extension  to  the  skin  may  be  followed  by 
ulceration.  A  wealth  of  detail  has  been  worked  out  by  surgeons  as  to  the 
mode  of  growth  and  extension,  and  an  interesting  series  of  observations  has 
been  made  upon  the  more  local  spread  by  Handley.  As  described  by  Borr- 
mann,  in  the  spread  of  carcinoma  of  the  stomach  through  the  stomach-wall, 
there  is  in  the  breast  a  radiating  growth  of  the  carcinoma  in  the  lymphatic 
plexus  which  extends  outward ,in  connection  with  the  deep  fascia.  The  lym- 
phatic channels  distended  with  tumor-cells  become  obliterated  and  disap- 
pear as  the  tumor  growth  passes  outward,  so  that  it  is  only  in  a  zone,  like 
the  spread  of  a  ringworm,  that  one  finds  these  lymphatics  actually  filled 
with  the  tumor-cells.  New  nodules  spring  up  into  the  skin  from  various 
points  in  their  course,  but  by  that  time  the  channels  much  farther  out  are 
filled.  In  rare  cases  the  skin  of  the  whole  chest-wall  may  be  involved  in  a 
layer  of  cancer  growth  which  ulcerates  at  many  points  (cancer  en  cuirasse) 


1060 


TEXT-BOOK    OF    PATHOLOGY 


Handley's  ideas  as  to  the  further  spread  into  lymph-glands  and  distant 
organs  are  not  so  convincing. 

It  is  known  that  in  nearly  every  case  metastatic  nodules  are  formed  in 
the  axillary  lymph-glands,  and  that  somewhat  later  the  subclavicular  and 
cervical  glands  may  be  involved.  Deep  invasion  through  the  pectoral 
muscles  and  extension  along  fasciae  at  that  plane  are  common,  and  one  not 
infrequently  traces  extension  through  the  intercostal  muscles  to  the  pleura 
and  finally  to  the  lung. 


Fig.  557.— Secondary  nodule  from  a  tumor  of  the  breast,  involving  upper  end  of  femur, 
and  producing  a  pathological  fracture. 

While  extension  thus  occurs  by  way  of  direct  growth  through  connective- 
tissue  spaces  and  along  fasciae,  as  well  as  by  continuous  growth  in  the  lym- 
phatics or  the  transportation  of  isolated  groups  of  cells  in  the  lymph-stream 
to  the  axillary  glands,  there  is  also  the  possibility  that  further  dissemination 
may  occur  by  way  of  the  blood-stream,  and  the  metastases  in  the  liver, 
bones  (Fig.  557),  ovaries,  and  other  distant  organs  seem  explicable  only 
on  this  basis.  Handley's  statement  that  emboli  of  tumor-cells  in  the  blood- 


GLAND-CELL   CARCINOMA 


1061 


vessels  are  destroyed  by  the  formation  of  a  thrombus  may  be  true  for  the 
majority  of  tumor-cell  emboli,  but  I  think  we  have  good  evidence  that  it  is 
not  true  for  all,  and  that  it  is  probably  no  such  mechanical  influence  which 
destroys  any  of  them.  Out  of  great  numbers  of  such  emboli,  it  seems  that 
almost  all  persist,  but  a  few  only  take  root  and  grow,  producing  the  dis- 
tant metastases. 

Microscopically,  these  tumors  are  found  to  resemble  rather  closely  in 


'•  •.',!  '•"•' .« :'•  V>:  v/'Jr'%j4  £  :'^?oX^  'iv.°.'V 

K """"J^B^iftf  ^ 
^i  «*<3^,''/<>*t-\  '  ^r  >,  »«*'<v|?*3»*e0^'p^ 
•  «i/'  ^^<V>'fc  .  H  i!  c«%i^  ^b  aftdo .<?„ 


»f/S*T«5aS-iwJi>   >•'     \N     '    'V*     ^-«I''   / 

t   ^^  |K^  -^  :•  %  v  \v  :^  Vc    "  - 

s  -  ; ,  iS^?»*..  V'^£  '•*•••  A  -\*  0<§  " 


Fig.  558. — Medullary  cancer  of  the  breast  with  necrosis  in  some  of  the  epithelial  strands. 

their  general  arrangement  the  softer  forms  of  epithelioma,  since  they  are 
composed  of  ramifying  solid  strands  of  epithelial  cells  which  push  their  way 
into  the  crevices  of  the  stroma.  Their  appearance  is  seen  in  Figs.  558,  559, 
560.  The  striking  feature  in  all  is,  of  course,  the  unbridled  growth  of  the 
cells,  which  is  so  energetic  that  no  basement  membrane  can  restrain  them 
and  they  penetrate  along  the  lines  of  least  resistance  everywhere. 

An  interesting  point  lies  in  their  relation  to  the  adenomata  of  the  breast 
and  to  the  so-called  cystic  mastitis  of  old  people.     It  is  not  uncommon  to 


1062 


TEXT-BOOK   OF   PATHOLOGY 


find  in  sections  of  a  breast  tumor  taken  for  diagnosis  that  the  tissue  has 
almost  everywhere  the  appearance  of  a  typical  benign  adenomatous  growth. 
Indeed,  it  is  surprising  to  learn  how  frequently  those  specimens  which 
offer  any  difficulty  in  diagnosis  are  of  this  character.  It  is  necessary  then 
to  determine  whether  in  all  places  the  epithelial  strands  and  tubules  main- 
tain strictly  their  orderly  form  and  their  sharp  outline  which  is  produced 


.  ;, 


Fig.  559.— Carcinoma  of  the  breast  showing  area  of  hyaline  degeneration  with  advanc- 
ing strands  of  epithelial  cells. 

by  the  basement  membrane.  In  true  innocent  adenomata  this  basement 
membrane  is  often  exaggerated,  so  that  it  appears  as  a  broad,  pink-staining 
hyaline  membrane,  which,  of  course,  leaves  no  doubt  as  to  the  benign 
nature  of  that  particular  area  of  the  growth.  With  the  beginning  of  a 
cancerous  growth,  which  one  may  often  detect  in  very  early  stages,  the  cells 
evidently  grow  so  rapidly  as  to  burst  through  this  membrane  and  spread 
rapidly  without  it.  Their  contact  with  the  connective  tissue  immediately 


GLAND-CELL   CARCINOMA 


1063 


becomes  far  more  intimate,  and  they  are  found  lying  loose,  strewn  in  con- 
tinuous or  broken  strands  through  the  spaces  in  the  stroma  (Fig.  561). 
This  seems  to  be  the  crucial  test  of  carcinoma  growth,  for  while  the  cells 
do  assume  an  appearance  different  from  that  of  the  normal,  it  is  not  a  change 
definite  enough  to  afford  any  chance  for  a  decision  as  to  the  carcinomatous 
nature  of  the  tumor. 


'y 


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:t^f'^>j^^V¥*  •••';  ' 

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S^^'t^Hu  •  •  '•k'f-^S'iV. W:|i\ J/ 
\!  SCS;^-|'  >r  S :# ist'  §  iS  -^  •?• :  ^'s'':^y 
v  *•••  ^ **•".-  t¥;>\^'^-.'*Vs  •  s,-'  •V'?-"-.'-- '.'«.«.>'•'.: "^/ 

%t%nr;k^v^'Vi  ^  •.^•>^i^v.-  ^7 


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^  1,*%3X.J  •'•  Vv  •'•*.?•  .T;^ 


:-*3v 


Tig.  560. — Carcinoma  of  breast.     The  epithelial  cells  are  growing  almost  in  single  file 
into  every  crevice  of  the  stroma. 

In  such  cases  it  seems  necessary  to  conclude  that  the  carcinoma  has 
developed  from  an  adenoma,  but  there  is  no  more  difficulty  in  this  assump- 
tion than  in  the  more  usual  one  that  it  develops  from  the  normal  epithelium 
of  the  gland. 

Carcinoma  growth  seems  especially  common  as  a  sequel  of  the  senile 
hyperplasia  with  cyst  formation,  which  is  often  referred  to  as  chronic 


1064 


TEXT-BOOK   OF   PATHOLOGY 


cystic  mastitis.  This  condition  comes  on  with  the  menopause  or  later,  and 
leads  to  the  formation  of  rather  dense  fibrous  tissue  throughout  the  gland, 
with  hypertrophy  of  the  acinous  tissue  into  adenomatous  structures,  often 
with  the  formation  of  many  cysts.  It  is  not  thought  to  be  due  to  any 
infectious  or  traumatic  injury,  and  the  scarring  is  really  a  normal  process  at 
the  time  of  menopause,  but  the  formation  of  cysts,  adenomata,  and  papil- 
lomatous  growths  must  be  considered  as  abnormal. 

The  scirrhous  tumors,  the  arrangement  of  which  is  shown  in  Fig.  562, 
grow  and  metastasize  much  more  slowly  than  do  the  softer  forms,  so  that 
such  a  tumor  may  exist  for  many  years  without  producing  a  fatal  extension. 
Nevertheless  Bloodgood  finds,  by  statistical  study  of  the  hospital  cases,  that 


Fig.  561.— Development  of  a  carcinomatous  nodule  in  an  adenofibroma  of  the  breast. 
The  invasive  character  of  the  carcinoma  cells  is  apparent. 

these  are  the  most  tenacious,  and  finally  lead  to  the  most  unfavorable 
results. 

The  adenocarcinomata  derived  from  the  ducts  or  from  adenomatous 
nodules  are,  in  some  instances,  as  in  the  form  described  by  Halsted,  relatively 
benign.  My  father  extirpated  such  a  tumor  from  each  breast  of  an  old 
woman  who  has  survived  many  years  without  lymph-node  metastases  or 
local  recurrence. 

In  other  cases,  however,  there  may  be  found  a  very  large  tumor  mass 
composed  chiefly  of  cysts  filled  with  glairy  fluid,  and  lined  with  high 
columnar  or  cubical  epithelium.  Between  these  are  dense  adenomatous 
masses.  From  the  walls  of  such  cysts  an  invasion  may  take  its  origin. 


GLAND-CELL   CARCINOMA 


1065 


The  colloid  tumors  are  uncommon,  but  Lange  collected  75  cases,  and 
from  their  study  learnt  that  metastases  were  rare,  and  that  the  tumors 
grow  very  slowly  and  are  relatively  benign  (Fig.  563). 

Carcinomata  of  the  ovary  may  be  primary  or  secondary.  Although  tumors 
distinctly  secondary  to  mammary,  gastric,  or  intestinal  carcinomata  have 
been  found  in  this  organ,  their  occurrence  is  rare  and  most  of  the  ovarian 


Fig.  562. — Scirrhous  cancer  of  the  breast.  The  epithelial  cells  are  greatly  reduced  in 
number  and  scattered  in  an  extremely  dense  hyaline  stroma.  The  blood-vessels  show 
thick  hyaline  walls. 

cancers  are  primary.  It  is  difficult  to  explain  why  they  so  frequently 
occur  simultaneously  in  both  ovaries.  They  are  solid  tumors,  tumors 
combined  with  cystomata,  or  papillomatous  growths,  and  almost  every 
type  of  cancer  observed  elsewhere  seems  to  be  represented  here.  When 
the  carcinoma  is  cystic  or  develops  in  connection  with  a  small  cyst,  it  may 
be  surmised  that  the  tumor  began  as  a  carcinoma.  When,  however,  the 


1066  TEXT-BOOK    OF    PATHOLOGY 

malignant  growth  appears  in  the  wall  of  a  large  cystadenoma  of  long  stand- 
ing, it  must  be  supposed  that  its  relation  to  the  cystadenoma  is  analogous 
to  that  of  the  carcinoma  of  the  breast  to  the  adenoma  within  which  it 
develops. 

Metastases  (Fig.  564)  vary  with  the  character  of  the  tumor,  and  may 
be  confined  to  intraperitoneal  implantations  in  the  papillary  forms.  In 
one  which  we  studied  recently  both  ovaries  were  replaced  by  cysts  of  about 


Fig.  563.— Colloid  carcinoma  of  the  breast.     The  colloid  appears  to  be  developed  in  the 
stroma  in  which  the  epithelial  cells  are  isolated. 

orange  size,  in  the  walls  of  which  there  were  thick,  yellow  masses  of  solid 
tumor.  There  were  metastases  in  the  liver,  and  especially  interesting  was  a 
continuous  chain  of  white  nodules  along  the  round  ligament  extending  into 
the  substance  of  the  liver.  It  is  possible  that  further  study  may  reveal  an 
unusual  method  of  invasion  of  the  liver  by  extension  along  the  lymphatics 
of  that  cord.  Handley  discusses  a  similar  occurrence  in  connection  with 
mammary  carcinomata. 


GLAND-CELL   CARCINOMA 


1067 


Krukenberg  described  as  a  form  of  sarcoma  a  tumor  which  is  obviously 
carcinomatous  and  which  often  involves  both  ovaries.  These  nodules  are 
rather  dense  and  infiltrated  with  loosely  arranged  epithelial  cells,  each  of 
which  is  swollen  with  a  globule  of  colloid  or  gelatinous  fluid.  They  are 
relatively  benign  growths. 

The  carcinomata  of  the  ovaries,  like  the  cystadenomata,  are  evidently 


Fig.  564.  —  Metastasis  from  carcinoma  of  the  ovary  in  an  axillary  lymph-gland.     The 
lymph-sinuses  are  filled  with  epithelial  cells. 


derived  from  invaginations  of  the  surface  epithelium,  although  many  other 
hypotheses  have  been  offered  as  to  their  -source.  There  seems  to  be  no 
good  evidence  that  they  arise  from  the  Pfliiger's  cords  or  from  Graafian 
follicles. 

Carcinomata  of  the  Thyroid.  —  These  tumors  have  been  studied  especially 
by  v.  Eiselsberg,  Kocher,  and  Langhans,  who  find  that  they  can  distinguish 


1068  TEXT-BOOK    OF    PATHOLOGY 

several  groups,  among  which  a  form  of  adenocarcinoma  or  proliferating 
struma  is  especially  common.  These  occur  as  single  nodules  containing 
every  transition  between  solid  strands  of  cells  and  colloid-containing 
alveoli,  closely  resembling  those  of  the  normal  gland.  They  are  not  very 
malignant,  but  occasionally  metastasize  in  distant  organs  or  bones.  The 
second  group,  called  by  Langhans  carcinomatous  struma,  has  the  arrange- 
ment in  irregular  solid  strands  of  epithelial  cells  seen  in  many  carcinomata 
of  the  breast.  These  quickly  burst  through  the  capsule  of  the  gland  and 
metastasize  abundantly.  Metastasizing  colloid  struma  forms  the  third 
group,  with  numerous  secondary  nodules,  composed  of  colloid-holding 
vesicles  in  which  no  striking  morphological  signs  of  its  malignancy  are 
to  be  seen.  The  tumors  of  the  fourth  group,  named  alveolar  large-cell 
struma,  are  also  malignant,  and  give  rise  to  numerous  metastases. 
They  are  composed  of  large  cuboidal  or  cylindrical  cells,  arranged 
in  small  alveoli  or  in  tubular  or  strand-like  j structures.  The  cells  in 
these  tumors  are  occasionally  very  large,  with  deeply  stained  nuclei. 
The  other  groups  comprise  the  papillomatous  tumors  of  the  thyroid,  in 
which  branching  processes  grow  into  cysts  or  cavities  in  the  thyroid,  and 
squamous  cell  epithelioma,  which  may  occur  in  the  substance  of  the  gland 
and  must  be  ascribed  to  a  congenital  displacement  of  cells. 

Primary  Carcinoma  of  the  Liver. — Reference  has  already  been  made  to 
the  cylindrical  cell  cancers  of  the  liver  which  originate  in  the  epithelium 
of  the  bile-ducts,  and  appear  as  solid  white  masses  in  the  substance  of  the 
organ.  There  is  another  type  quite  different  from  this,  which  is  so  char- 
acteristic and  constant  in  form  that,  once  seen,  it  can  never  be  forgotten  or 
mistaken  for  any  other  tumor.  This  is  the  primary  cancer  which  originates 
from  the  liver-cells  themselves,  and  occurs  in  multiple  nodules  closely  set 
throughout  the  whole  liver.  Whatever  remains  of  liver  tissue  is  profoundly 
scarred,  as  in  the  most  advanced  cirrhosis.  The  liver  is  greatly  enlarged, 
and  dark  green  or  grayish,  rounded  nodules  project  everywhere.  On  sec- 
tion nearly  the  whole  cut  surface  is  occupied  by  these  velvety  green  or  gray 
rounded  masses  which  stand  up  from  the  remaining  liver  substance  (Fig. 
565).  There  is  usually  quite  deep  jaundice,  and  often  a  terminal  hemor- 
rhage from  the  rupture  of  some  softened  nodule  which  projects  into  the 
peritoneal  cavity.  There  are  generally  no  metastases,  but  branched 
emboli  of  tumor-cells  may  be  found  plugging  the  terminal  twigs  of  the  pul- 
monary artery  in  the  lung.  In  the  last  case  we  have  seen,  however,  there 
were  many  metastases  as  large  as  marbles  in  the  lungs  and  all  the  adjacent 
pulmonary  arterioles  were  full  of  the  tumor.  There  were  also  pleural  and 
diaphragmatic  nodules.  On  opening  the  portal  and  hepatic  veins  masses 
of  the  tumor  are  often  found  projecting  into  the  lumen  of  one  or  other  of 
these  veins. 

Microscopically,  it  is  found  that  the  liver  tissue  between  the  nodules  and 
in  areas  unoccupied  by  them  presents  the  irregular  masses  of  distorted  liver- 
cell  strands  and  the  broad  bands  of  collapsed  framework  and  scar  tissue, 


GLAND-CELL   CARCINOMA 


1069 


with  numerous  bile-ducts  which  are  seen  in  the  ordinary  nodular  cirrhosis. 
The  tumor  nodules  are  composed  of  anastomosing  strands  of  rather  large 
cells,  corresponding  fairly  closely  with  the  liver-cells,  but  with  larger  nuclei 
rich  in  chromatin,  and  with  swollen  cell-bodies  which  take  a  rather  deep 
stain.  Great  irregularities  occur,  and  there  are  many  huge  cells  with 
several  nuclei.  There  is  a  tendency  toward  an  arrangement  in  broad 
strands  of  cells  separated  by  narrow  capillaries,  and  in  many  places  it  is 
seen  that  these  strands  hang  in  the  lumen  of  a  blood-vessel,  where  they  are 
surrounded  by  blood  and  everywhere  covered  with  endothelium.  It  is 
extremely  common  to  find  blood-vessels  thus  packed  with  bunches  of 


Fig.  565. — Primary  adenocarcinoma  of  the  liver,  with  cirrhosis.     There  are  multiple 
nodules,  and  the  portal  vein  with  its  branches  is  filled  with  the  tumor. 

strands  of  tumor-cells  which,  on  account  of  their  endothelial  covering, 
cause  no  thrombosis.  The  larger  invasions  of  the  branches  of  the  veins 
seem  to  maintain  this  characteristic  growth.  Quite  apart  from  the  well- 
formed  tumor  nodules,  there  may  be  found  in  the  cirrhotic  liver  tissue 
minute  groups  of  tumor-cells  recognizable  by  their  abnormal  form,  but 
standing  in  direct  continuity  with  the  surrounding  liver-cells,  which 
they  compress  by  their  rapid  growth.  These  seem  to  be  beginning  tumor 
nodules. 

The  multiplicity  of  these  growths  and  their  lack  of  power  to  form 
metastases  have  caused  much  speculation.     They  have   been  thought 


1070  TEXT-BOOK    OF    PATHOLOGY 

to  arise  simultaneously  in  many  situations  in  the  liver  as  the  result  of  an 
over-stepping  of  the  bounds  of  what  might  be  regarded  as  normal  in 
the  compensatory  hyperplasia  of  the  liver-cells  in  an  advanced  cirrhosis. 
Winternitz  advanced  the  idea  that  they  are  really  metastatic  nodules, 
secondary  to  an  original  growth  near  the  hilum  of  the  liver,  which  invades 
the  portal  vein  and  scatters  its  cells  through  the  whole  liver.  If  such 
exquisite  power  of  metastasis  exists  in  the  liver,  it  is  difficult  to  under- 
stand why  these  same  cells  should  be  completely  incapable  of  growing  else- 
where, although  they  can  be  found  as  emboli  in  the  capillaries  of  the  lung 
in  great  abundance.  It  must  be  admitted  that,  whatever  explanation  is 
accepted,  the  behavior  of  this  tumor  is  peculiar  and  unlike  that  of  the 
other  carcinomata. 

LITERATURE 
Breast—  Fr.  Lange:  Bruns,  Beitrage  z.  kl.  Chir.,  1896,  xvi,  1. 

v.  Winiwarter:  Beitrage  z.  Statistik  der  Carcinome,  Stuttgart,  1878. 
Greenough  and  Hartwell:  Jour.  Med.  Research,  1903,  ix,  416. 
Bloodgood:  Kelly  and.Noble,  Gynecology  and  Abdominal  Surgery,  1907,  ii,  180. 
Halsted:  Trans.  Amer.  Surgical  Assoc.  (Adenocarcinoma),  1898,  xvi,  144. 
Ovary.— Pfannenstiel:  Veit's  Handb.  d.  Gynakologie,  Wiesbaden,  1908,  i.  Halfte,  177. 

Glockner:  Arch.  f.  Gynakologie,  1904,  Ixxii,  410. 
Thyroid.— Langhans:  Virch.  Arch.,  1907,  clxxxix,  69. 

Th.  Kocher:  Deut.  Ztschr.  f.  Chir.,  1907,  xci,  197. 
Liver. — v.  Heukelom:  Ziegler's  Beitrage,  1894,  xvi,  341. 

Travis:  Johns  Hopkins  Hosp.  Bull,  1902,  xiii,  108. 

Wegelin:  Inaugural  Dissertation,  Bern,  1905.     Virch.  Arch.,  1905,  clxxix,  95. 

Winternitz:  Virch.  Arch.,  1913,  ccix,  239. 


CHORIONIC  EPITHELIOMATA 

In  the  study  of  the  formation  of  the  placenta  there  has  never  been  complete 
unanimity  of  opinion  as  to  the  origin  of  the  syncytial  layer  which  covers  the 
chorionic  villi.  The  other  cells  which  cover  these  villi  and  which  are 
arranged  in  a  more  sharply  defined  layer  (Langhans'  cell  layer)  are  uni- 
versally recognized  as  the  foetal  ectoderm,  but  for  the  syncytium,  at  least 
three  ideas  have  been  expressed:  (a)  That  it  is  derived  from  the  maternal 
uterine  epithelium;  (6)  that  it  is  a  modification  of  maternal  endothelium, 
and  (c)  that  it  belongs,  like  the  Langhans'  layer,  to  the  foetal  ectoderm. 
The  weight  of  evidence  seems  to  be  in  favor  of  the  last  view. 

During  pregnancy  there  is  normally  a  curious  invasive  growth  of  the 
chorionic  villi  into  the  uterine  wall,  and  it  is  by  no  means  uncommon  to  find 
masses  of  syncytium-like  giant-cells  with  many  nuclei  lodged  in  the 
interstices  of  the  muscle,  quite  deep  down  in  the  uterine  wall.  Indeed, 
such  masses  have  been  found  to  invade  blood-vessels  and  to  be  carried  as 
emboli  into  distant  organs.  Nevertheless,  this  invasive  growth  ends  harm- 


CHORIONIC    EPITHELIOMATA  1071 

lessly,  and  the  cells  presently  disappear  from  the  tissue  as  though 
the  body  had  some  mechanism  for  destroying  them  when  pregnancy 
is  over. 

Two  curious  abnormal  conditions  may  arise  during  pregnancy  which 
bring  about  a  result  quite  different  from  the  usual  normal  ending.  One 
of  these  is  the  development  of  the  hydatidiform  mole,  the  other  the  growth 
and  metastases  of  the  chorionic  epithelioma.  In  the  case  of  the  hydatidi- 
form mole  it  is  found  that,  when  pregnancy  approaches  its  termination, 
there  may  be  expelled  from  the  uterus,  not  a  child  with  the  cord  and  placenta, 
but  a  great  mass  of  polypoid,  gelatinous  structures,  which  hang  together 
like  a  huge  bunch  of  grapes.  There  may  be  no  fcetus  at  all,  or  the  shrunken 
remnants  of  one,  and  the  placenta  is  converted  into  the  villous  mole,  which 
receives  its  name  from  its  resemblance  to  the  clusters  of  hydatids  or  cysts 
of  the  tsenia  Iarva3  which  are  sometimes  seen.  (Mole  is  used  here  in  the 
old  sense — mass.)  Microscopically,  these  polypoid  blebs  are  swollen 
chorionic  villi  enormously  enlarged  and  covered  with  greatly  proliferated 
epithelium.  It  is  rare  to  see  such  a  mass  in  situ,  but  in  the  uterus  removed 
after  the  expulsion  of  the  mole  it  is  found  that  the  villi  grow  into  the 
uterine  musculature  and  sometimes  give  rise  to  malignant,  tumor-like 
extension  and  metastasis.  Nevertheless,  such  invasive  growth  is  by  no 
means  constant,  and  the  woman  may  recover  her  health  perfectly  and  even 
give  birth  to  a  second  or  third  hydatidiform  mole. 

This  has  intimate  relations,  as  will  be  seen,  with  the  chorionic  epithe- 
lioma. The  pregnancy  may  be  interrupted  by  the  development  of  a 
hsemorrhagic  tumor  in  the  uterine  wall,  or  after  pregnancy  is  over  such  a 
tumor  may  develop  even  several  months  later.  Curettings  have  the 
appearance  of  placental  tissue,  except  that  the  cells  are  more  profuse 
in  these  growths  and  are  much  better  preserved  than  those  found  in  curetted 
remnants  of  retained  placenta.  Still,  it  is  only  through  determining  the 
relation  of  the  tissue  to  the  uterine  muscle,  together  with  the  alarming 
clinical  symptoms  of  haemorrhage,  that  a  diagnosis  can  be  made  with  any 
certainty.  Frequently  there  is  found  a  conspicuous  hsemorrhagic  tumor 
in  the  vaginal  wall  which  will  make  the  diagnosis  clear. 

With  such  partial  removal  of  the  tumor  as  is  possible  by  curettage  com- 
plete recovery  occurs  in  some  cases,  and  all  traces  of  tumor  growth  dis- 
appear. In  other  cases  the  patient  coughs  up  blood  and  bleeds  from  the 
uterus,  and  at  the  autopsy  there  is  found  a  tumor  invading  the  uterine  wall 
and  growing  in  metastatic  nodules  in  the  lungs,  liver,  brain,  and  elsewhere. 
The  tumor  in  the  uterine  wall  is  a  soft,  ragged,  intensely  haemorrhagic 
mass,  variegated  in  color  by  gray  or  whitish  areas,  and  by  brownish  patches 
in  which  the  blood  has  undergone  decomposition,  with  the  formation  of 
pigment.  The  metastases  in  the  lungs  are  often  round  nodules,  of  about  the 
size  of  a  cherry,  scattered  abundantly  through  the  organ.  They,  too,  are 
deep  red  from  haemorrhage.  There  may  be  large,  more  ragged,  and  pig- 


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mented  masses.     In  the  brain  the  metastatic  tumor  may  produce  apoplecti- 
form  symptoms  from  haemorrhage  and  compression. 

Microscopically,  these  tumors  are  found  to  be  made  up  almost  entirely 
of  broad,  irregular,  and  ragged  anastomosing  strands  of  the  two  types  of 
chorionic  epithelium,  in  which  the  Langhans'  cells  can  be  readily  dis- 
tinguished by  their  smaller  and  more  regular  form,  with  pale  or  almost 
clear  protoplasm,  and  fairly  sharp  cell  outline,  while  the  syncytial  material 
spreads  over  them  or  forms  solid  areas  of  protoplasm  which  stains  much 


t 


rSfr&k* 


Fig.  566. — Chorionic  epithelioma,  metastatic  nodule  in  the  lung,  showing  Langhans' 

cells  and  syncytium. 

more  deeply,  and  in  which  numerous  nuclei,  often  of  great  size,  are 
embedded.  The  stroma  and  blood-vessels  are  inconspicuous  or  entirely 
lacking,  since  the  tumor  seems  to  grow  into  blood-channels,  and  every- 
where the  tissue  is  torn  and  disarranged  by  extensive  haemorrhages  (Hg. 
566). 

It  was  thought  for  a  long  time  that  these  tumors  were  of  sarcomatous 
or  endothelial  nature,  and  that  they  had  preceded  pregnancy  and  were 
stimulated  by  it  to  more  rcpid  growth.  It  was  thought  by  others  that 


CHORIONIC   EPITHELIOMATA  1073 

they  were  derived  from  the  decidua,  and  they  were,  therefore,  spoken  of 
as  malignant  deciduomata,  but '  the  work  of  Marchand  cleared  up  the 
whole  situation  by  showing  clearly  that  none  of  these  theories  had  any 
foundation,  and  that  the  tumor  originates  in  the  chorionic  epithelium  or 
foetal  ectoderm  of  the  placenta,  and  that  both  layers  of  this  epithelium 
are  involved. 

The  tumors  are  especially  interesting  from  the  fact  that  a  somewhat 
analogous  growth  and  invasion  of  the  chorionic  epithelium  occurs  normally, 
and  that  an  exaggeration  of  the  development  of  the  villi,  often  ending  in 
the  formation  of  a  malignant  tumor,  is  found  in  the  hydatidiform  mole. 
The  fact  that  definite  chorionic  epitheliomata  seem  to  retrogress  sometimes 
and  disappear  completely  is  also  peculiar,  and  has  led  to  speculation 
(Fleischmann)  as  to  whether  there  is  some  substance  formed  in  the  maternal 
blood  at  the  end  of  pregnancy,  which,  like  the  experimentally  produced 
syncytiolysin  of  Scholten  and  Veit,  has  the  function  of  destroying  the 
syncytial  elements  which  remain  buried  in  the  uterine  wall  or  lodged  in 
distant  organs.  The  failure  of  this  substance  might  allow  the  unchecked 
development  of  the  tissue  jnto  a  destructive  tumor,  while  its  late  formation 
might  account  for  the  disappearance  of  the  tumor. 

On  the  other  hand,  it  is  found  that  in  a  large  proportion  of  cases  the 
development  of  a  hydatidiform  mole  or  a  chorionic  epithelioma  is  accom- 
panied by  a  peculiar  enlargement  of  the  ovaries,  sometimes  to  the  size  of  a 
large  grape-fruit.  This  is  due  to  the  formation  of  numerous  cysts,  most  of 
which  are,  like  the  cysts  derived  from  corpora  lutea,  lined  with  several 
layers  of  yellow  lutein  cells.  The  well-known  theory  of  Fraenkel  and  Born, 
according  to  which  the  corpus  luteum  is  an  organ  of  internal  secretion  con- 
trolling and  forwarding  the  embedding  of  the  ovum  and  the  development 
of  the  placenta,  is  brought  into  play  by  Runge,  Pick,  and  others  as  a  ready 
explanation  of  this  association.  If  there  is  a  great  overgrowth  and  excessive 
activity  of  the  corpus  luteum  tissue,  it  may  produce  excessive  growth  of  the 
chorionic  villi  over  which  its  secretion  is  supposed  to  preside.  Dunger 
reverses  the  idea  and  suggests  that  the  excessive  growth  of  the  chorion 
requires  the  development  of  additional  corpus  luteum  tissue.  L.  Loeb 
finds  that  irritation  and  injury  of  the  mucosa  of  the  uterus  in  guinea-pigs 
after  coitus  will,  under  certain  conditions,  produce  very  large  growths  of 
tissue,  which  he  calls  placentomata.  In  his  papers  he  emphasizes  the 
alteration  in  environmental  conditions  of  the  mucosa,  and  recognizes  in 
these  and  other  papers  the  importance  of  the  influence  of  the  corpora 
lutea. 

The  matter  requires  further  study,  and  it  seems  to  offer  an  extremely 
interesting  border-line  condition  the  comprehension  of  which  might  throw 
much  light  upon  tumor  growth  in  general. 


1074  TEXT-BOOK    OF    PATHOLOGY 


LITERATURE 

Risel:  Ergebn.  d.  allg.  Path.,  1907,  xi2,  928. 
Gaylord:  Amer.  Jour.  Obstetrics,  1902,  xlv,  465. 
Marchand:  Monatsschr.  f.  Geburtsh.  u.  Gynak.,^1895,  i,  419.     Ztschr.  f.  Geburtsh.  u. 

Gynak.,  1895,  xxxii,  405.     Ibid.,  1898,  xxxix,  173. 
Fleischmann:    Monatsschr.  f.  Geburtsh.  u.  Gynak.,  1905,  xxi,  353. 
Runge:  Arch.  f.  Gynak.,  1903,  Ixix,  33. 
R.  T.  Frank:  New  York  Med.  Jour.,  1906,  Ixxxiii,  793. 
L.  Loeb:  Arch.  f.  Entwicklungsmech.  d.  Organismen,  1911,  xxxii,  67.     Ztschr.  f.  Krebs- 

forschung,  1912,  xi,  259. 


CHAPTER  LV 
TERATOMATA;  COMPOSITE  TUMORS 

Chorionic  epithelium  in  tumors  of  the  male.  Teratomata.  Early  development  of  the  ovum, 
potency  of  blastomeres.  Their  inclusion  in  the  formation  of  double  monsters.  Formation 
of  solid  teratomata.  Dermoid  cysts.  Cutaneous  and  branchial  cysts.  Cholesteatomata. 
Mixed  tumors  of  salivary  glands;  of  the  kidney.  Congenital  cystic  kidney.  Mixed  tumors 
of  the  breast  and  of  the  testicle.  Chordoma. 

IN  the  last  pages  there  has  been  given  a  description  of  the  hydatidiform 
mole  and  of  the  chorionic  epithelioma  which  may  develop  in  connection 
with  pregnancy,  and  it  was  pointed  out  that  these  are  tumors  of  a  more 
suggestively  parasitic  nature  than  the  others  which  have  been  considered 
in  previous  chapters,  since  they  are  composed  of  the  tissue  of  a  different 
individual.  This  is  not  enough  to  shake  our  faith  in  the  belief  that  the 
ordinary  tumors  are  composed  of  the  tissue  of  the  same  individual,  but  at 
least  it  causes  us  to  reflect  upon  this  question. 

The  existence  of  tumors  morphologically  identical  with  the  chorionic 
epithelioma  of  women,  but  growing  in  the  testicle  of  men,  is  especially 
calculated  to  rouse  our  interest  in  this  question.  These  tumors  belong  to 
the  composite  type  called  teratomata,  which  contain  tissue  of  many  sorts, 
representing  all  of  the  three  germinal  layers,  and  give  rise  to  metastases 
which  are  composed  of  Langhans'  cells  and  syncytium.  Chorionic  epi- 
thelium occurs  also  in  the  tumors  themselves,  and  may,  indeed,  be  the  only 
tissue  found,  in  which  case  it  is  thought  that  the  other  types  have  been 
overgrown  and  obliterated  by  it.  Scott  and  Longcope  described  a  tumor 
of  the  testicle  composed  entirely  of  chorionic  epithelium,  and  Frank  had  a 
similar  case,  but  most  of  these  tumors  have  contained  a  mixture  of  other 
tissues  as  well,  which  often  resemble  disorted  organs  in  such  a  way  as  to 
suggest  an  abortive  attempt  at  the  formation  of  a  fcetus. 

We  have  recently  seen  a  beautiful  example  of  this  type  of  tumor  in  which 
metastases  in  the  brain,  lungs,  omentum,  and  elsewhere  had  all  the  char- 
acteristics of  a  chorionic  epithelioma.  The  original  tumor  in  the  testicle 
showed,  however,  cartilage,  various  gland-like  epithelial  structures,  and 
other  tissues  of  a  complex  fcetal  inclusion.  Of  all  the  tissues  concerned 
in  the  abortive  growth  of  an  included  fcetus,  only  those  of  the  rudimentary 
chorion  metastasized. 

It  is  to  be  observed  that  in  this  case  the  tumor  belongs  to  the  same 
generation  as  the  host,  while  in  the  chorionic  epithelioma  in  a  woman  it 
is  derived  from  the  fcetal  tissues,  and  therefore  belongs  to  an  individual  of 
the  next  generation. 

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Such  a  suggestion  of  the  formation  in  a  man's  testicle  of  a  foetus  with 
chorionic  epithelium,  however  abortive,  demands  explanation,  and  numer- 
ous hypotheses  have  been  put  forward.  Schlagenhaufer  points  out,  first  of 
all,  the  value  of  such  an  observation  in  settling  the  origin  of  the  syncytial 


Fig.  567. — Teratomatous  tumor  of  testicle  invading  vena  cava  through  spermatic 
and  renal  veins.  Hydatidiform,  grape-like  structures  hang  free  in  the  circulating 
blood. 


layer  of  the  chorion.  It  must  be  derived  from  foetal  ectoderm,  since  in  this 
situation  there  is  no  uterine  mucosa  to  give  it  origin.  He  regards  the 
tumor  as  an  imperfect  foetus  which  has  formed  about  itself  foetal  membranes 
which  spread  into  the  tissue  of  the  host,  and  metastasize  to  distant  organs. 


TERATOMATA;  COMPOSITE  TUMORS  1077 

Risel  insists,  however,  that  it  is  unnecessary  to  assume  the  formation  of  a 
chorionic  membrane  with  villi,  since  the  foetal  ectoderm  can  produce  such 
chorionic  epithelium  easily  enough. 

Schlagenhaufer,  finding  that  the  tumors  occasionally  grow  into  large 
veins  in  polypoid  clusters  of  translucent,  grape-like  bodies,  suggested  that 
this  was  analogous  to  the  formation  of  a  hydatid  mole.  I  have  studied 
one  of  the  four  or  five  tumors  of  this  nature,  and  find  that  the  villus-like 
bodies  (Fig.  567)  are  not  covered  with  chorionic  epithelium.  It  is,  there- 
fore, as  Risel  explains,  only  an  accidental  resemblance. 

Teratomata. — While  such  foetus-like  tumors  with  chorionic  epithelium  are 
rare,  there  are  others  in  which  rudimentary,  organ-like  masses  of  tissue  are 
mingled  together  as  though  in  an  unsuccessful  attempt  to  form  a  foetus,  but 
without  any  development  of  chorionic  elements.  These  are  the  solid  terato- 
mata  or  embryomata  which  are  not  very  uncommon,  and  may  occur  in  the 
ovary  or  testicle,  or  in  almost  any  other  situation  in  the  body.  They  are  es- 
pecially frequently  found  at  the  poles  of  the  body,  springing  from  the  roof 
of  the  mouth  or  from  the  sacrum,  or,  in  somewhat  different  form,  in  the 
brain,  in  the  orbit,  in  the  mediastinum,  or  abdomen.  Some  of  them  project 
outwardly  and  are  covered  with  skin,  even  presenting  at  times  a  vague 
resemblance  to  limbs  or  other  parts  of  the  body:  others  are  completely 
inclosed  within  the  body  cavity,  where  they  may  be  connected  by  a  stalk 
with  surrounding  organs,  or  enveloped  in  a  capsule. 

Dissection  of  such  masses  shows  that  they  are  not  like  ordinary  tumors, 
inasmuch  as  they  are  not  merely  composed  of  one  type  of  tissue,  but  con- 
tain representations  of  all  three  germinal  layers.  There  are  structures  of 
every  degree  of  complexity,  composed  of  skin  and  its  appendages;  mal- 
formed teeth  are  found  sometimes  in  connection  with  bony  structures, 
sometimes  embedded  in  soft  tissues.  Misshapen  eyes  or  masses  of  brain 
tissue,  portions  of  intestinal  mucosa  or  convoluted  canals  resembling  the 
intestines  alternate  with  cysts  lined  with  epithelium  difficult  to  recognize, 
and  masses  of  cartilage  or  thyroid  tissue  (Fig.  568).  There  is  no  tissue 
which  may  not  be  represented,  although  liver  and  pancreas,  testicle  and 
ovarian  tissue  and  chorionic  epithelium  are  usually  absent.  Ganglion- 
cells  are  abundant,  as  a  rule,  embedded  in  a  connective  tissue  which  may 
assume  almost  any  form.  More  detailed  description  of  any  one  case  would 
hardly  repay  us,  because  in  the  next  a  different  set  of  tissues  might  be  repre- 
sented. But  it  is  evident  that  the  whole  mass  represents  in  some  sense  a 
frustrated  attempt  at  the  formation  of  a  human  body  in  which  the  whole 
plan  has  failed  through  the  lack  of  the  necessary  parts,  and  the  distortion 
and  disarrangement  of  those  which  were  available.  It  is  obvious  that,  for 
an  explanation,  we  must  go  back  to  the  beginnings  of  embryonic  develop- 
ment, in  the  hope  that  at  some  point  a  mechanism  may  be  recognized  by 
which  it  is  possible  for  one  individual  or  a  rudiment  of  an  individual  to  be 
inclosed  within  another. 


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In  the  beginning  the  ripening  ova  cast  off  some  of  their  chromatin  in  the  form  of 
polar  bodies,  after  which  they  are  ready  for  fertilization.  There  are  vague  and  unsatis- 
factory statements  that  the  polar  bodies  may  be  fertilized  by  spermatozoa  and  undergo 


Fig.  568,-Teratoma  of  testicle  with  cartilage,  (a)  nerves,  striated  muscle,  and  cavi- 
ties (6)  lined  with  various  kinds  of  epithelium. 

cleavage  to  a  certain  extent  in  insects,  but  not,  so  far  as  I  can  learn,  in  higher  animals. 
Upon  fertilization  the  ovum  divides  into  two  segments,  and  these  again  divide  into  two 
until  there  is  a  rounded  mass  of  blastomeres.  By  imagination  or  gastrula  formation 


TERATOMATA;  COMPOSITE  TUMORS  1079 

ectoderm  and  entoderm  are  distinguished,  and  from  them  there  is  formed  the  mesoderm, 
which  at  first  consists  of  two  layers  of  cells,  later  dividing  into  the  myotome  and  another 
mass  which,  by  division,  forms  the  middle  plate,  and  the  splanchnopleure  and  somato- 
pleure,  which  enclose  the  coelom.  From  the  middle  plate  there  arise  the  Wolffian  body, 
the  kidney,  and  the  genital  glands.  The  original  Wolffian  duct  comes  into  very  close 
relationship  with  the  ectoderm  at  this  point,  a  fact  which  is  of  interest  hi  connection  with 
the  development  of  certain  tumors. 

The  genital  cells  at  first  contain  somatic  material,  but  they  lose  this  in  the  course  of 
division  and  become  purely  sex  cells  at  a  very  early  stage.  Since  they  retain  their 
chromatin  tenaciously  they  appear  as  deeply  stained  cells. 

The  power  of  development  of  the  cells  in  each  stage  is  of  especial  interest 
in  any  attempt  to  explain  the  formation  of  tumors.  Much  has  been  said 
of  the  possibility  of  the  growth  of  the  original  sex  cells,  or  of  the  ripening 
ovum,  into  differentiated  tissues,  but  there  is  no  real  evidence  that  such 
parthenogenetic  development  can  occur  within  the  body,  and  any  idea  of 
internal  fertilization  in  the  tissues  rests  upon  no  support.  There  is  no 
reason  to  deny  the  possibility  of  the  fertilization  and  development  of  polar 
bodies,  but  although  that  idea  has  been  put  forward  by  Marchand,  there  is 
practically  no  evidence  in  its  favor,  and  it  has  been  pointed  out  that  there 
may  be  multiple  teratomatous  tumors  which  could  not  be  explained  on  this 
basis,  since  at  most  there  are  two  polar  bodies.  The  fertilized  ovum  is 
totipotent;  that  is,  it  is  capable  of  giving  rise  to  all  the  tissues  of  the 
body.  So,  too,  are  the  first  segmentation  spheres,  as  is  proven  by  the 
development  of  twins  from  a  single  ovum.  These  twins  are  always  of  the 
same  sex,  and  resemble  each  other  very  closely — they  are  more  nearly 
related  than  other  brothers  and  sisters. 

In  later  stages  of  segmentation  the  blastomeres  remain  multipotent  or 
capable  of  producing  several  tissues,  but  probably  not  a  perfect  individual. 
Still  later,  the  destiny  of  the  cells  becomes  much  more  rigidly  prescribed, 
and  they  are  limited  to  the  formation  of  certain  tissues.  When  the  germ 
layers  are  defined,  elements  from  each  of  these  layers  have  the  power  of 
producing  ectoderm,  entoderm,  or  mesodermal  structures  only,  and  are 
even  more  closely  confined,  according  to  their  point  of  origin  in  the  layer. 

Nevertheless,  it  is  obvious  that  there  is  a  chance  for  the  development  of  a 
mass  of  tissue  of  almost  any  degree  of  complexity  from  a  blastomere,  if  we 
.are  willing  to  assume  that  it  may  become  independent  of  the  others  at  some 
stage  in  the  segmentation.  This  idea  involves  the  further  assumption  that 
this  independently  growing  blastomere  may  remain  attached  to  the  main 
embryo,  or  become  partly  or  completely  surrounded  by  it  in  its  growth,  so 
as  to  be  finally  included  in  its  body. 

There  is  such  abundant  material  illustrating  every  stage  of  attachment, 
inclusion,  and  final  complete  enclosure  of  one  body  in  the  other,  that  no 
assumption  is  required  and  the  story  is  practically  complete.  It  has  been 
said  that  the  complete  separation  of  the  first  two  segmentation  spheres 
results  in  the  so-called  single  ovum  twins.  The  developing  segments  may, 
however,  remain  attached  or  fuse  in  the  course  of  their  development,  as  we 


1080  TEXT-BOOK    OF    PATHOLOGY 

see  in  the  case  of  the  well-known  Siamese  twins,  and  in  hosts  of  other  double 
monsters  in  which  the  two  bodies  are  united  by  their  sternal,  sacral,  or 
cranial  regions.  While  these  individuals  seem  to  be  more  or  less  inde- 
pendent, there  are  important  structures  common  to  the  two  bodies,  and 
other  double  monsters  are  not  wanting  in  which  the  fusion  becomes  much 
more  complete.  When  the  isolated  blastomere  or  group  of  blastomeres  is 
derived  from  a  somewhat  later  stage,  so  as  to  be  incapable  of  producing  a 
whole  body,  or  when  a  totipotent  blastomere  in  its  development  is  out- 
grown by  the  other,  there  results  a  parasitic  monster;  that  is,  an  incomplete 
individual  attached  to  its  brother  or  partly  embedded  in  his  body  and  deriv- 
ing all  its  nutrition  thence.  Such  an  abortive  individual  may  project  in 
the  form  of  incomplete  arms  or  legs  from  the  epigastric  or  pubic  or  other 
region  of  the  host  or  "autosite."  From  this  it  is  but  a  short  step  to  the 
still  more  rudimentary  organ  masses,  which  are  completely  inclosed  within 
the  abdomen  or  thoracic  cavity,  and  which,  while  maintaining  a  degree  of 
independence,  draw  their  blood  supply  from  the  adjacent  tissues  of  the 
host.  The  solid  teratomata,  with  their  cysts  and  aimless  organ  rudiments, 
are  practically  of  this  nature.  Of  course,  if  the  isolated  blastomere  and 
the  main  group  of  segmentation  spheres  begin  to  develop  at  the  same  time, 
we  should  expect  the  tissues  of  host  and  teratoma  to  appear  to  be  of  the 
same  age  or  maturity,  while  if  the  isolated  blastomere  should  remain  stag- 
nant during  the  growth  of  the  host,  it  might  be  expected  to  produce  by 
later  growth  a  teratoma  composed  of  embryonic  tissues.  It  is  said  that 
this  distinction  can  be  made.  No  one  has  found  and  recognized  such 
latent  blastomeres,  and  the  tissues  of  all  teratomata  are  often  so  abnormal  in 
appearance  that  it 'is  difficult  to  judge  of  their  maturity,  so  that  this  state- 
ment about  the  age  of  the  growth  is  somewhat  speculative. 

It  seems  that  the  evidence  in  favor  of  the  isolation  of  a  blastomere  as  the 
origin  of  teratomatous  tumors  is  incomparably  stronger  than  that  for  any 
of  the  other  modes  of  formation  which  have  been  suggested.  With  this 
explanation  there  is  no  difficulty  whatever  in  understanding  the  localiza- 
tion of  a  teratoma  in  the  testicle  or  in  the  brain,  while  with  the  others, 
which  involve  fertilization  and  development  of  ova,  etc.,  insuperable 
obstacles  are  met  with  in  many  cases.  With  this  explanation,  too,  there 
is  no  difficulty  in  comprehending  the  formation  of  teratomata  of  all  degrees 
of  complexity  down  to  the  simplest  cysts,  composed  of  only  one  or  two 
types  of  tissue,  whereas  if  they  arose  from  fertilized  polar  bodies,  primary 
sex  cells,  etc.,  we  should  expect  in  every  case  growths  more  closely  sim- 
ulating complete  individuals.  The  formation  of  teratomata  with  chorionic 
epithelium  becomes  intelligible,  since  a  blastomere  in  its  development  is 
like  a  growing  embryo,  capable  of  forming  certain  tissue,  whatever  its  own 
situation.  It  becomes  clear  that  there  is  a  difference  between  the  metasta- 
sizing  chorionic  epithelioma  of  women,  and  that  which  occurs  in  the  testicle, 
in  that  the  former  is  tissue  of  the  offspring  of  the  woman  and  belongs 
to  another  generation,  while  the  latter  belongs  to  the  individual  himself, 
and  therefore  is  co-aetaneous,  or  pertaining  to  the  same  generation. 


TERATOMATA;  COMPOSITE  TUMORS 


1081 


The  solid  teratomata  may  grow  to  a  great  size,  especially  when  they  are 
enclosed  in  the  abdominal  cavity  and  attached  to  the  retroperitoneal  tissue 
or  sacrum,  but  they  are,  as  a  rule,  in  themselves  quite  benign  masses  with 
no  capacity  for  unlimited  growth.  Nevertheless  they  produce  extra- 
ordinary mechanical  disturbances  at  times.  I  remember  one  case  especially 
well  in  which  a  great  mass  appeared  in  the  abdomen  of  a  man  and  grew 
slowly.  It  was  found  impossible  to  extirpate  it,  and  after  some  months  he 
died  with  signs  of  the  presence  of  a  tumor  in  the  lung.  At  the  autopsy  there 
was  found  a  huge  mass,  in- 
extricably entangled  in  the 
intestines,  and  springing 
from  the  retroperitoneal  re- 
gion. It  contained  con- 
voluted, intestinelike  chan- 
nels and  several  large  cysts, 
in  the  walls  of  one  of  which 
a  carcinoma  had  developed. 
All  the  rest  of  the  mass 
showed  only  an  organ-like 
arrangement  of  tissues,  and 
the  metastases  in  the  man's 
lungs  were  from  this  car- 
cinoma. While  it  is  true 
that  the  teratoma  itself  is 
benign,  it  is  not  at  all  un- 
common to  find  the  devel- 
opment of  a  distinct  car- 
cinoma at  some  point  in  its 
epithelium,  exactly  as  we 
find  it  in  the  body  in  gen- 
eral. 

Dermoid  Cysts. — A  sim- 
pler form  of  teratoma  is  that 
which  is  known   as   a  der-     Fig.  569.— Dermoid  cyst  of  ovary,  showing  sebaceous 
moid  cyst.     These  may  oc-  material  and  hair, 

cur  almost  anywhere,   but 

are  perhaps  most  common  in  the  ovary,  where  there  may  be  several.  They 
are,  as  the  name  implies,  composed  essentially  of  derivatives  of  the  ecto- 
dermian  layer,  but  there  is  no  line  between  them  and  the  more  complex 
teratomata— indeed,  all  dermoids  on  closer  examination  prove  to  have  a 
more  complicated  structure  than  is  apparent  at  first  sight.  A  dermoid  cyst 
is  round  or  irregularly  multilocular,  and  on  incision  is  found  to  have  a 
tough,  hard  wall  and  to  be  filled  with  a  soft,  greasy  mass  of  granular,  but- 
tery consistency,  in  which  there  are  often  tangles  of  hair  (Fig.  569).  Some 
times  the  hair  may  be  extremely  long  and  abundant.  It  does  not  spring 


1082  TEXT-BOOK    OF    PATHOLOGY 

evenly  from  the  whole  wall,  but  has  its  roots  in  a  thickened  patch  which  is 
constantly  present  in  the  wall  of  such  cysts  (Wilms).  The  thick  area  pro- 
jects into  the  lumen  of  the  cyst,  and  is  sometimes  very  irregular  and  rough. 
It  is  covered  with  thick  epidermis,  and  bears  the  roots  of  the  hairs  and  an 
exaggerated  array  of  sebaceous  glands  (Figs.  570  and  571).  It  is  from  these 
sebaceous  glands  that  the  buttery  contents  of  the  cyst  are  secreted.  They 
may  open  in  the  hair-sheaths,  but  most  commonly  open  directly  into 
the  cyst.  There  are  sebaceous  glands  around  the  whole  wall  of  the  cyst, 
quite  away  from  the  hair-bearing  patch.  Opposite  this  patch  the  dis- 
tal ends  of  the  hairs  may  become  buried  in  the 'wall  and  encapsulated  by 
granulation  tissue,  so  that  they  seem  to  have  taken  root  there.  In  the 
mass  of  tissue  which  projects  into  the  cavity  there  may  be  smooth  muscle, 


Fig.  570. — Wall  of  dermoid  cyst,  showing  solid  projection  covered  with  epidermis. 
There  are  many  hair  and  sebaceous  glands  on  the  surface. 

like  the  arrectores  pilorum,  and  fat  and  dense  connective  tissue.  That 
these  dermoid  cysts  verge  on  the  more  solid  teratomata  is  seen  from  the 
fact  that  some  of  them  have  teeth  in  their  walls  often  set  in  connection  with 
a  bony  mass  which  lies  deeper  in  the  wall  (Fig.  572).  If  there  are  pig- 
mented  rudiments  of  an  eye  or  elements  of  the  central  nervous  system, 
the  approach  to  the  complexity  of  the  more  solid  teratomata  is  even 
closer.  Wilms  points  out  the  fact  that  most  of  the  structures  seen  in  der- 
moid cysts  are  such  as  might  be  developed  from  the  head,  that  part  of  the 
embryo  which  develops  most  rapidly.  Various  degenerative  changes  occur 
in  such  cysts,  the  walls  become  calcified,  their  epithelium  disappears  and 
is  replaced  by  granulation  tissue,  the  sebaceous  contents  shrink  and  become 
solidified,  and  in  some  cases  carcinomatous  tissue  develops  in  the  wall. 


TERATOMATA;  COMPOSITE  TUMORS 


1083 


Still  simpler  cysts  occur  in  which  the  origin  from  a  misplaced  blastomere 
is  not  so  evident.  These  are  the  wens  or  epidermoid  cysts,  which  are  found 
in  the  scalp,  and  are  lined  with  stratified  epithelium  which  grows  in  quan- 
tity and  is  desquamated  into  the  interior  to  form  a  soft,  flaky  substance. 
They  may  perhaps  be  explained  as  displacements  of  ectoderm  at  a  much 
later  stage.  So,  too,  with  the  atheromatous  cysts  or  branchial  cysts,  which 
are  developed  from  an  imperfectly  obliterated  and  isolated  part  of  a  branch- 
ial cleft.  Either  cylindrical  or  squamous  epithelium  may  form  their  lining, 
and  they  sometimes  grow  in  a  ramifying  way  far  up  behind  the  ear  and 


Fig.  571.— Wall  of  teratomatous  cyst  of  the  ovary.  There  is  an  epidermal  lining  with 
sebacous  glands.  In  the  deeper  portions  there  is  a  mass  of  cartilage  and  structures 
resembling  salivary  glands. 

down  into  the  neck.  In  one  which  we  have  recently  studied  the  epithelial 
lining  was  very  thick,  and  had  desquamated  enough  of  its  cells  to  produce 
a  soft,  yellowish  material  like  the  caseous  centre  of  a  tubercle.  They  are 
hard  to  extirpate  and  tend  to  recur. 

Cholesteatomata.— Another  teratoid  growth  which  may  occur  in  the 
brain  in  connection  with  the  meninges,  or  about  the  hypophysis,  is  a  thin 
•epidermal  sac,  which,  from  its  abundant  content  of  cholesterine  crystals 
jnixed  with  epidermal  scales,  is  called  a  cholesteatoma.  Such  growths 


1084 


TEXT-BOOK    OF    PATHOLOGY 


which  are  lined  with  skin-like  epidermis,  and  distended  with  desquamated 
epidermal  cells,  may  occur  in  the  orbit,  or  at  times  in  the  middle  ear,  where 
they  do  harm  by  occupying  space. 

Mixed  Tumors.— This  leads  us  to  the  composite  or  mixed  tumors,  which 
represent  the  teratomata  derived  from  the  isolation  of  cells  already  in  an 
advanced  state  of  differentiation,  whose  capabilities  are  therefore  limited 
and  pretty  strictly  determined.  There  is  much  dispute  as  to  their  nature 
and  origin,  but  this  explanation  seems  to  me  most  acceptable  and  credible. 


Fig.  572. — Teratomatous  cystoma  of  the  ovary,  containing  teeth  and  a  tongue-like 
structure  covered  with  hair. 


Such  tumors  are  found  in  immediate  connection  with  the  salivary  glands, 
in  the  kidneys  in  children,  in  the  breast,  in  the  testicle,  and  elsewhere,  but  it 
must  not  be  supposed  that  they  resemble  each  other  in  these  different  situa- 
tions. All  they  have  in  common  is  the  principle  upon  which  they  are 
formed. 

Mixed  Tumors  of  the  Salivary  Glands. — In  their  gross  appearance  these 
tumors  resemble  one  another  very  closely — they  are  rounded  or  nodular, 


TERATOMATA;  COMPOSITE  TUMORS 


1085 


elastic  masses,  which  grow,  as  a  rule,  not  in  the  gland,  but  in  close  proximity 
to  it,  being  generally  attached  to  its  capsule.  They  spring  in  this  way  from 
the  parotid  or  submaxillary,  and  may  reach  a  very  great  size.  On  extirpa- 
tion they  may  recur,  but  even  then  they  run  a  benign  course.  On  section 
such  a  tumor  presents  extensive,  rather  translucent,  areas,  with  occasional, 
patches  of  denser  opaque  tissue  and  rare  points  of  calcification.  Micro- 


Fig.  573.—  Mixed  tumor  of  the  parotid  gland,  showing  cartilage  and  narrow  strands  of 

epithelial  cells. 

scopically,  the  most  varied  appearances  are  seen  (Fig.  573).  The  stroma  is 
hyaline  or  like  the  matrix  of  cartilage;  there  may  be  true  cartilage,  mingled 
with  dense  fibrous  tissue.  Everywhere  there  are  masses  of  cells  arranged 
tubules  or  cysts,  or  in  long  tapering  strands  which  anastomose  am 


n 


, 

finally  fade  into  the  crevices  of  the  stroma.    In  some  cases,  but  not  in  all, 
there  are  patches  of  this  cellular  tissue  which  are  distinctly  and  unmis- 


1086  TEXT-BOOK   OF   PATHOLOGY 

takably  composed  of  stratified  epithelium  with  concentric  epithelial  pearls. 
These  were  recognized  by  Landsteiner,  who  declared  the  tumors  to  be  of 
epithelial  origin.  Volkmann  had  studied  many  cases,  and  had  decided 
that  the  narrow  strands  of  cells  were  derived  from  endothelium,  and  indeed 
these  parotid  tumors  make  up  a  great  part  of  the  material  for  his  mono- 
graph on  endotheliomata.  Krompecher  thinks  of  them  as  basal-cell 
tumors.  Marchand,  Wilms,  and  others  regard  them  now  as  composite 
tumors  in  which  epithelium  plays  the  most  prominent  part,  and  trace  them 
to  an  origin  analogous  to  that  of  the  teratomata,  except  in  that  the  embry- 
onic rudiment  is  separated  at  a  later  stage. 

Composite  Tumors  of  the  Kidney. — In  infants  and  children  there  occur 
tumors  of  the  kidney  which  grow  to  an  enormous  size,  and  metastasize 
into  distant  organs.  They  may  appear  as  congenital  growths  in  new-born 
infants,  and  are  composed  of  a  mixture  of  tissues  in  which  cartilage,  fat, 
smooth  muscle,  and  myxomatous  connective  tissue,  together  with  complex 
arrangements  of  epithelium,  take  part.  Unlike  the  hypernephromata,  they 
cause  no  haematuria,  and  are  recognized  by  their  growth  to  a  great  mass  in 
the  abdomen.  Wilms,  Busse,  Hedren,  and  others  discuss  their  origin  at 
length.  While  Busse  thinks  they  may  be  derived  from  the  kidney,  or  at 
least  from  its  embryonal  rudiment,  Wilms  places  their  origin  farther  back, 
in  the  middle  plate,  after  its  separation  from  the  myotome.  This  tissue 
might  well  furnish  all  the  elements  which  are  found  in  such  tumors.  Stri- 
ated muscle  does  not  occur,  and  hence  the  myotome  is  not  involved,  but 
stratified  epithelium  does  occur,  and  offers  difficulties  to  Wilms'  view. 
Nevertheless  the  intimate  relation  of  the  anterior  end  of  the  Wolffian  duct 
to  the  ectoderm — possibly  a  remaining  trace  of  its  old  arrangement  as  a 
nephridial  tube  opening  on  the  skin — may  account  for  this  epithelium. 

The  morphology  of  these  tumors  is  so  variable  that  no  single  description 
will  apply.  The  student  is  referred  to  the  paper  of  Hedren,  in  which  the 
literature  is  reviewed  and  in  which  there  are  many  illustrations.  In  general, 
the  epithelial  cells  are  small  and  are  arranged  in  irregular,  gland-like  tubules, 
interspersed  with  solid  cords. 

Congenital  Cystic  Kidney. — There  is  no  good  place  in  which  to  mention  this  condi- 
tion, since  our  knowledge  of  its  nature  is  so  unsatisfactory,  and  for  that  reason  a  brief 
space  may  be  devoted  to  it  here. 

This  is  a  peculiar  affection  of  the  kidneys  which  leads,  during  embryonic  development, 
to  the  formation  of  cysts  throughout  both  kidneys,  and  frequently  to  the  formation  of  cysts 
in  the  liver  as  well.  Most  of  the  substance  of  the  kidneys  is  occupied  by  these  cysts,  and 
there  is  extremely  little  functional  tissue  left  between  them.  Yet  such  people  may  grow  to 
adult  life  without  knowing  that  there  is  anything  amiss  with  their  kidneys.  In  later 
life  they  may  die  of  renal  insufficiency  after  the  injury  of  the  scarcely  sufficient  tissue. 
In  infancy  the  kidneys  form  huge  masses  of  gelatinous  cystic  tissue,  so  large  in  one  case 
which  I  studied  that  they  had  to  be  removed  before  birth  was  possible.  This  child  was 
otherwise  extensively  malformed.  Reconstruction  (Meader)  shows  that  the  cysts  may 
be  in  immediate  relationship  with  the  glomeruli,  or  may  be  developed  in  the  first  part 
of  the  convoluted  tubule  and  connected  by  a  narrow  canal  with  the  glomeruli. 


TERATOMATA;  COMPOSITE  TUMORS 


1087 


Ribbert  puts  forth  a  theory  that  the  cysts  are  caused  by  interference  with  the  union 
of  the  glomerular  part  of  the  tubule  with  the  other  rudiment,  which  grows  up  from  the 
ureter  to  join  it.  Hence  the  glomerular  portion  dilates  into  a  cyst.  The  end  of  the 
ureteral  portion  may  also  become  cystic.  Others  regard  the  whole  process  as  an  ade- 
nomatous  growth,  which  it  is  said  might  account  for  the  similar  growth  of  cysts  in  the 
liver.  It  seems  to  me  more  plausible  to  base  the  change  on  anomalies  of  embryonic  de- 
velopment. 

In  the  adult  the  cystic  kidneys  may  form  two  huge  tumors  occupying  the  whole 
abdominal  cavity  on  each  side  (Fig.  574).  At  autopsy  they  are  found  to  be  no  longer 
gelatinous,  but  made  up  of  cysts  about  the  size  of  a  cherry  or  larger,  filled  with  clear, 
or  dark  brown,  or  turbid  fluid.  Between  these  cysts,  which  are  lined  with  low  cubical 
epithelium,  there  are  scattered  normal  tubules  and  glomeruli. 

In  infants  one  may  occasionally  see  another  type  of  cystic  dilatation  of  the  tubules 
which  occupies  the  pyramid  and  leads  to  the  fusiform  widening  of  the  conducting  tubules. 


Fig.  574. — Congenital  cystic  kidney.    Remnants  of  a  pelvis  are  seen  in  the  centre  at 

the  lower  part  of  the  figure. 

Composite  tumors  of  the  breast  are  rare  and  are  made  up  of  stratified 
epithelium,  together  with  various  types  of  connective  tissue.  They  are  of 
less  importance  than  the — 

Mixed  Tumors  of  the  Testicle.— Perhaps  these  should  not  be  referred 
to  again,  since  they  are  undoubtedly  of  teratomatous  character,  but  it  is 
intended  to  emphasize  the  point  that  in  many  of  these  tumors,  whether 
because  of  their  late  origin  in  the  course  of  embryonic  development,  or 
because  one  tissue  has  outgrown  the  others,  the  structure  is  relatively 
simple.  The  most  common  tumor  of  the  testicle  is  that  in  which  in  most 
parts  the  cells  are  uniform  in  appearance  and  are  large  round  cells,  arranged 
in  irregular  masses  or  strands,  with  a  stroma  which  is  infiltrated  with 
lymphocytes  (Fig.  575).  These  are  commonly  called  round-cell  sarcomata 
of  the  testicle,  and  possibly  this  is  correct  in  some  cases,  but  in  many  others 
there  are  transitions  to  other  forms  of  tissue  and  admixtures  of  epithelium 


1088 


TEXT-BOOK   OF   PATHOLOGY 


which  indicate  the  more  complex  character  of  the  tumor.  Other  tumors 
of  the  testicle  contain  cartilage  and  cysts.  Their  main  tissue  is  arranged 
like  epithelium,  in  complex,  gland-like  structures  often  resembling  an 
adenocarcinoma.  Still  other  more  complicated  forms  occur,  and  we  find 
ourselves  once  more  approaching  the  the  solid  teratomata.  Still  it  is  the  rule 
for  these  testicular  tumors  that  they  grow  with  extreme  malignancy,  and 
extend  into  the  spermatic  cord  and  metastasize  by  way  of  the  veins  with 
great  rapidity.  In  this  respect  they  are  unlike  the  ordinary  teratomata^ 


Fig.  575. — Teratomatous  tumor  of  the  testicle  composed  largely  of  tissue  like  that  of  a 

round-cell  sarcoma. 


and  we  must  assume  that  if  they  began  as  teratomata  they  have  acquired 
the  character  of  malignant  tumors. 

Chordomata. — Mention  may  be  made  here  of  a  rather  rare  tumor  which 
usually  springs  from  the  body  of  the  sphenoid  bone,  and  projects  into  the 
cranial  cavity,  compressing  the  brain  and  the  cranial  nerves.  Similar 
tumors  may  arise  from  the  sacrum  and  other  parts  of  the  vertebral  column. 
They  are  shown  to  be  malignant  by  their  invasive  mode  of  growth,  which 
allows  them  to  destroy  the  bone  extensively  and  to  penetrate  into  veins. 
Nevertheless,  no  metastases  in  other  organs  have  been  found.  The  tumor 
is  lobulated,  the  lobules  being  composed  of  groups  and  strands  of  large  and 


TERATOMATA;  COMPOSITE  TUMORS  1089 

small  cells  in  a  homogeneous  ground-substance  which  takes  a  bluish  stain 
with  hsematoxylin.  They  are  rich  in  glycogen.  The  work  of  various 
authors,  and  particularly  that  of  Marchand's  pupil,  Nebelthau,  has  shown 
that  these  growths  are  derived  from  remnants  of  the  chorda  dorsalis. 

LITERATURE 

Chorionic  Epithelioma  of  Testicle.— Scott  and  Longcope:   Proc.  Path.  Soc.  Phila.,  1909, 

xii,  8. 

Frank:  Jour.  Amer.  Med.  Assoc.,  1906,  xlvi,  248. 
Schlagenhaufer:    Verb.  d.  Dtsch.  Path.  Gesellsch., 

1902,  v,  209. 

Risel:  Ergebn.  d.  allg.  Path.,  1906,  xi,  929. 

Teratomata  in  General— Seydel :  Ergebn.  d.  allg.  Path.,  1901,  vi,  858. 
Wilms:  Die  Mischgeschwlilste,  Leipzig,  1899. 
Marchand:  Missbildungen :  Eulenberg's  Realencyklopadie, 

1897,  xv,  503. 
Dermoid  Cysts. — Saxer:  Ziegler's  Beitrage,  1902,  xxxi,  452. 

Katsurada:  Ibid.,  1901,  xxx,  179. 

Salivary  Tumors. — Landsteiner:  Ztschr.  f.  Heilkunde,  1901,  xxii;  Abth.  f.  path.  Anat.,  1. 
Hinsberg:  Dtech.  Ztschr.  f.  Chir.,  1899,  li,  281. 
Wood:  Annals  of  Surgery,  1904,  xxxix,  57. 

Mixed  Tumors  of  Kidney.— Hedren :  Ziegler's  Beitrage,  1907,  xl,  1. 
Pusse:  Virch.  Arch.,  1899,  clvii,  346. 
wilms:   Loc.  cit. 

Congenital  Cystic  Kidney.— Ribbert:  Verh.  d.  Dtsch.  Path.  Gesell.,  1900,  ii,  187. 
Busse:  Virch.  Arch.,  1904,  clxxv,  442. 
Meader:  Johns  Hopkins  Hosp.  Bull.,  1907,  xviii,  354. 
Mixed  Tumors  of  Testicle.— Debernardi :    Ziegler's  Beitrage,  1908,  xliii,  89. 

Chevassu:  Tumeurs  du  testicule,  Paris,  1906. 

Chordoma—  Jelliffe  and  Larkin:  Ztschr.  f.  d.  ges.  Neurol.  u.  Psychiat.,  1911,  v,  590. 
Wegelin:  Atti  del  I  Congresso  Internaz.  dei  Patologi,  Torino,  1911,  70. 

70 


CHAPTER  LVI 
CLASSIFICATION  OF  TUMORS 

THE  only  satisfactory  classification  of  tumors  would  be  on  the  basis  of 
their  aetiology.  Since  we  know  nothing  of  this,  they  are  classed  very  much 
as  animals  or  plants  would  be,  on  the  basis  of  their  most  striking  char- 
acters. The  most  fundamental  available  characteristics  are:  (1)  The 
type  of  tissue  which  they  resemble,  and  from  which  we  suppose  them  to  be 
derived;  (2)  the  degree  in  which  they  diverge  from  the  type,  and  the 
extent  to  which  they  have  acquired  the  power  of  invasion  and  coloniza- 
tion, and  (3)  the  form  which  the  tumor  assumes,  that  is,  its  architecture 
as  a  papillary,  cystic,  glandular,  or  solid  growth. 

In  other  words,  we  have  tumors  derived  from  one  or  more  of  the  three 
germ  layers,  or  more  specifically  from  a  tissue  originating  from  one  of  these 
'  layers.  They  may  be  benign  or  malignant,  and  may  grow  in  one  or  other 
of  the  many  arrangements  adopted  by  normal  tissues,  or  in  combinations 
or  perversions  of  these  forms.  Rather  than  assume  too  accurate  a  knowl- 
edge of  the  ultimate  derivation  of  the  tumors,  I  have  preferred  to  arrange 
them  according  to  the  general  character  of  their  tissues,  both  anatomical 
and  biological,  and  their  form. 

Other  classifications  as  given  in  the  various  text-books  and  treatises  on  the 
subject  should  be  consulted.  The  following  list  is  mainly  for  convenience 
in  summarizing  the  various  forms  as  they  have  been  considered  here.  It  is 
an  arrangement,  not  a  classification. 

1.  Benign  tumors  of  connective-tissue  character: 

Fibroma. 

Lipoma. 

Chondroma. 

Osteoma. 

Xanthoma. 

2.  Tumors  composed  of  tissue  of  muscular  character: 

Leiomyoma. 
Rhabdomyoma. 

3.  Tumors  composed  of  tissue  of  nervous  character: 

Neurocytoma,  neuroblastoma,  sympathoblastoma. 

Ganglioneuroma. 

Paraganglioma. 

Glioma. 

4.  Tumors  composed  of  blood  and  lymph  channels — angiomata: 

Haemangioma. 
Lymphangioma. 

1090 


CLASSIFICATION    OF   TUMORS  1091 

5.  Malignant  tumors  of  connective-tissue  character — sarcomata: 

Spindle-cell  sarcoma. 
Mixed-cell  sarcoma. 
Round-cell  sarcoma. 
Alveolar  sarcoma. 
Giant-cell  sarcoma. 
Osteosarcoma. 
Myxoma. 

6.  Pigmented  tumors: 

Nsevus. 

Melanotic  sarcoma  or  melanoma. 

7.  Tumor  composed  of  tissue  resembling  adrenal  cortex: 

Hypernephroma. 

8.  Tumors  thought  to  originate  from  endothelium — "endotheliomata" 

Lymphangioendothelioma. 

Cylindroma. 

Pleural  and  peritoneal  tumors. 

Meningeal  tumors. 

Hsemangioendothelioma. 

9.  Benign  epithelial  tumors: 

Papilloma. 
Adenoma. 
Cystadenoma. 

10.  Malignant  epithelial  tumors — carcinomata. 
Flat-celled  epithelioma. 
Adamantinoma. 

Basal-cell  cancer. 

Cylindrical-cell  cancer  or  adenocarcinoma. 

Gland-cell  cancer. 

11.  Chorionic  epithelioma. 

12.  Mixed  tumors  and  teratoma. 


CHAPTER  LVII 
GENERAL  DISCUSSION  OF  TUMORS 

General  character  of  tumors;  relation  to  tissues  of  host.  Their  independence  of  the  laws 
governing  the  growth  of  normal  tissues;  consequent  abnormal  architecture  and  metabolism. 
Distinction  between  tumors  and  infectious  processes.  Nature  of  cells  of  tumors;  specific 
relation  to  those  of  host;  relation  to  embryonic  stages  of  cell  development;  atypical  character. 
Growth;  implantation,  extension,  metastasis,  recurrence.  Contributory  causes  of  tumor 
growth:  injury  and  irritation  (physical,  chemical,  parasitic;  Rous'  filterable  tumor);  in- 
ternal secretions;  malformations;  disposition;  senility;  heredity. 
Resistance  and  immunity. 

Theories  as  to  the  (Etiology  of  tumors:  Theory  of  parasitic  origin  of  tumors;  theory  of  tumor 
growth  as  the  effect  of  irritants;  theories  emphasizing  a  disturbance  of  equilibrium  of  tissues; 
Cohnheim's  theory;  Ribbert's  theory;  theories  of  tumor  growth  depending  upon  changes  in 
the  cells. 

General  Character  of  Tumor. — Up  to  this  point  we  have  considered  the 
characters  of  tumors  as  though  they  were  plants  in  a  garden,  observing 
their  general  structure  and  their  mode  of  growth  in  individual  cases.  It  is 
necessary  now  to  make  an  attempt  to  learn  whether  there  are  common 
features  in  these  respects,  and  whether  we  can  discover  the  causes  of 
their  appearance  and  growth  and  of  their  peculiar  relations  to  the  host. 
Otherwise  it  must  remain  extremely  difficult  to  give  a  definition  of  what  a 
tumor  really  is. 

It  is  clear  from  what  has  been  said  of  all  these  tumors  that  they  are 
composed  of  the  tissue  of  the  host.  This  was  recognized  by  Johannes 
Miiller,  and  in  spite  of  Virchow's  rather  generous  idea  that  carcinomata, 
as  well  as  other  tumors,  might  be  formed  in  a  connective-tissue  matrix, 
Waldeyer  insisted  that  the  specific  relation  was  closer  and  that  cancers 
which  are  composed  of  epithelium  could  arise  only  from  epithelium.  After 
that  the  intimate  relationship  of  each  tumor  to  one  form  or  other  of  normal 
tissue  was  looked  for  and  usually  found,  although  we  are  still  puzzled  to 
trace  this  relationship  in  many  cases. 

But  if  it  is  possible  to  feel  sure  that  a  given  tumor  is  of  epithelial  or 
connective-tissue  origin,  or  even  that  it  belongs  to  the  stratified  or  cylin- 
drical epithelium,  it  is  nevertheless  equally  certain  that  it  does  not  resemble 
that  tissue  precisely.- 

The  laws  which  govern  the  growth  of  normal  human  tissue  and  organs 
are  very  rigid.  The  form  of  the  normal  cells  is  so  constant,  and  their 
relations  to  one  another  in  the  architecture  of  the  organ  so  fixed,  that  we 
become  familiar  with  their  appearance,  and  instantly  recognize  any 
divergence  from  the  accepted  form.  We  know  well  too  what  changes 

1092 


GENERAL   DISCUSSION    OF   TUMORS  1093 

occur  in  the  morphology  of  normal  cells  as  the  result  of  variations  in  their 
functional  activity,  and,  above  all,  we  know  the  plan  upon  which  they 
grow.  Their  reactions  in  all  these  respects,  to  a  great  variety  of  recogniz- 
able injuries  and  pathological  disturbances,  are  very  familiar,  and  we  realize 
that  under  those  circumstances  the  cells  and  tissues  still  obey  the  laws 
which  govern  their  growth  under  normal  conditions,  and  strive  to  restore 
as  quickly  as  possible  the  forms  and  relations  which  have  been  established 
by  ages  of  evolution. 

In  tumors  we  find  the  cells  abnormal  in  form,  in  their  relations  to  one 
another,  and  in  their  relation  to  surrounding  tissues.  They  are  abnormal 
in  every  functional  activity,  and  in  many  cases  in  their  increased  vigor  of 
growth.  Great  stress  is  usually  laid  upon  this  increased  energy  of  growth, 
although  in  many  tumors  it  is  at  a  very  low  ebb,  and  in  the  most  rapidly 
invading  forms  is  not  to  be  compared  with  that  of  the  growing  embryo. 

The  really  essential  difference  between  tumors  and  normal  tissue  is  not 
the  increased  energy  of  growth,  but  the  emancipation  of  the  tissue  from 
obedience  to  the  laws  which  govern  the  growth  of  normal  tissues.  That 
this  is  closely  related  to  the  abnormality  in  the  form  of  the  cells  is  probable. 
It  is  as  a  direct  expression  of  this  complete  lawlessness  that  the  tissue  pro- 
duced by  these  cells  has  no  regular  architectural  arrangement,  that  it  never 
forms  organs  that  could  be  of  any  possible  use,  and  that  it  pays  no  regard 
to  the  rights  of  other  organs,  but  bursts  its  way  recklessly  through  their 
boundaries  and  their  tissues,  destroying  their  cells  as  it  goes.  Its  behavior 
is  like  a  complete  disregard  of  international  law,  which  has  been  established 
for  the  welfare  of  the  whole  world. 

In  the  development  of  the  body  some  people  may  hold  that  the  equilib- 
rium which  is  maintained  between  various  tissues  depends  entirely  upon  the 
power  of  each  to  grow,  but  it  is  evident  enough  that  a  balance  is  maintained 
by  a  higher  law  than  this,  and  that  such  an  organ  as  the  liver  does  not  main- 
tain a  precise  number  of  cells,  because  it  has  not  the  power  to  form  more,  but 
because  the  law  of  the  general  welfare  demands  that  many,  and  no  more. 
If  some  are  destroyed,  or  if  the  general  situation  is  changed,  the  liver  will 
form  more  cells  to  restore  precisely  the  balance.  Hence  even  though  it 
can  be  defined  only  vaguely,  we  are  aware  that  there  is  a  delicate  but  effec- 
tive power  which  controls,  possibly  by  way  of  the  nervous  system,  the  rela- 
tions of  tissues  to  one  another.  They  are  disciplined,  and  grow  when 
they  are  required,  but  not  of  their  own  initiative. 

It  is  far  otherwise  with  tumors.  No  tumor  of  glandular  character  has  a 
duct,  nor  have  its  glands  any  such  arrangement  that  they  could  discharge  a 
secretion.  It  is  true  that  tumors  of  the  organs  of  internal  secretion  may 
sometimes  form  a  useful  secretion,  but  one  has  the  impression  that  this  is  a 
rare  occurrence  and  inadvertent  on  their  part.  No  tumors  are  known 
to  be  under  the  control  of  the  nervous  system.  They  seem  to  have  no 
nerves  except  those  accidentally  enclosed  in  their  growth  and  possibly 
vasomotor  nerves  in  their  blood-vessels.  It  is  true  that  Young  was  able 


1094  TEXT-BOOK   OF   PATHOLOGY 

to  demonstrate  the  nerve-fibres  in  a  number  of  tumors  by  staining  with 
methylene-blue,  but  he  could  not  show  that  they  really  belonged  to  the 
tumor  tissue,  and,  as  far  as  I  can  learn,  no  one  has  been  more  successful. 
Tumors  are  not  even  subject  to  the  normal  conditions  of  nutrition,  and 
withstand  in  the  most  surprising  way  starvation  which  causes  the  rest  of 
the  body  to  waste.  A  lipoma  in  a  starving  animal  remains  a  plump  tumor, 
distended  with  fat  when  all  the  other  fat  has  disappeared.  It  is  true  that 
Moreschi  found  that,  by  starving  mice  inoculated  with  a  tumor,  he  could" 
inhibit  its  growth,  but  Rous  found  that  if  the  tumor  were  well  established, 
it  continued  to  grow.  In  human  beings  the  contrast  between  the  appear- 
ance of  huge  cancerous  growths  in  full  progress,  and  extreme  emaciation  of 
the  rest  of  the  body,  is  often  very  striking. 

Thus  the  isolation  and  independence  of  the  tumor  form  the  essential 
difference  between  its  nature  and  that  of  the  normal  tissues.  In  virtue 
of  this  it  behaves  in  such  a  way  as  to  be,  in  nearly  every  instance,  harmful 
to  its  host,  either  through  occupying  space  and  requiring  nutrition,  or  by 
actually  invading  and  destroying  useful  tissues.  Since  tumors  are  com- 
posed of  human  tissues,  however,  we  cannot  accept  this  inimical  attitude 
as  a  natural  thing  as  we  would  in  the  case  of  an  animal  parasite,  and  every 
effort  has  been  directed  toward  learning  why  and  how  such  independence 
has  been  attained. 

Notwithstanding  this  general  statement  that  a  tumor  is  a  growth  of 
abnormal  tissue  which  is  largely  independent  of  the  laws  governing  and 
controlling  the  growth  of  normal  tissues,  it  is  often  very  difficult  to  decide 
what  is,  and  what  is  not,  to  be  called  a  tumor.  Histological  study  often 
leaves  us  uncertain,  and  some  growths  are  so  sluggish  that  even  a  survey  of 
their  whole  biological  relations  is  hardly  sufficient  to  inform  us  as  to 
whether  they  have  arisen  as  a  response  to  some  injury,  or  are  really  inde- 
pendent and  transgressing  the  regulations  which  govern  the  normal  tissues. 
Indeed,  we  not  infrequently  discover  that  something  which  has  long  been 
regarded  as  a  tumor  is  really  the  slow  product  of  a  chronic  infection,  and 
Virchow's  great  book,  Die  krankhaften  Geschwulste,  is,  perhaps  inten- 
tionally, full  of  such  examples.  Tumors  are  simulated,  on  the  one  hand, 
by  the  reactions  of  the  body  to  infection  and  injury,  which  often  produce 
considerable  masses  of  new  and  peculiar  tissue;  on  the  other  hand,  by  mal- 
formations and  displacements  of  tissue,  with  which,  as  has  already  been 
shown,  their  relations  are  especially  intimate.  Whether  we  can  draw  a 
boundary  line  to  separate  sharply  the  group  of  tumors  from  these  is  doubt- 
ful. It  is  relatively  easy  in  the  case  of  such  typical  malignant  tumors 
as  the  carcinomata,  but  not  easy  when  we  consider  such  processes  as  Hodg- 
kin's  disease,  leukaemia,  leukosarcoma,  lymphosarcoma,  and  round-cell 
sarcoma.  In  the  case  of  z-ray  burns,  psoriasis,  xeroderma,  etc.,  it  is  not 
even  easy  to  say  when  the  normal  reaction  ceases  and  tumor  growth  begins; 
nor  at  the  other  extreme  is  it  easy  to  determine  when  a  mixed  tumor  becomes 


GENERAL   DISCUSSION   OF   TUMORS  1095 

a  teratoma,  or  where  the  term  teratoma  should  be  given  up  and  reference 
be  made  to  an  imperfect  or  abnormal  foetus,  or  even  to  a  twin  brother. 

It  seems,  however,  that  if  we  were  able,  in  each  instance,  to  decide 
accurately  as  to  whether  the  normal  laws  of  growth  had  been  broken  or  not, 
we  could  outline  sharply  the  whole  group  of  tumors.  The  independence  of 
tumors  involves  the  progressive  and  unlimited  character  of  their  growth. 
They  never  reach  any  goal  and  are  never  complete,  nor  do  their  cells  ever 
reach  any  stage  comparable  to  maturity  and  functional  perfection.  The 
reaction  to  infection  and  mechanical  or  chemical  irritation  keeps  pace  with 
the  injury;  it  exists  only  so  long  as  the  injury  persists,  and  then,  in  complete 
obedience  to  the  laws  of  growth  and  the  regulation  of  the  internal  relations 
of  the  tissues,  returns  as  quickly  as  possible  to  the  normal.  Misplaced 
embryonic  tissues,  no  matter  how  complicated,  proceed  to  the  ordinary 
maturity  of  the  tissue,  and  then  remain  as  stationary  as  normal  tissues. 
They  are  still  abnormal  and  harmful  to  the  host  because  they  are  out  of 
place,  but  not  because  they  are  actively  transgressing  the  law  of  the  inter- 
relation of  organs.  Of  course,  many  teratomata  show  themselves  ulti- 
mately to  be  malignant  tumors,  but  these  are  instances  in  which  a  tumor 
has  developed  in  the  tissues  of  a  teratoma  and  grown  to  invade  the  tissues 
of  the  host.  Such  a  tumor  grows  usually  from  only  one  of  the  types  of  tis- 
sue which  make  up  the  teratoma,  and  is  precisely  comparable  to  a  tumor 
which  develops  anywhere  else  in  the  host.  So  too  after  long  irritation  or 
infection  the  reacting  tissue  may  reveal  itself  as  a  carcinoma,  but  it  is  a 
tumor  which  has  freshly  developed  in  pathological  tissue,  just  as  it  might 
anywhere  else.  Far  more  often  the  reacting  tissue  does  not  give  rise  to  a 
tumor  growth. 

If  in  such  an  obscure  condition  as  Hodgkin's  disease  we  were  able  to 
remove  or  destroy  an  infectious  agent  and  to  observe  thereupon  the  im- 
mediate retrogression  of  the  tumor-like  nodules,  we  might  conclude  at 
once  that  they  were  not  true  tumors.  Since  we  have  not  definitely  rec- 
ognized an  infectious  agent,  we  are  not  quite  sure  whether  Hodgkin's  disease 
is  a  tumor  or  not.  How,  then,  one  may  well  ask,  can  we  be  sure  that 
cancers  and  sarcomata  are  not  infectious  processes,  since  we  do  not  know 
their  cause?  We  are  not  sure,  and  although  every  bit  of  evidence  points  to 
their  being  of  a  different  character,  we  cannot  be  absolutely  sure  until  some 
other  cause  of  their  growth  is  definitely  demonstrated. 

In  this  state  of  knowledge  it  seems  best  to  hold  to  the  one  striking 
feature  of  tumor  growth  as  contrasted  with  that  of  other  tissue  growth — 
its  independence  of  the  mechanical  laws  which  govern  the  hereditary  form 
of  the  body. 

Of  course,  we  must  some  day  discover  the  cause  of  this  alteration  in  the 
behavior  of  the  tumor-cells,  and  it  is  conceivable  that  it  may  prove  to  be 
some  parasite  which  accompanies  or  lives  in  the  cells,  perverting  their  course 
of  life  from  that  which  is  normal,  and  keeping  them  forever  growing  and 
dividing  to  produce  new  cells.  It  is  difficult  to  imagine,  however,  what 


1096  TEXT-BOOK   OF   PATHOLOGY 

kind  of  parasite  that  could  be.  One  may  implant  a  carcinoma  of  a  mouse 
into  a  normal  mouse  and  from  that,  after  it  has  grown,  transplant  a  frag- 
ment to  another  mouse,  and  repeat  this  for  hundreds  of  generations  until 
the  mouse  from  which  the  tumor  was  originally  taken,  and  all  its  contempo- 
raries and  their  offspring,  have  been  dead  for  years  of  old  age,  and  still  the 
tumor-cells  are  alive  and  thriving  with  exactly  the  same  anatomical  and 
histological  characters  that  they  possessed  at  first.  It  is  a  kind  of  arti- 
ficial immortality  that  seems  to  require  only  nutrition,  and  none  of  the 
reinvigoration  which  other  living  things  usually  gain  from  a  sexual  union 
with  their  kind.  Nevertheless,  it  is  not  yet  proved  that  unicellular  organ- 
isms die  after  long  periods  of  multiplication  by  fission  without  sexual  con- 
jugation, and  Woodruff  seems  to  hold  that  they  may  go  on  indefinitely  in 
this  way.  Plants,  such  as  banana  trees,  have  in  the  same  way  been  culti- 
vated for  hundreds  of  years  from  cuttings  without  any  recourse  to  fertiliza- 
tion and  seed  planting. 

We  may  pause  here  to  review  the  general  character  of  tumor  growths 
before  discussing  the  theories  which  have  been  proposed  as  to  their  causa- 
tion. 

GENERAL  CHARACTERS  OF  TUMOR  GROWTH 

Tumors  are  composed  of  the  tissues  of  the  host,  as  has  long  been  agreed, 
in  spite  of  such  efforts  as  those  of  Kelling,  who  attempted  to  prove  that 
they  are  made  up  of  the  tissues  of  cows,  pigs,  or  chickens  which  had  been 
used  for  food.  By  the  enormous  amount  of  work  which  has  been  done  in 
the  last  ten  years  in  transplanting  tumors  from  one  animal  to  another  it 
has  been  shown  that  their  tissues  are  exquisitely  specific  and  will  grow  con- 
tinuously only  in  another  animal  of  the  same  species.  Thus  a  carcinoma 
of  a  white  mouse  will  grow  in  another  white  mouse,  but  fails  to  reach  any 
considerable  size  in  a  gray,  or  wild  mouse,  or  in  a  rat,  and  finally  undergoes 
retrogression.  This  explains  easily  the  complete  failure  of  those  experi- 
ments in  which  it  has  been  attempted  to  transplant  human  tumors  to  dogs, 
rabbits,  and  other  animals.  Even  in  monkeys  such  transplants  have  failed. 
Resemblance  to  Normal  Cells.  — We  have  observed  in  previous  chap- 
ters the  extent  of  the  resemblance  of  tumors  to  normal  tissues  both  in 
appearance  and  in  histological  characters,  and  have  realized  that  there 
are  extreme  variations,  so  that,  while  the  cells  of  some  tumors  are  almost 
precisely  like  the  normal  cells,  even  in  their  arrangement  (thyroid  tumors, 
etc.),  others  depart  very  widely  from  this  form  and  become  quite  unrecog- 
nizable. We  have  learned  that  many  tumors  are  composed  of  cells  which 
seem  to  belong  unquestionably  to  the  same  stage  of  development  as  those 
of  the  surrounding  tissues,  while  others  are  made  up  of  tumor-cells  which 
have  the  morphology  and  arrangement,  and  possibly  also  the  biological 
characters  of  the  cells  of  some  tissue  in  the  early  stages  of  its  development. 
Examples  of  the  latter  condition  are  found  in  the  neuroblastomata,  in  which 
cells  belonging  to  an  early  stage  in  the  development  of  the  sympathetic 


GENERAL  CHARACTERS  OF  TUMOR  GROWTH        1097 

nervous  system  persist  in  that  stage,  and  multiply  excessively  to  form  a 
tumor,  and  in  rhabdomyomata,  which  contain  cells  resembling  embryonic 
muscle-cells.  Nevertheless,  I  have  never  used  the  expression  "  return  to 
an  embryonic  state"  in  speaking  of  such  tumors  as  sarcomata,  which  are 
commonly  spoken  of  as  composed  of  " undifferentiated "  or  "unripe,"  con- 
nective tissue,  because  I  do  not  believe  that  there  is  evidence  to  show 
that  there  is  anything  embryonic  about  that  tissue.  It  is  true  that  the  cells 
are  unlike  the  normal  cells,  but  they  do  not  especially  resemble  the  con- 
nective-tissue cells  of  the  embryo,  and  are  often  extremely  unlike  them.  It 
seems  far  more  plausible  that  they  are  cells  so  modified  that  their  sole  func- 
tion is  to  reproduce  themselves  rapidly,  for  which  reason  they  never  assume 
the  form  of  the  normal  cells,  nor  lie  dormant  in  abundant  intercellular 
substance.  It  is  conceivable  that  they  are  cells  which  have,  like  the  neuro- 
blasts,  never  passed  the  embryonic  stage  of  development,  but  this  is  a  diffi- 
cult explanation  which  is  neither  required  nor  supported  by  any  facts. 
It  does  not  seem  at  all  probable  that  any  cell  of  a  mature  animal  can  ever 
return  to  the  embryonic  condition.  Even  those  cells  of  the  blood-forming 
organs  which  continually  produce  new  blood-cells,  and  the  cells  of  the  epi- 
dermis, which  form  new  epithelial  cells,  are  in  no  true  sense  embryonic  cells. 
They  have  retained  the  function  of  becoming  differentiated  into  one 
type  of  cell,  but  are  even  then  far  advanced  from  the  condition  of  embryonic 
cells.  The  idea  that  cells  may  in  tumor  formation  return  to  the  embryonic 
state  is  based  no  doubt  upon  the  desire  to  explain  their  new  energy  of  growth, 
but  this  new  character  of  their  growth  is  not  at  all  like  that  of  embryonic 
cells.  In  the  embryo,  the  cells  pass  through  a  definite  development  to 
become  mature.  If  they  grow  rapidly,  it  is  only  in  this  respect  that  the  cells 
of  a  tumor  resemble  them,  because  tumor-cells  pass  through  no  such  regular 
development  but  merely  continue  to  grow  and  divide.  They  do  not  ap- 
proach the  character  of  the  embryonic  cells,  but  assume  a  totally  new 
character,  in  which  they  only  roughly  resemble  the  cells  of  the  embryo  in 
form  and  in  the  rate  at  which  they  grow.  It  is  difficult  enough  to  believe 
that  embryonic  cells  can  be  isolated  and  remain  latent  for  years  embedded 
in  the  normal  growing  tissues,  but  far  more  difficult  to  believe  that  normal 
cells,  once  matured,  can  return  to  the  embryonic  state.  For  the  former 
possibility  we  have  proofs;  for  the  latter  we  have  no  evidence  whatever, 
so  far  as  I  can  see. 

Although  we  speak  so  easily  of  deriving  tumor-cells  from  tissue  of  one 
type  or  another,  we  really  depend  largely  upon  their  morphological  re- 
semblance for  our  proof  of  the  relation.  It  is  possible  that  we  are  often 
wrong  in  this,  but,  on  the  whole,  the  chance  of  error  seems  relatively 
slight. 

Dependence  upon  Host  for  Nutrition. — Tumors,  whatever  the  inde- 
pendence of  their  cells,  are  dependent  upon  their  host  for  their  nutrition. 
If  the  host  dies,  the  tumor  dies  too.  If  a  blood-vessel  is  plugged  in  a  tumor, 
the  area  which  should  be  supplied  with  blood  becomes  an  infarct,  just  as  it 


1098  TEXT-BOOK   OF   PATHOLOGY 

would  in  the  kidney.  Bashford  has  compared  the  mouse,  in  which  a  huge 
tumor  larger  than  itself  is  growing,  to  a  sort  of  nutritive  machine  engaged 
in  feeding  the  tumor.  Its  heart  hypertrophies  to  keep  up  the  pumping  of 
blood  through  the  enormous  mass  of  new  tissue.  Its  liver  and  sometimes 
its  kidneys  enlarge.  Price  Jones  found  no  great  modification  in  the  differ- 
ential count  of  the  bone-marrow  of  these  animals,  but  states  that  there  was 
great  enlargement  of  the  spleen.  Studies  of  the  vascular  supply  of  tumors 
by  methods  of  injection  show  that  great  numbers  of  blood-vessels  run 
to  the  rapidly  growing  tumor — numbers  far  in  excess  of  those  which  supply 
normal  tissues.  These  are  new  formed  at  the  demand  of  the  growing  tumor, 
and  carry  with  them  the  supporting  stroma  of  connective  tissue.  Bash- 
ford  and  his  co-workers  make  much  of  the  importance  of  the  stroma,  which 
they  think  is  specifically  adapted  to  each  type  of  tumor.  It  is  their  belief 
that  it  is  only  in  animals  which  respond  by  the  production  of  an  adequate 
stroma  and  blood  supply  that  an  implanted  tumor  can*  succeed  in  growing. 
Others  lay  much  less  stress  upon  the  importance  of  the  stroma. 

When  a  tumor  is  implanted  in  a  susceptible  animal,  its  stroma  and  part 
of  its  specific  cells  undergo  necrosis,  but  the  surviving  tumor-cells  grow  and 
are  quickly  invaded  by  a  new  stroma  formed  from  the  host,  with  new  blood- 
vessels. It  seems  clear  that  the  tumor-cells  act  as  a  dominant  tissue,  con- 
trolling and  stirring  up  the  development  of  the  vascular  strorna,  practically 
as  epithelial  cells  do  in  the  development  of  an  organ  in  the  embryo.  Sub- 
servient as  this  stroma  is,  it  does  not  always  remain  so.  Ehrlich  and  others 
have  found  that,  after  a  time,  when  a  carcinoma  has  been  implanted,  the 
stroma  itself  may  assume  the  characters  of  tumor  tissue,  and  grow  vigor- 
ously as  a  sarcoma,  oppressing  and  finally  destroying  the  epithelial  cells. 
Such  a  tumor,  when  transplanted,  may  continue  its  growth  as  a  sarcoma, 
extorting  now  the  new  formation  of  another  vascular  stroma  from  its 
host. 

Still,  nothing  has  been  observed  as  to  the  ingrowth  of  nerves  into  such  a 
tumor,  although  this  would  seem  to  be  a  matter  of  the  utmost  importance. 
Little  is  written  of  the  formation  of  lymphatic  channels,  although  we  know 
by  injection  experiments  (Evans)  that  lymphatics  are  present  in  abundance 
in  human  tumors  of  many  sorts. 

Atypical  Character  of  Tumor-cells-Adaptation.— All  the  tumor-cells  are 
atypical  in  the  ways  mentioned.  They  are  characterized  not  only  by  their 
powers  of  growth,  but  especially  by  their  tendency  to  continue  indefinitely 
to  divide  and  produce  new  cells,  regardless  of  any  need  or  of  any  plan  for  the 
arrangement  of  these  new  cells  or  even  of  the  existence  of  any  space  in  which 
they  can  be  lodged,  and  these  new  cells  proceed  in  the  same  aimless  way  to 
produce  others.  That  they  are  specifically  related  to  animals  of  their  own 
species  is  shown  by  their  ability  to  grow  indefinitely,  in  contact  with  the 
tissues  of  that  species  only.  But  the  adaptation  can  be  intensified  by 
repeated  transplantation  into  animals  of  the  same  species,  for  at  first  it  is 
necessary  to  transplant  a  great  number  of  pieces  from  a  spontaneous 


FORM  OF  GROWTH,  EXTENSION;  IMPLANTATION;  METASTASIS  1099 

tumor  into  as  many  mice  in  order  to  obtain  one  successful  implantation. 
After  that,  however,  with  repeated  transplantations  the  tumor  acquires 
the  power  to  grow  in  practically  every  mouse.  This  does  not  necessarily 
mean  that  it  grows  more  rapidly,  or  more  destructively,  or  to  a  larger  size. 
It  is  merely  a  matter  of  adaptation  to  its  surroundings,  and  whether  we 
regard  the  cell  as  independently  originating  the  growth,  or  as  impelled  by 
some  parasite,  the  explanation  of  the  adaptation  must  be  the  same. 

FORM  OF  GROWTH,  EXTENSION;   IMPLANTATION;   METASTASIS 

The  form  of  the  growth  is,  as  we  have  learned,  extremely  variable,  and 
there  are  all  gradations  between  tumors  which  surround  themselves 
with  a  smooth  capsule  and  grow  expansively,  and  those  which  scatter 
their  isolated  cells  like  spray  in  every  direction,  or  send  out  long  threads 
of  cells  which  insinuate  themselves  between  the  cells  and  fibres  of  the 
tissues,  and  even  into  the  walls  of  blood-vessels  and  lymphatics.  The 
former  mode  of  growth  usually  appears  in  a  benign  tumor,  the  latter  in  a 
malignant  tumor.  These  two  forms  are  doubtless  in  large  part  the  ex- 
pression of  differences  in  the  rate  and  continuity  of  multiplication  of  the 
cells.  The  encapsulated  benign  form  is  far  less  exposed  to  the  action  of  the 
cells  and  fluids  of  the  organism  than  the  spreading  malignant  form.  Through 
this  very  fact  the  latter  seems  to  become  adapted  to  existence  anywhere  in 
the  body,  and  is  thereby  aided  in  spreading  and  even  in  establishing  colonies 
in  distant  organs. 

As  to  the  spread  or  extension,  we  have  already  described  several  forms. 

Implantations. — In  the  older  literature  there  were  many  descriptions 
of  instances  in  which  a  carcinoma  was  thought  to  be  transmitted  by  con- 
tact to  another  person.  Some  of  these  were  cases  in  which,  through 
intimate  contact,  as  in  the  transfer  of  a  genital  carcinoma  from  husband  to 
wife  or  the  reverse,  there  was  a  semblance  of  probability,  but  in  others, 
in  which,  for  example,  a  nurse  contracted  a  carcinoma  of  the  breast  from 
tending  a  patient  with  a  similar  carcinoma,  there  was  unquestionably  only  a 
coincidence.  Recent  reports  of  such  occurrences  are  rare.  There  are, 
however,  instances  of  implantation  of  a  tumor  upon  contiguous  epithelial 
surfaces  in  the  same  individual,  as,  for  example,  the  formation  of  a  car- 
cinoma of  the  vagina  opposite  the  ulcerated  surface  of  a  carcinoma  of  the 
cervix  uteri.  These,  too,  seem  questionable,  and  it  is  perhaps  more 
probable  that  such  tumors  are  really  due  to  transportation  by  way  of  the 
lymph-channels,  although  theoretically  there  is  no  reason  why  some  abra- 
sion of  the  opposite  mucous  surface  should  not  allow  the  implantation  of 
cancer-cells. 

Much  more  familiar  is  the  implantation  of  the  cells  of  a  tumor  in  the 
raw  edges  of  a  wound  made  for  the  extirpation  of  the  growth,  with  the 
development  of  nodules  in  the  resulting  scar.  Even  this  is  a  rather  un- 
common occurrence,  however.  Within  the  body,  the  implantation  of  free 
fragments  of  tumor  or  tumor-cells  is  frequently  seen  in  the  peritoneal 


1100  TEXT-BOOK   OF   PATHOLOGY 

cavity  and  other  serous  cavities.  It  is  especially  common  with  papil- 
lomatous  cystadenomata  of  the  ovary  and  with  colloid  carcinomata,  but 
it  occurs  also  with  various  other  tumors.  Whether  the  nodules  so  often 
found  on  the  surface  of  the  lungs  as  growths  secondary  to  a  carcinoma,  or 
sarcoma  situated  elsewhere  are  produced  by  implantation  from  the  pleural 
cavity  or  by  extension  from  the  substance  of  the  lung  is  rather  difficult  to 
tell.  They  occur  as  large,  button-like  nodules,  or  as  smaller  masses  like 
beads,  or  even  as  tiny,  flattened,  confluent,  or  discrete  thickenings  of  the 
pleura,  and  in  every  case  they  are  continuous  with  growths  of  tumor-cells 
in  the  underlying  lymph-channels.  Sometimes  these  extend  in  the  inter- 
lobular  spaces  or  in  the  walls  of  blood-vessels  or  bronchi  quite  through  the 
lung  to  the  hilum,  where  the  lymph-glands  are  generally  involved.  Thus 
it  is  possible  that  the  tumor  may  have  grown  from  the  hilum  or  any  part 
of  the  lung  through  the  lymphatics  to  the  surface,  spreading  out  and 
developing  there,  and,  indeed,  in  the  absence  of  a  tumor  mass  invading 
the  pleural  cavity  this  seems  the  more  probable  course.  In  other  cases  in 
which  a  tumor  of  the  stomach  or  gall-bladder  has  distributed  metastases 
on  the  under  side  of  the  diaphragm,  the  course  of  its  extension  to  the  pleural 
cavity  and  the  surface  of  the  lungs  can  be  readily  traced  through  the  dia- 
phragmatic lymphatics. 

Extension. — The  actual  extension  of  an  invasive  tumor  occurs,  as  we 
have  seen,  through  the  growth  of  strands  of  tumor-cells  into  the  interstices 
of  the  surrounding  tissue.  These  cells  may  become  really  isolated,  but,  as 
a  rule,  the  strands  or  threads  of  cells  maintain  their  continuity  for  a  long 
time.  With  the  widening  of  the  strands  the  peripheral  parts  of  the  tumor 
become  more  condensed  and  the  intervening  normal  tissue  is  destroyed. 
Frequently  the  advancing  margin  is  much  more  compact,  and  the  normal 
tissue  is  largely  pushed  aside  and  compressed,  so  that  the  tumor  grows  by 
the  invasion  of  coarse  projecting  masses.  In  many  instances  these,  as  well 
as  the  finer  strands,  are  guided  by  meeting  with  a  dense  fascia  or  other 
resistant  tissue,  and  spread  along  its  surface. 

Far  more  commonly,  however,  the  cells  break  through  the  walls  of 
lymphatic  channels  and  spread  themselves  like  an  injection  mass  along 
their  lumina  so  as  to  fill  them  completely.  This  is  particularly  character- 
istic of  the  carcinomata,  and  has  been  studied  carefully  for  such  cancers  as 
are  of  common  occurrence  (breast,  uterus,  etc.).  Handley  finds  that  the 
extension  in  carcinoma  of  the  breast  is  through  the  plexus  of  lymphatic 
channels  which  accompany  the  fasciae,  and  that  these  may  become  obliter- 
ated after  the  tumor  has  moved  along  their  course.  Thus  in  a  wide  halo 
around  the  tumor  there  are  lymph-channels  full  of  tumor-cells  ready  to 
grow  into  nodules  or  to  wander  farther,  although  the  obliterated  channels 
by  which  they  reached  that  point  are  no  longer  visible.  That  this  net- 
work of  lymphatics  in  the  deeper  part  of  the  skin  and  in  the  fasciae  may  act 
in  this  way  is  shown  by  the  numerous  small  tumor  nodules  which  often 
appear  in  these  regions,  quite  far  from  the  original  tumor.  Handley, 


FORM  OF  GROWTH,  EXTENSION;  IMPLANTATION;  METASTASIS      1101 

therefore,  suggests  that  an  extremely  wide  area  of  skin  should  be  removed 
in  order  to  extirpate  the  tumor  completely. 

Metastasis. — Even  more  familiar  and  common  is  the  transportation  of 
loose  clumps  of  tumor-cells,  or  even  single  cells,  by  the  stream  of  lymphatic 
fluid  along  the  course  of  the  channel  until  they  are  caught  and  held  in  the 
complex  sinuses  of  a  lymph-gland.  Since  the  distribution  of  the  lymphatics 
is  well  known,  one  may  foretell  easily  which  gland  is  likely  to  receive  the 
first  emboli  of  this  nature.  There  the  tumor-cells  develop  into  a  new  tumor 
which  gradually  invades  and  replaces  the  tissue  of  the  lymph-gland.  Other 
emboli  of  the  cells  may  pass  to  more  distant  lymph-glands,  or  the  process 
may  be  repeated  with  the  metastatic  nodule  as  the  source  for  new  emboli. 
If  such  floating  cells  reach  the  thoracic  duct,  they  may  lodge  in  its  walls 
and  there  grow,  but  they  are  far  more  likely  to  be  swept  on  into  the  blood- 
stream, whence  they  are  caught  up  in  the  capillaries  of  the  lungs. 

While  such  metastasis  by  way  of  the  lymphatic  channels  is  very  common 
for  carcinomata,  it  is  somewhat  less  common  for  sarcomata  and  some  other 
malignant  tumors.  These  tend  to  grow  in  such  a  way  as  to  penetrate  the 
walls  of  the  veins  and  discharge  themselves  directly  into  the  blood-stream. 
Carcinomata  do  this  also  and  it  is  by  no  means  uncommon  to  find  meta- 
static nodules  which  could  be  explained  in  no  other  way  than  by  a  trans- 
portation of  the  carcinoma  cells  by  way  of  the  blood.  The  invasion  of 
sarcomata  is  frequently  a  very  gross  process,  so  that  great  masses  of  the 
tumor  hang  in  the  vein,  or  fill  it  completely.  This  is  especially  true  of  the 
hypernephromata,  and  we  have  already  described  a  case  in  which  the 
whole  vena  cava  was  filled  wTith  a  tumor  mass.  The  carcinomata  primary 
in  the  liver  exhibit  the  same  tendency. 

The  transportation  of  liberated  cells  proceeds,  of  course,  with  the 
stream  of  blood,  and  we  should  expect  to  find  them  lodged,  first  of  all,  in 
the  lungs.  That  this  is  commonly  the  case  is  shown  by  the  development  of 
numerous  tumor  nodules  in  the  lung  tissue,  but  it  is  quite  common  to  find 
metastases  only  in  the  liver,  or  in  some  other  organ  in  the  systemic  circula- 
tion. Of  course,  if  the  primary  tumor  is  situated  in  the  intestinal  tract,  it 
is  easy  to  comprehend  that  the  tumor-cells  carried  by  the  portal  blood 
should  lodge  and  grow  in  the  liver,  but  in  other  cases  we  must  assume  that 
the  floating  cells  have  passed  through  the  wide  capillaries  of  the  lung  to 
reach  the  other  organs,  unless  there  are  also  large  metastases  in  the  lungs 
themselves  from  which  a  secondary  embolism  might  occur. 

Distribution  of  Metastases. — Numerous  curious  distributions  of  metas- 
tases occur,  as  when  a  neuroblastoma  beginning  in  the  adrenal  gives  rise 
to  multiple  secondary  growths  which  are  confined  to  the  liver,  or  when  a 
carcinoma  of  the  prostate  establishes  practically  all  its  secondary  growths 
in  the  marrow  of  the  bones.  Virchow  made  the  statement  that  in  those 
organs  in  which  tumors  are  commonly  primary,  metastases  rarely  occur, 
while  primary  growths  are  rare  in  those  situations  which  seem  to  form  the 
best  soil  for  secondary  nodules.  Thus  the  stomach  and  uterus  are  common 


1102  TEXT-BOOK   OF   PATHOLOGY 

sources  of  primary  tumors,  but  rarely  the  seat  of  metastases,  while  the 
reverse  is  true  of  the  liver.  Although  this  cannot  be  said  to  be  universally 
true,  it  introduces  the  suggestion  that  certain  tissues  form  an  especially 
suitable  ground  upon  which  the  tumor-cells  may  take  root  and  thrive, 
and,  further,  that  this  is  not  the  same  for  all  types  of  tumors.  Indeed,  there 
are  many  tissues,  such  as  the  pancreas,  thyroid,  heart-wall,  muscle,  etc., 
which  seem  especially  unsuited  to  support  the  growth  of  the  tumor-cells, 
although  these  tissues  must  receive  many  emboli.  There  is  no  difficulty 
in  accepting  the  idea  that  the  tumor-cells  may  slip  through  the  capillaries 
of  the  lungs,  for  in  many  cases  they  are  not  much  larger  than  the  blood- 
cells  and  ought  to  pass  readily.  It  should  be  realized,  however,  that 
many  emboli  must  pass  into  the  organs  and  even  into  those  most  favorable 
to  their  growth,  without  ever  developing  into  tumor-nodules.  Instead,  as 
M.  B.  Schmidt  has  shown,  they  are  surrounded  by  minute  thrombi  and 
later  destroyed. 

The  secondary  growth  may  far  outstrip  in  size  the  primary  tumor: 
As  a  rule,  it  reproduces  the  histological  structure  of  the  primary  nodule 
with  considerable  fidelity,  so  that  one  may  often  form  an  idea  of  the  posi- 
tion of  that  tumor  by  examining  the  secondary  growth.  Nevertheless,  as 
Hansemann  points  out,  the  metastasis  tends  to  diverge  further  from  the 
normal  architecture  than  did  the  primary  growth.  A  tertiary  nodule, 
derived  by  metastasis  from  the  secondary  one,  might  show  an  even  greater 
departure  from  the  normal.  Hansemann  describes  this  as  an  increase  in 
anaplasia,  by  which  he  means  a  peculiar  divergence  from  the  normal  mor- 
phology and  functional  nature  which  is  characteristic  of  tumor-cells  and 
which  is  often  associated  with  irregularities  in  the  process  of  mitosis. 

Nature  of  Metastasis. — The  phenomena  of  metastatic  growth  show  that 
the  formation  of  a  tumor  in  a  distant  organ  depends  upon  the  transporta- 
tion of  the  cells  of  the  original  tumor  to  a  new  site,  and  the  secondary  nodule 
is  seen  to  develop  from  these  cells,  and  to  reproduce  the  type  of  tissue  which 
makes  up  the  original  growth.  This  is  a  totally  different  process  from  the 
metastasis  which  occurs  in  infections,  in  which  we  can  recognize  the  causa- 
tive agent,  since  there  the  infective  agent  alone  is  transported,  and  any 
nodule  of  new  tissue  which  it  may  produce  in  the  new  situation  is  seen  to 
be  derived  entirely  from  the  tissue  of  the  organ  in  which  it  lodges.  It  is 
the  result  of  the  reaction  of  those  tissues  to  injury,  and  proceeds  according 
to  the  well-known  laws  which  govern  the  behavior  of  normal  tissues  when 
they  act  in  unison  to  combat  an  injury.  In  the  tumor-nodule  one  tissue 
opposes  another — the  local  tissue  antagonizes  the  immigrant  tissue.  If  we 
assume  that  a  parasite  is  the  cause  of  the  growth  of  tumor-cells,  we  have  no 
evidence  that  it  can  exist  without  them,  for  we  never  find  secondary  tumors 
derived  from  the  tissues  of  the  organs  in  which  they  form.  Since  such 
hypothetical  parasites  must  be  so  closely  dependent  upon  the  cells  originally 
affected  as  to  be  practically  an  inseparable  constituent  of  them,  it  is  quite 


CONTRIBUTORY  CAUSES  OF  TUMOR  GROWTH        1103 

as  easy  to  assume  that  the  cells  themselves  take  the  initiative  in  the 
abnormal  process. 

Recurrences. — Tumors  removed  at  operation  may  recur  in  the  same 
place,  or  in  the  neighborhood,  and  from  this  it  must  be  assumed  that,  in  the 
field  of  operation,  particles  or  cells  have  been  left  in  the  tissues  which  may 
grow  again  after  the  wound  has  progressed  toward  healing.  This  may  be 
because  the  excision  was  not  extensive  enough  to  include  in  the  extirpation 
all  the  prolongations  of  the  tumor,  or  because,  in  the  course  of  the  manipu- 
lations, loose  cells  were  strewn  in  the  exposed  wound  surface.  Regional 
recurrences  which  appear  in  the  skin  or  deeper  tissues  at  a  little  distance 
from  the  site  of  the  original  tumor  are  explained  as  growths  from  those 
lymphatics  filled  with  tumor-cells  which  have  been  shown  to  radiate  from 
the  original  growth. 

CONTRIBUTORY  CAUSES  OF  TUMOR  GROWTH 

It  may  be  said  in  advance  that  nothing  is  known  of  the  actual  cause  of 
tumor  growth.  Nevertheless,  there  are  several  things  which  must  be 
seriously  considered  as  bearing  some  relation  to  the  development  of  tumors, 
since  they  have  long  been  known  to  be  intimately  associated  with  the  begin- 
ning of  their  growth,  and  have  been  regarded  as  predisposing  or  con- 
tributory causes.  These  are  as  follows:  injury  or  irritation  of  physical  or 
chemical  nature  with  chronic  inflammation;  the  effect  of  disturbances  of 
internal  secretions;  malformations  and  displacements  of  tissue,  and  such 
general  predisposing  conditions  as  senility  and  inherited  tendencies. 

As  causes  of  irritation,  numerous  parasites  of  all  kinds  have  been 
described,  but  in  no  case  has  a  definite  causal  relation  been  proven. 

Injuries  and  Irritation. — Single  severe  injuries,  such  as  blows  or  fractures, 
have  frequently  been  followed  by  the  development  of  a  sarcomatous  tumor, 
although  rarely  by  a  carcinoma.  Thousands  of  such  injuries  have  no  such 
result,  however,  and  it  may  well  be  questioned  whether  the  connection 
is  not  an  accidental  one.  Injuries  which  produce  scars  have  sometimes 
resulted  in  a  very  striking  way  in  the  formation  of  a  cancer  in  the  scar. 
Thus  a  girl  was  burnt  from  shoulder  to  hip  and  recovered  with  a  scar  cover- 
ing that  whole  area.  Years  later,  a  huge  carcinoma  appeared  occupying 
the  site  of  the  scar  (v.  Bergmann). 

Chronic  or  repeated  mechanical  irritation,  the  changes  produced  by  light, 
x-rays,  and  radium,  and  by  chemical  irritants  and  bacteria,  are  more 
generally  associated  with  the  development  of  carcinoma.  After  explaining 
that  they  lead  to  chronic  inflammatory  processes  and  scar  formation, 
which  forms  a  transition  between  trauma  and  tumor  formation,  Borst  sum- 
marizes the  well-known  examples  of  such  tumors  as  follows: 

Carcinoma  occurs  in  the  penis  in  cases  of  phimosis,  in  the  tongue  and 
cheek  in  association  with  the  irritation  of  a  carious  tooth,  in  the  mammary 
gland  from  pressure  of  a  corset.  There  are  the  lip  cancer  of  pipe-smokers, 
cancers  of  the  gall-bladder,  renal  pelvis,  and  urinary  bladder  in  connec- 


1104  TEXT-BOOK   OF   PATHOLOGY 

tion  with  stone  formation,  the  cancers  of  the  ostia  of  the  body  and  the 
normally  narrow  passages  in  the  digestive  tract,  the  occupational  cancers, 
paraffin,  tar,  and  chimneysweep's  cancers,  cancer  of  the  bladder  and  kidney 
in  aniline  workers,  pulmonary  cancer  of  metal  workers,  workers  in  spinning 
mills  and  cigar  factories,  the  carcinoma  on  the  basis  of  chronic  eczema 
(Paget's,  Darier's  diseases),  on  the  basis  of  ulcerations  (ulcer  of  leg,  ulcer  of 
stomach),  carcinoma  developing  in  fistulse  and  scars,  carcinoma  following 
chronic  endometritis, /cystitis,  chronic  syphilis,  and  tuberculosis  of  the  skin, 
cirrhosis  of  the  liver,  chronic  nephritis,  and  various  skin  diseases,  such  as 
leucoplakia,  hyperkeratoses,  polyps,  and  condylomata. 

In  this  heterogeneous  collection  the  common  principle  appears  to  be  the 
long-standing  irritation  which  brings  about  inflammatory  reaction,  destruc- 
tion and  replacement  of  tissue,  with  distortion  and  disarrangement  of 
cells.  Nevertheless,  since  there  are  many  more  cases  in  which  the  same 
irritations  never  result  in  cancer  formation,  no  one  believes  that  they  are 
an  efficient  cause  of  its  development.  No  one  has  ever  succeeded  in  pro- 
ducing a  cancer  experimentally  by  subjecting  animals  to  such  influences 
so  that  there  must  be  another  main  cause  which  remains  hidden. 

B.  Fischer  found  that  the  injection  into  the  skin  of  Scharlach  R  or  Sudan 
III,  dissolved  in  oil,  would,  if  the  solution  were  injected  with  force,  result 
in  the  production  of  an  extraordinary  tumor-like  growth  of  epithelium. 
Others  have  confirmed  this,  and  Helmholz  was  able  to  produce  in  this  way 
a  tumor  composed  of  cartilage.  With  the  absorption  of  the  stain  and 
the  oil  these  growths  gradually  recede  and  disappear.  They  never  form 
metastases. 

Certain  aniline  bases  had  a  similar  but  much  less  marked  effect,  and  a  4 
per  cent,  solution  of  ether  in  water  was  found  by  others  to  accelerate 
greatly  and  intensify  the  growth  of  tissues.  Askanazy  found  that  implanted 
embryonic  tissue,  if  first  treated  with  ether  water,  would  grow  into  a  large 
teratoma,  more  bulky  than  those  which  grew  without  this  treatment. 
Loeb  and  others  have  pointed  out  that  these  are  all  lipoid  solvents,  and 
that  their  effect  is  in  some  way  related  to  the  existence  of  a  lipoid  capsule 
about  each  cell. 

Yamagiwa  and  Ichikawa  have  found  it  possible  to  produce  abundant 
nodular  growths  of  epithelium  on  the  skin  of  rabbits  by  rubbing  in  crude 
tar  for  a  long  time.  These  growths  have  all  the  appearances  of  epitheli- 
omata  and,  indeed,  metastasize  into  the  regional  lymph-glands.  Never- 
theless in  many  if  not  in  most  cases  they  tend  to  undergo  retrogression, 
and  are  healed  by  scar  formation  and  new  growth  of  epithelium  over  the 
ulcer  left  by  their  necrosis  and  disintegration. 

It  has  already  been  stated  that  carcinomata  have  been  found  to  develop 
in  the  scars  and  eczematous  areas  produced  by  the  action  of  z-rays  and 
radium.  No  good  explanation  is  offered  for  this,  but  it  seems  that  this  is 
the  one  method  by  which  it  might  be  attempted  to  produce  malignant 
tumors  by  experimental  means  with  some  chance  of  success. 


CONTRIBUTORY  CAUSES  OF  TUMOR  GROWTH        1105 

The  part  played  by  parasites  has  been  studied  at  enormous  length,  and 
every  conceivable  sort  of  parasite  has  been  described,  both  such  as  resemble 
known  organisms  and  such  as  have  no  resemblance  to  any  recognized 
living  thing.  Bacteria  of  several  sorts  have  been  incriminated,  and  the 
Micrococcus  neoformans  of  Doyen  is  perhaps  the  one  most  widely  known. 
Erwin  Smith's  researches  on  the  crown  gall  of  various  plants  show  that 
these  tumor-like  growths  are  independent  of  the  ordinary  laws  of  growth 
and  atypical  in  the  arrangement  and  form  of  the  cells.  They  are  the  result 
of  infection  with  the  Bacillus  tumefaciens,  and  can  be  produced  at  will 
by  inoculation  of  this  organism.  He  claims  no  relation  between  the  or- 
ganism and  tumors  of  animals  or  man,  but  suggests  that  there  are  certain 
analogies  in  the  methods  or  mechanisms  of  tumor  production  in  plants  and 
animals.  Blastomyces  and  yeasts  have  been  cultivated  from  many  tumors, 
and  have  been  inoculated  into  animals  with  various  results,  sometimes  pro- 
ducing tumor-like  nodules.  But  none  of  these  has  stood  before  the  ordinary 
tests  which  are  applied  to  the  recognition  of  the  causal  relation  of  bacteria  in 
infectious  diseases.  Borrel  has  tried  to  show  the  intimate  relationship 
between  certain  acarians,  including  the  Demodex  folliculorum,  and  epi- 
thelial tumor  growth,  and  has  insisted  that,  even  though  they  may  have  no 
power  in  themselves  to  cause  the  growth  of  the  tumor,  they  may  transfer 
the  unknown  virus  from  one  animal  to  another.  The  number  of  spon- 
taneous tumors  in  mice  kept  in  cages  infected  with  these  mites  is  very  strik- 
ing. Somewhat  similar  is  the  observation  of  Fibiger,  who  found  that 
a  type  of  flat-cell  epithelioma  of  the  stomach  and  oesophagus  occurs  in 
rats  in  which  a  peculiar  nematode  worm,  a  species  of  spiroptera  which 
passes  its  larval  stage  in  the  cockroach,  is  found  embedded  among  the  cells 
of  the  tumor.  Such  tumors  could  be  produced  in  normal  rats  by  feeding 
with  cockroaches  containing  the  larvae.  Metastases  are  found  in  distant 
organs  in  which  no  nematodes  or  their  eggs  are  discoverable.  Fibiger 
thinks  that  the  tumor  is  produced  by  the  irritating  action  of  some  poison 
formed  by  the  nematode,  and  states  that  this  is  the  first  instance  of  the 
experimental  production  of  a  metastasing  tumor. 

Analogous  to  this  are  the  numerous  observations  of  the  development  of 
carcinomata  in  the  bladder-wall  in  Bilharzia  infection,  in  the  liver  in  infec- 
tion with  other  trematodes  (Opisthorchis,  Distomum  Japonicum,  etc.), 
and  in  the  neighborhood  of  cysticerci  from  tsenise  in  various  situations. 
Most  interesting  in  this  and  other  connections  are  the  studies  of  Rous,  who 
discovered  a  peculiar  tumor  of  a  hen  which  he  was  able  to  transplant  to 
other  hens  of  the  same  breed.  'The  tumor  in  the  course  of  repeated  trans- 
plantation acquired  an  astounding  power  of  growth  and  adaptation  and 
could  be  successfully  inoculated  by  the  mere  introduction  into  tissues  of  a 
needle  which  had  been  plunged  into  the  growth.  It  was,  then,  possible 
to  transplant  it  to  fowl  of  other  breeds.  The  tumor  has  the  form  of  a 
sarcoma  with  long,  spindle-shaped,  and  branched  cells,  and  produces  huge 
tumor  masses  in  the  connective  tissues  of  the  fowl.  Most  significant,  how- 


1106  TEXT-BOOK   OF   PATHOLOGY 

ever,  is  the  fact  that  this  tumor  can  be  successfully  transmitted  by  the 
inoculation  of  dried  and  powdered  material,  or  even  by  the  injection,  into 
the  tissues,  of  a  clear,  cell-free  fluid,  obtained  by  filtering  a  suspension 
through  a  Berkefeld  filter.  Naturally,  there  has  been  much  difference  of 
opinion  as  to  whether  this  is  a  true  tumor  or  the  reaction  of  connective 
tissue  to  some  extraordinary  infection.  The  fact  that  it  may  be  trans- 
mitted by  a  cell-free  filtrate  seems  to  indicate  that  it  is  caused  by  an  ex- 
tremely minute  living  organism. 

Effects  of  Internal  Secretions  in  Relation  to  Tissue  and  Tumor  Growth. — 
There  are  many  examples  of  the  extraordinary  growths  of  tissues  which 
appear  to  be  associated  with  activity  of  the  organs  of  internal  secretion, 
and  most  of  these  have  been  mentioned  elsewhere.  The  growth  of  the 
breasts  during  pregnancy,  of  the  antlers  of  the  deer  during  the  season  of  rut, 
of  various  transitory  tissue  masses  in  frogs  and  salamanders,  and  fishes 
during  the  analogous  period,  are  instances  in  point.  The  theory  of  Fraenkel 
and  Born,  which  is  to  the  effect  that  the  secretion  of  the  corpus  luteum  is 
necessary  to  the  proper  progress  of  pregnancy,  may  throw  some  light 
on  the  development  of  malignant  growths  from  the  chorionic  epithelium, 
since  masses  of  persistent  corpus  luteum  tissue  are  found  in  the  enlarged 
ovaries  in  many  of  those  cases.  L.  Loeb  has  even  suggested  that  the 
internal  secretion  of  the  ovary  or  some  of  its  derivatives  has  an  influence 
upon  the  growth  of  mammary  cancer,  for  mice  castrated  at  an  early  age 
were  found  to  develop  cancer  in  far  fewer  cases  than  those  not  castrated. 

Malformations. — The  relation  of  tumor  growth  to  malformation  has 
already  been  discussed  in  describing  teratomata,  and  will  be  referred  to 
again  in  connection  with  theories  of  the  causation  of  tumors.  It  is  of 
interest  here,  as  an  example  of  the  ^contributory  causes  of  tumor  growth,  to 
recall  the  fact  that  malignant  tumors  frequently  develop  from  one  tissue 
of  a  teratomatous  growth  and  metastasize  alone,  although  in  the  absence 
of  this  specific  change  such  teratomata  are  benign.  The  mere  displace- 
ment and  subsequent  development  of  embryonic  tissue  does  not  lead  to 
true  tumor  growth. 

Disposition;  Senility;  Heredity. — We  have  some  vague  information  with 
regard  to  these  predisposing  causes  of  tumor  growth,  but  it  is  unsatisfactory. 
That  there  may  be  a  constitutional  tendency  to  the  development  of  a  tumor 
may  easily  be  said,  but  it  is,  after  all,  a  matter  about  which  only  a  general 
impression  can  be  gained.  Hereditary  transmission  of  tumor  growth  or 
rather  of  susceptibility  to  tumor  growth  should  be  accessible  to  more 
exact  investigation.  Bashford,  in  analyzing  English  statistics,  concludes 
that  there  is  no  evidence  whatever  to  show  the  existence  of  any  such  heredi- 
tary taint,  and  states  that  in  his  thousands  of  experimental  animals  there 
has  been  nothing  to  show  that  it  occurs.  Even  when  carcinoma  animals  were 
intentionally  inbred,  so  as  to  increase  the  chance  of  inheritance,  no  larger 
number  of  spontaneous  tumors  was  found  than  occurred  in  normal  ;mice. 
Murray  shows,  however,  in  a  later  paper  from  Bashf  ord's  laboratory,  that  the 
incidence  of  spontaneous  cancer  is  much  higher  in  mice,  whose  immediate 


RESISTANCE   AND   IMMUNITY  1107 

ancestors  developed  cancer,  than  in  those  in  whose  pedigree  only  remote 
ancestors  were  cancerous.  Tyzzer  found  that  the  susceptibility  of  a  parent 
mouse  to  inoculation  with  a  certain  tumor  may  be  transmitted  to  its  off- 
spring even  though  the  other  parent  be  insusceptible,  and  Maud  Slye, 
from  a  large  experience  with  mice,  states  that  spontaneous  tumors  occur  in 
the  offspring  of  those  which  have  had  tumors,  in  accordance  with  Mendel's 
law.  In  her  more  recent  experiments  she  has  been  able  to  mate  animals, 
on  the  basis  of  her  knowledge  of  this  Mendelian  heredity,  in  such  a  way  as 
to  bring  about  the  appearance  of  tumors  in  the  offspring,  and  even  to  plan 
for  the  development  of  a  known  type  of  tumor  in  a  particular  organ  or 
location.  Much  remains  to  be  learned  in  this  matter. 

Morgan  and  his  students  have  done  something  similar  in  flies,  in  which 
both  malignant  lethal  and  benign  tumors  develop.  Their  work  has  been 
especially  concerned  with  the  recognition  of  the  particular  chromosome 
with  which  this  hereditary  growth  is  associated.  These  studies  appear  to 
offer  a  whole  new  conception  of  the  nature  of  tumor  growths,  but  it  is 
scarcely  yet  possible  to  interpret  them  with  certainty. 

The  incidence  as  affected  by  age  is  more  clearly  recorded.  It  is  a  matter 
of  general  experience  that  carcinomata  tend  to  appear  in  persons  who  have 
reached  or  passed  middle  age  and  are  rare  in  young  people.  On  the  con- 
trary, many  sarcomata  and  those  mixed  tumors  which  sometimes  occur 
congenitally,  are  more  frequent  in  young  people.  It  is  possible  that  some 
of  the  contributory  causes  which  favor  tumor  growth  are  really  necessary 
in  the  case  of  cancerous  tumors,  for  it  is  known  that,  while  cancers  originate 
in  old  persons  and  old  animals  which  have  long  been  exposed  to  those 
influences,  young  mice  are  far  more  susceptible  than  old  ones  to  the  artificial 
implantation  of  these  tumors. 

LITERATURE 
Yamagiwa  and  Ichikawa:  Mitth.  d.  med.  Fakultat  d.  k.  Univ.  zu  Tokyo,  1915,  xv,  295; 

1917,  xvii,  19.    Japan.  Ztschr.  f.  Krebsforschung,  1916,  x,  Heft  4;  1917,  xi,  Heft  2. 
Erwin  Smith:  Jour,  of  Cancer  Research,  1916,  i,  231.     Jour.  Agricult.  Research,  1917, 

viii,  165. 
T.  H.  Morgan  and  others:  Jour.  Cancer  Res.,  July,  1918;  Jour.  Exp.  Zool.,  Feb.,  1919; 

Proc.  Nat.  Acad.  of  Sciences,  1919,  v,  573. 


RESISTANCE  AND  IMMUNITY 

Only  the  briefest  outline  of  this  subject  can  be  given  here,  although  an 
enormous  amount  of  labor  has  been  devoted  to  it  in  recent  years. 

Undoubtedly,  many  persons  are  highly  resistant  or  incapable  of  harbor- 
ing certain  forms  of  tumor  growth,  although  they  may  be  susceptible  enough 
to  the  growth  and  extension  of  another  form.  We  have  no  way  of  deter- 
mining this  accurately,  but  we  do  know  that  when  a  tumor  is  already 
established  in  the  body  and  is  discharging  into  the  circulation  many  emboli 
of  its  cells,  most  of  these  may  be  destroyed  by  the  activities  of  the  tissue 
fluids.  Much  light  has  been  shed  upon  the  question  by  the  experimental 


1108  TEXT-BOOK   OF    PATHOLOGY 

study  of  tumors  in  animals.  In  mice,  for  example,  malignant  tumors  which 
are  transplanted  from  spontaneously  developed  nodules  to  normal  mice 
fail  to  take  at  first,  except  in  a  very  small  percentage  of  the  experiments. 
Later,  with  increasing  adaptation  to  the  conditions  met  with  in  the  body 
of  the  mouse,  the  tumors,  after  repeated  transplantation,  acquire  the 
power  of  growing  in  nearly  every  inoculated  mouse.  Nevertheless,  there 
are  some  mice  which  show  themselves  refractory  to  the  best  adapted 
tumors.  This  is  a  natural  immunity.  If  a  mouse  recovers  spontaneously 
by  destroying  the  tumor  growth  already  begun  in  its  tissues,  or  even  if  the 
tumor  is  completely  extirpated  after  growing  for  a  time  there,  it  becomes 
immune  and  cannot  be  again  inoculated  successfully  with  that  tumor. 
It  is  even  immune  with  respect  to  other  tumors,  and  Ehrlich  has  named 
this  condition  panimmunity.  In  this  respect  immunity  from  experimental 
tumors  differs  from  the  more  specific  immunity  against  infections.  Even 
the  inoculation  of  tissue  or  blood  from  another  normal  animal  of  the  same 
species  will  confer  an  immunity  from  tumor  inoculation.  In  all  cases  the 
immunity  is  dependent  upon  the  inoculation  of  living  cells,  whether  they 
be  tumor-cells  or  those  of  the  normal  tissue.  Ehrlich  has  offered  an 
explanation  of  immunity  which  rests  on  the  idea  that  a  tumor  requires  for 
its  growth  a  certain  specific  substance.  He  found  that,  by  inoculation  of  a 
rapidly  growing  tumor,  he  could  render  impossible  the  growth  of  a  second 
tumor,  and,  thinking  that  the  first  tumor  had  used  up  all  this  specific 
food  substance,  called  this  condition  athrepsia.  There  have  been  many 
attacks  on  the  validity  of  this  theory,  and  it  is  not  yet  decided  whether  it 
will  hold,  since  many  investigators  have  found  it  possible  to  implant  a 
second  tumor  in  an  animal  already  bearing  one.  The  well-known  zigzag 
transplantation  from  mouse  to  rat  and  back  formed  the  strongest  element 
of  Ehrlich's  proof.  A  mouse  tumor  implanted  in  a  rat  grows  for  a  few 
days,  but  then  regresses  and  dies,  unless  it  be  retransplanted  into  a  mouse, 
where  it  once  more  thrives.  Ehrlich  thinks  that  the  tumor  must  have 
lacked  a  particular  food-stuff  in  the  rat,  necessary  for  its  growth. 

These  principles  have  not  been  applied  to  any  great  extent  to  the  study 
of  human  tumors,  and  little  is  known  of  the  conditions  of  immunity  in  the 
human  body. 

Histological  Character  of  the  Immunity  Reactions.— Several  writers, 
among  whom  da  Fano  may  be  mentioned,  have  studied  the  histological 
reaction  to  the  invasion  of  tumors  and  have  found  that  lymphocytes  and 
plasma  cells  are  especially  concerned  in  this  reaction.  Murphy  and  his 
associates  have  found,  quite  recently,  that  the  susceptibility  to  tumor  im- 
plantation is  enormously  increased  by  the  destruction  of  the  lymphocytes 
by  exposure  to  the  z-ray  or  by  the  administration  of  benzol.  They  look 
upon  the  accumulation  of  lymphocytes  about  a  tumor,  for  this  reason,  as 
a  protective  or  combative  reaction.  These  views  are  supported  by  others 
of  their  experiments  which  show  that  an  embryo  in  which  no  lymphocytes 
have  yet  appeared  is  extremely  susceptible  to  tumor  inoculation,  while  the 


THEORIES   AS    TO    THE    AETIOLOGY   OF   TUMORS  1109 

implantation  of  a  fragment  of  lymphoid  tissue  from  an  adult  into  the  body 
of  the  embryo  confers  upon  it  a  resistance  practically  equal  to  that  of  the 
adult. 

THEORIES  AS  TO  THE  ETIOLOGY  OF  TUMORS 

We  are  as  yet  quite  ignorant  of  the  actual  cause  of  tumor  growth.  It  is  a 
question  which  has  occupied  the  minds  of  pathologists  and  clinicians  for 
many  years,  and  theories  in  incredible  numbers  have  been  proposed.  Some 
of  these  theories,  put  forward  by  men  who  had  worked  very  intimately 
with  tumors,  have  survived  to  this  day,  but  it  is  rather  discouraging  to 
find  that  most  of  the  modern  theories  are  merely  fantastic  inventions  of  a 
philosophic  character,  proposed  by  men  who  do  not  seem  to  have  lived 
with  tumors,  nor  even  to  have  been  particularly  familiar  with  them.  They 
always  introduce  many  new  terms  and  a  new  classification  of  tumors,  with 
specially  constructed  Greek  names,  and  the  whole  merely  adds  to  the  con- 
fusion and  reminds  one  of  the  writings  of  the  scholastics  of  the  middle  ages. 
We  are  quite  ignorant  of  the  real  cause  of  tumor  growth,  and  therefore  the 
theories  may  all  be  wrong.  In  the  meanwhile,  until  the  real  cause  is  ascer- 
tained, we  may  learn  along  what  lines  these  attempts  at  explanation  have 
been  made. 

Theory  of  Parasitic  Origin  of  Tumors.— The  most  obvious  explanation 
would  lie  in  the  existence  of  a  living  organism,  continually  stirring  the  tis- 
sues to  grow,  but  in  that  case  it  would,  as  we  have  explained,  be  necessary 
for  the  parasite  to  associate  itself  indissolubly  with  the  cell,  and  accompany 
it  in  all  its  wanderings  and  divisions.  No  such  minute  organism  has  been 
found,  and  the  gross  parasites  which  have  been  described  seem  quite 
incapable  of  such  subtle  and  constant  relations,  for  it  is  not  a  reaction  of 
any  contiguous  tissue  that  they  provoke,  but  the  irresistible  growth  of  one 
sort  of  tissue,  which  wanders  into  new  situations  and  maintains  an  inde- 
pendent existence.  If  there  are  parasites,  we  must  be  prepared  to  find 
them  quite  different  from  any  which  we  now  know,  and  capable  of  produc- 
ing tissue  reactions  quite  at  variance  with  all  the  laws  of  normal  growth 
and  normal  reaction  to  injury.  They  must  be  so  included  in  the  growing 
cells  as  to  multiply  with  them  and  accompany  them  wherever  they  go, 
since  otherwise  it  seems  impossible  that  they  could  maintain  their  stimu- 
lating effect  upon  cells  which  had  been  transplanted  to  a  distant  organ. 
If  the  parasite  never  shows  itself  alone  or  through  its  effects  on  tissues  in 
general,  but  only  in  this  intimate  relation  with  its  own  tumor-cells,  it  must 
remain  difficult  to  distinguish  it  from  an  acquired  quality  of  the  tumor-cells 
themselves.  There  must  be  a  different  parasite  for  each  of  the  many  sorts 
of  tumors,  and  every  one  of  these  parasites  must  have  these  characters 
of  intimate  affinity  for  the  special  cells  which  it  chooses  to  stimulate.  It 
must  merge  its  ability  to  produce  antibodies  in  the  affected  animal  in  that 
of  the  cells,  since  that  immunity  seems  to  be  of  cytotoxic  character  and  not 
very  specific.  Lambert  has  shown  that  tumor-cells  will  grow  in  vitro  in  the 


1110  TEXT-BOOK   OF   PATHOLOGY 

plasma  of  an  animal  insusceptible  to  the  growth  of  that  tumor,  but  are 
injured  or  destroyed  by  the  plasma  of  an  animal  immunized  against  it. 
Since  a  cytotoxic  immunity  can  be  produced  against  the  implantation  of 
the  tumor  by  the  introduction  of  normal  tissues  of  an  animal  of  the  same 
species,  the  parasite  must  be  killed,  too,  and  must,  therefore,  have  acquired 
the  specific  character  of  the  cells.  It  really  seems  that  it  must  have  become 
identical  with  the  cell. 

Theories  of  Tumor  Growth  Based  on  the  Effect  of  Irritants. — Numerous 
instances  of  tumor  growth  following  upon  irritation  or  injury  with  inflam- 
matory reaction  have  been  mentioned,  and  there  has  long  been  a  desultory 
argument  tending  toward  the  emphasis  of  their  importance  as  causes  of 
tumor  growth.  Bashford  lays  stress  upon  the  direct  connection  which  is  so 
often  observed,  and  although  it  fails  in  most  cases,  it  is  very  striking  when 
it  does  occur.  Only  yesterday,  while  writing  somewhat  skeptically  of  this 
relation,  a  man  aged  seventy  showed  me  his  leg,  which  he  had  struck  against 
a  bath-tub  some  months  before,  producing  an  abrasion  which  had  failed  to 
heal.  He  had  no  suspicion  that  anything  had  happened  except  that  it  had 
not  healed,  but  covering  the  site  of  the  injury  there  was  actually  a  rough, 
flattened  tumor,  which  appeared  to  be  of  the  nature  of  a  basal-cell  car- 
cinoma. Most  of  these  tumors  appear  after  the  irritation  has  existed  a 
long  time  and  has  produced  extensive  inflammatory  infiltration  and  re- 
paratory  changes  in  the  underlying  connective  tissues,  as  well  as  in  the 
epithelium  itself.  No  one  has  succeeded  in  producing  them  experimentally, 
except  perhaps  by  the  use  of  x-rays  or  the  introduction  of  certain 
gross  parasites,  and  the  question  arises  as  to  whether  a  predisposition 
through  senile  changes  or  otherwise  may  not  be  necessary  for  their  initia- 
tion. 

The  idea  of  the  influence  of  irritants  recalls  to  our  attention  the  whole 
question  of  the  action  of  stimuli  upon  the  growth  of  tissue,  which  has  been 
so  long  discussed.  Many  investigators  accept  the  existence  of  direct  stim- 
uli to  growth,  and  bring  forward  numerous  instances  in  the  history  of  tuber- 
culosis, syphilis,  and  a  host  of  other  infectious  diseases  and  banal  injuries. 
Others  hold  that  the  tendency  to  grow  is  roused  only  indirectly  through 
functional  needs,  and  Weigert  has  claimed  that  new-growth  is  essentially 
a  reparatory  process,  attempting  to  make  up  for  tissue  which  has  been 
destroyed,  thereby  restoring  the  disturbed  equilibrium  of  the  tissues.  In 
ordinary  circumstances  it  is  usually  possible  to  explain  the  new  growth  of 
tissue  as  the  effect  of  reparatory  processes,  even  though  in  the  cases  of 
excessive  growth  it  often  appears  that  it  is  the  response  to  repeated 
injuries  which  may  affect  the  repairing  tissue  itself.  Nevertheless,  this 
explanation  is  complicated,  and  it  is  much  easier  to  assume  that  injuries 
or  irritants  may  directly  stimulate  the  tissues  to  grow.  In  any  case  the 
new  tissue  remains  subject  to  the  general  laws  which  govern  the  archi- 
tecture of  the  body,  and  tends  to  return  to  the  normal  relations  when  the 
irritation  ceases. 


THEORIES   AS   TO    THE   AETIOLOGY   OF   TUMORS  1111 

In  the  case  of  a  tumor,  a  new  element  is  introduced  by  the  failure  of  the 
tissue  to  evince  this  general  tendency  to  return  to  the  normal  relations  after 
the  irritation  has  ceased.  The  finality  of  its  departure  from  the  laws  of 
growth  is  as  though  a  train  suddenly  ran  off  the  track,  and  careered  through 
the  neighboring  streets  and  houses.  Even  though  we  accept  the  idea  that 
irritation  may  directly  stimulate  tissue  to  grow,  our  explanation  of  the 
history  of  a  tumor  must  really  begin  with  its  continuous  independent  and 
unlimited  growth,  which  might  be  initiated,  but  not  maintained  in  distant 
situations,  by  such  irritants  as  are  usually  discussed. 

Theories  of  Tumor  Growth  Depending  upon  Disturbance  of  the  Equi- 
librium of  Tissues. — So  firmly  established  is  the  evidence  of  mutual  support 
and  restraint  among  the  tissues,  that  many  writers  have  sought,  in  a  dis- 
turbance of  this  equilibrium,  the  explanation  of  the  unlimited  growth  of 
tumors.  Thiersch  thought  that,  with  senility,  the  energy  of  growth  of  the 
connective  tissue  failed,  so  that  the  epithelium  could  invade  it  and  grow 
at  will,  while  Waldeyer  offered  the  reverse  explanation,  stating  that  the 
failure  of  the  epithelium  to  maintain  its  ranks  enabled  the  connective 
tissue  to  surround  and  isolate  some  of  it,  which  then  grew  in  its  new  situa- 
tion. The  inadequacy  of  these  explanations  is  evident,  and  Hanseman 
pointed  out  at  once  the  fact  that  tumors  occur  in  the  young  and  are  es- 
pecially malignant.  Ribbert  has  pursued  these  ideas,  explaining  the  in- 
growth of  epithelium  as  dependent  upon  primary  changes  in  the  underlying 
connective  tissue,  which  becomes  relaxed  and  infiltrated  with  leucocytes, 
so  that  it  is  exposed  to  the  invasion  of  the  epithelium,  which  it  surrounds 
and  isolates,  thereby  allowing  unlimited  growth  through  the  disarrange- 
ment of  equilibrium.  The  inflammatory  infiltration  of  lymphocytes,  upon 
which  Ribbert  lays  stress,  appears  now  to  be  the  protective  reaction  which 
Murphy  has  shown  to  be  so  important  in  preventing  the  extension  of 
tumors.  While  Ribbert's  theory  involves  the  primary  activity  of  the 
altered  connective  tissue,  it  does  not  rest  solely  on  that  basis,  but  is  related 
in  certain  ways  to  other  theories,  so  that  it  must  be  referred  to  again. 

Theories  of  Tumor  Growth  Depending  upon  Displacement  of  Embry- 
onic Cells. — Cohnheim's  Theory. — Another  theory,  associated  especially 
with  the  name  of  Cohnheim,  assumes  that  since  certain  tumors  which  occur 
congenitally  are  traceable  to  congenital  maldevelopment,  it  is  possible,  or 
•even  probable,  that  a  disarrangement  of  cells  in  the  course  of  embryonic 
growth  may  lie  at  the  root  of  tumor  growth  in  general.  Cohnheim's  idea 
was  that  at  some  stage  of  embryonic  life  cells  might  become  isolated  while 
still  possessed  of  great  energy  of  growth  and  potentialities  which  would 
have  carried  them  on  to  the  development  of  some  specific  tissue  of  the  body, 
had  they  remained  in  their  normal  connection  with  the  rest  of  the  cells  of 
the  embryo.  These  cells  are  conceived  of  as  lying  dormant  among  the 
growing  tissues,  and  showing  no  tendency  to  unfold  their  own  powers  of 
growth  during  years.  Then,  when  the  other  tissues  have  become  organs 
of  an  adult  man,  and  commonly  late  in  the  life  of  this  man,  the  hidden 


1112  TEXT-BOOK   OF   PATHOLOGY 

group  of  cells,  still  endowed  with  embryonic  vigor,  begins  to  grow.  Cohn- 
heim  did  not^think  that  these  cells  would  begin  their  growth  without  some 
stimulus,  but  that,  once  started,  they  would  exhibit  a  capacity  for  growth 
comparable  only  to  that  of  the  embryo. 

Numerous  criticisms  have  been  made,  of  course.  It  is  difficult  to  believe 
that  such  misplaced  cells  or  groups  of  cells  could  remain  latent  for  many 
years  and  still  maintain  their  youthful  vigor.  Further  it  is  known  that 
when  such  displacements  of  tissue  obviously  occur,  the  cells  tend  to  pro- 
ceed through  their  allotted  course  of  maturation  and  development,  to  pro- 
duce finished  tissue,  rather  than  to  continue  as  embryonic  cells,  although 
there  are  some  teratomata  in  which  the  peculiar  form  of  cells  has  been 
interpreted,  rightly  or  wrongly,  as  embryonic.  Since  tumors  may  occur 
anywhere,  and  are  frequently  initiated  by  irritation,  it  is  necessary  to 
assume  an  extremely  wide  distribution  of  displaced  cells  if  a  group  of  them 
is  to  be  ready  wherever  the  irritation  may  act.  While  Cohnheim's  theory 
may  explain  perfectly  the  teratomata  and  other  growths  which  are  obviously 
related  to  foetal  inclusions,  it  does  not  explain  the  malignant  type  of 
growth,  since  it  does  not  explain  why  the  cells  of  a  tumor  behave  differ- 
ently from  those  of  an  embryo,  in  that  they  continue  to  grow  in  the  same 
atypical  form  and  never  proceed  to  anything  resembling  the  end-product  of 
tissue  growth. 

Ribberfs  Theory. — Ribbert  also  assumes  that  the  most  important  and 
indispensable  basis  for  the  origin  of  a  tumor  is  the  independence  of  a  tissue 
germ,  attained  through  isolation  of  the  cells,  through  which  the  always 
adequate  capacity  for  growth  of  the  cells  is  liberated.  Not  every  isolated 
group  of  cells  forms  a  tumor,  and  those  which  do  are  dependent  upon 
favorable  conditions  of  development,  nutrition,  etc.  The  character  of  the 
tumor  depends  upon  the  type  of  tissue  in  the  rudiment,  its  degree  of  inde- 
pendence, and  its  energy  of  growth  at  the  time  of  its  isolation  from  the  sur- 
rounding cells.  This  isolation  occurs  most  frequently  in  embryonic  life, 
but  may  also  occur  in  adults,  and  is  produced  by  abnormal  processes  of 
growth.  Another  tissue  may  grow  in  such  a  way  as  to  cut  off  a  group  of 
cells  from  its  normal  relations  with  its  own  tissue.  The  growth  of  the 
other  tissue  is  in  a  sense  a  preliminary  stage,  which  ends  in  the  initiation  of  a 
tumor,  when  it  has  isolated  a  group  of  cells  which  act  as  the  germ  of  the 
tumor.  Tumor-cells  are  not  biologically  different  from  normal  cells,  and 
only  the  conditions  under  which  they  find  themselves  decide  them  upon 
tumor  formation. 

When  Ribbert  accepts  in  its  general  principle  the  Cohnheim  theory,  he 
modifies  it  by  the  statement  that  the  isolation  of  the  cells  which  are  to 
produce  the  growth  may  occur  in  adult  life,  and  that  this  isolation  is  brought 
about  by  the  irregular  growth  of  other  tissues.  Ribbert's  other  contention 
is  that  tumors  are  in  a  sense  unicentric,  that  they  grow  out  of  their  own 
material,  invading  the  other  tissue,  it  is  true,  but  not  infecting  it  or  stim- 
ulating it  to  grow.  He  emphasizes  particularly  the  statement  that  it  is. 


THEORIES   AS   TO   THE   AETIOLOGY   OF   TUMORS  1113 

tt7rong  to  regard  the  growing  margin  of  an  epithelial  tumor  as  a  transi- 
tional zone  between  normal  and  tumor  tissue,  in  which  the  normal  tissue  is 
being  converted  into  tumor  tissue.  Instead,  the  tumor  is  entirely  depen- 
dent upon  its  own  dividing  cells,  which  may  burst  through  and  upheave 
the  adjacent  epithelium  or  even  heal  together  with  it,  but  which  do  not 
convert  it  into  tumor  tissue.  Borst  and  many  others  accept  this  statement, 
but  Hauser  and  several  more  recent  writers  question  its  truth.  It  is  well 
known  that  there  is  commonly  a  modification  of  the  epithelium  in  the 
neighborhood  of  a  primary  epithelial  tumor  which  resembles  that  at  the 
edge  of  an  old  ulcer.  The  epithelial  downgrowths  between  the  papillae 
may  be  exaggerated,  and  are  surrounded  by  an  exudate  of  lymphocytes. 
Whether  this  is  capable  of  being  shown  to  be  a  preliminary  to  actual  con- 
version into  cancer  tissue  remains  to  be  determined.  Lubarsch  points  out 
the  fact  that  the  epithelial  tissue  adjacent  to  a  metastasis  in  an  internal 
organ  from  an  epithelioma  of  the  skin  is  very  much  less  distinctly  changed 
than  that  which  adjoins  the  primary  growth. 

Somewhat  analogous  to  these  theories  which  invoke  the  aid  of  the 
embryonic  energy  of  growth  are  those  more  faintly  expressed  ideas  which 
depend  upon  the  possibility  of  a  new  fertilization.  J.  Loeb  has  shown  that 
the  eggs  of  some  animals  may  be  stirred  to  parthenogenetic  development 
by  the  action  of  chemical  substances.  The  disturbance  of  the  lipoid  sheath 
by  some  solvent,  allowing  the  oxidative  processes  to  go  on,  appears  to  be 
the  mechanism  concerned,  and  this  explanation  has  been  transferred  to 
those  experiments  in  which  the  introduction  of  scharlach  oil,  ether-water, 
etc.,  have  stirred  up  a  new  growth  of  cells.  There  have,  indeed,  been  efforts 
to  show  that  an  actual  conjugation  of  adjacent  cells  may  take  place  after  a 
preliminary  heterotypic  division,  with  reduction  of  chromosomes  to  half 
their  normal  number  (Farmer,  Moore,  and  Walker).  Such  conjugation 
ought  to  confer  a  new  impulse  to  growth,  exactly  as  in  the  fertilization  of 
the  ovum.  The  idea  is  a  most  tempting  one  at  first  sight,  but  the  proofs 
of  the  actual  existence  of  this  process  have  not  been  satisfactorily  brought 
forward. 

Theories  of  Tumor  Growth  Depending  upon  Changes  in  the  Cells. — 
Hauser  was  among  the  first  to  insist  that  tumor  growth  could  be  explained 
only  on  the  assumption  of  a  profound  change  in  the  character  of  the  cells 
of  which  it  is  composed.  He  speaks  of  new  cell  races,  and  recognizes 
especially  their  independence  and  their  arrogance  in  overcoming  other 
tissues  and  cells.  Marchand,  Beneke,  and  Ziegler  hold  somewhat  similar 
views.  Hansemann  has  elaborated  the  idea  by  attempting  to  define  the 
character  of  this  change  in  the  cells,  which  he  describes  as  anaplasia,  an 
alteration  in  the  cell  not  always  easily  recognizable  by  its  form,  but  con- 
sisting in  changed  histological  characters  which  allow  it  to  proliferate  rather 
than  to  functionate.  This,  in  its  more  intense  degrees,  is  accompanied 
by  changes  in  form  and  arrangement  of  the  cells,  and  is  associated  with 
atypical  or  asymmetrical  mitoses.  Anaplasia  is  not  the  cause  of  tumor 


1114  TEXT-BOOK   OF   PATHOLOGY 

growth,  but  the  term  is  descriptive  of  the  changes  which  occur  in  the  cells, 
tforst,  recalling  the  infinite  complexity  of  the  process  of  distribution  of 
parental  characters  to  all  the  cells  of  the  developing  body,  regards  the  change 
in  the  cells  which  leads  to  tumor  growth  as  due  to  some  irregularity  in  the 
formation  of  their  " idioplasm,"  which  one-sided  development  does  not 
necessarily  incapacitate  them  for  an  ordinary  function  in  the  ranks  of  other 
cells,  but  leaves  them  capable  of  independent  and  atypical  growth. 
Schwalbe  adheres  to  this  idea,  which  he  expresses  differently,  inasmuch  as 
he  speaks  of  congenital  pathological  abnormality  of  the  cells,  or  cell  mal- 
formation. 

It  was  said  in  the  beginning  that  we  do  not  know  the  cause  of  tumor 
growth,  and  it  seems  quite  unprofitable  to  attempt  new  theories  except  on 
the  basis  of  adequate  new  facts.  Those  at  our  disposal  have  been  so  well 
pondered  over  that  the  newer  theories  prove  to  be  merely  the  invention  of 
new  terms  to  express  the  old  vague  ideas. 

Nevertheless,  I  must  express  my  own  impressions  of  what  has  been 
learned  and  written  of  tumor  growth  without  advocating  any  new  theory. 
We  have  a  fairly  clear  conception  of  the  laws  of  normal  growth  from  the 
beginning  to  the  end  of  life.  Those  laws  apply  equally  well  to  the  growth 
of  the  embryo  and  to  the  growth  of  the  adult.  Tumor  growth  does  not 
obey  these  laws,  but  transgresses  them  in  every  direction.  It  seems  idle, 
therefore,  to  attempt  its  explanation  by  assuming  that  embryonic  cells  per- 
sist and  grow  in  the  adult  body.  That  may  explain  teratomata  very  well, 
since  they  are  essentially  finite  growths  that  obey  the  normal  laws,  as  well 
as  they  can  with  their  incomplete  tissues  and  in  their  cramped  situations. 
But  it  does  not  explain  the  growth  of  tumors. 

On  the  other  hand,  we  are  quite  familiar  with  the  effects  of  every  sort  of 
injurious  influence  in  disturbing  temporarily  the  normal  growth  of  tissue, 
and  can  formulate  general  laws  for  these  effects  which  are  found  to  be  always 
respected.  But  tumors  do  not  respect  them  at  all.  For  that  reason  I 
have  written  of  tumor-growth  separately  from  all  the  rest  of  pathology  as 
a  thing  apart,  not  to  be  dealt  with  according  to  the  laws  of  reaction  of  normal 
tissues.  Although  we  discuss  every  sort  of  injury  as  a  possible  cause  of 
their  growth,  we  cannot  conceive  of  one  which  would  have  this  result  with- 
out assuming  some  abnormal  character  in  the  tissue  itself.  No  known 
injury  can  elicit  such  a  reaction  in  normal  tissue,  and  it  must  be  a  parasite 
of  a  totally  unimagined  kind  which  could  do  it. 

We  are  left  with  the  impression  that  there  is  somehow  produced  a 
sudden,  profound,  and  permanent  change  in  the  character  of  the  cells 
themselves,  and  that  other  tissues  which  are  invaded  or  form  the  stroma  are 
affected  by  their  activity;  but  although  we  realize  this  irrevocable  change, 
we  cannot  assign  a  reason  for  it,  nor  even  tell  precisely  in  what  structural 
alteration  it  may  be  recognized. 


THEORIES   AS   TO   THE   .ETIOLOGY   OF   TUMORS  1115 

LITERATURE 

Only  such  treatises  as  are  of  general  character  and  give  further  references  to  the 
literature  are  given  here: 

Virchow:  Die  krankhaften  Geschwiilste,  Berlin,  1863-1867. 

Borst:    Die  Lehre  von  den  Geschwiilsten,  Wiesbaden,   1902.     Wiirzburger  Abhand- 

lungen,   1906,  vi,  221.     (Excellent  paper.)     Ziegler's  Beitrage,    1910,   xlix,   638. 

Aschoff:   Pathol.  Anat.,  1913,  i,    51. 
Ribbert:  Geschwlilstlehre,  Bonn,  1904,  with  Supplements.  Das  Carcinom  des  Menschen, 

Bonn,  1911.     (cf.  Orth,  Ztschr.  f.  Krebsforsch.,  1913,  xiii,  566,  for  a  criticism  of  this 

work  and  Ribbert's  theories.) 
Ewing,  J. :  Neoplastic  Disease,  1919. 
E.  Albrecht:  Verh.  d.  Dtsch.  Path.  Gesellsch.,  1904,  viii,  89.     Monatsschr.  f.  Geburtsh. 

u.  Gynak.,  1904,  xx,  123. 

v.  Dungern  and  Werner:  Wesen  der  bosartiger  Geschwiilste,  Leipzig,  1907. 
Israel:  Berl.  kl.  Woch.,  1900,  xxxvii,  608,  644,  667. 

Schwalbe:  Verb.  Naturh.  Mediz.  Verein  zu  Heidelberg,  1906,  N.  F.  viii,  337. 
M.  B.  Schmidt:    Verbreitungswege  der  Karzinome,  Jena,  1903. 
Apolant  and  Ehrlich:   Genese  des  Carcinoms,  Verh.  Dtsch.  Path.  Gesellsch.,  1908,  xii, 

3. 

Verse:   Problem  des  Geschwulstmalignitat,  Jena,  1914. 
Lubarsch:  Pathol.  Anat.  u.  Krebsforschung,  Wiesbaden,  1902. 
Wolff:   Lehre  von  der  Krebskrankheiten,  Jena,  1911. 
Da  Fano:  Ztschr.  f.  Immunitatsforschung,  1910,  v,  1. 
Murphy:  Jour.  Exp.  Med.,  1913,  xvii,  482;  1914,  xix,  513;  1915,  xxii,  204. 
Rous:  Jour.  Exp.  Med.,  1910,  xii,  696;  1911,  xiii,  397;  1912,  xv,  119,  etc. 
Apolant:  Ztschr.  f.  allg.  Physiologic,  1909,  ix,  63,  Ref .    (Review  of  experimental  work.) 
Hansemann:   Anaplasie,  bosartigen  Geschwiilste,  Berlin,  1893-1897. 
Borrel:  Probleme  du  Cancer,  Paris,  1907.     BuU.  Inst.  Pasteur,  1907,  v,  206.     Ann.  de 

1'Inst.  Pasteur,   1909,  xxiii,  97. 
Fibiger:  ZtSchr.  f.  Krebsforschung,  1913,  xiii,  217. 

Herxheimer  and  Reinke:  Ergebn.  d.  allg.  Path.,  1910,  xiii2,  356;  1913,  xvi2,  1. 
Bashford  and  others:  Publications  Imperial  Cancer  Research  Fund,  1904-1912. 
Woglom:  Studies  in  Experimental  Cancer,  Crocker  Research  Fund,  New  York,  1913. 
Levin,  Lambert,  Hanes,  and  others.     MacCallum,  General  Introduction:  Experimental 

Studies  hi  Cancer,  Crocker  Research  Fund,  N.  Y.,  1912. 


INDEX 


NOTE. — Page  references  to  illustrations  appear  in  italics.  In  cases  where  there  are 
several  references  to  discussions  of  the  same  subject,  the  more  important  references  are 
printed  in  heavy  type. 


ABSCESS,  283,  224,  229,  262,  512 

amoebic,  of  liver,  769,  770,  77* 
of  lung,  772 

cold,  685 

liquefaction  of,  156,  265 

of  brain,  519,  542 

of  heart,  467 

of  intestine,  265 

of  kidney,  268,  457,  537 

of  liver,  264 

amcebic,  769,  770,  771 

in  suppurative  cholangitis,  4*4>  414 

of  lung,  259,  538 
amcebic,  772 
pysemic,  265 

of  pancreas,  419 

of  pericardium,  535 

of  skin,  263 

psoas,  224 

Acapnia  in  shock,  380 
Acetone  bodies  in  diabetes,  868 
Acidosis,  172 

in  diabetes,  175,  869 

in  infectious  diseases,  175 

in  other  conditions,  175 
Acromegaly,  187,  900,  900,  901,  902,  903 

relation  of  hypophysis  to,  899 
Actinomyces  bovis,  630 

relation  of,  to  streptothrix,  629 
Actinomycosis,  629,  631 

amyloid  in,  633 

character  of  lesions,  630 

localization  of,  631 

mode  of  infection,  630 

of  bones,  631 

of  Fallopian  tubes,  632 

of  intestines,  631 

of  jaw,  631 

of  liver,  632,  632 

of  lung,  631 

of  ovary,  632 

of  spleen,  632 


Actinomycosis,    references   to   literature, 
632 

sinuses  in,  224 
Adamantinoma,  1030,  1031 
Adaptation  of  growth  to  function,  179 
Addison's  disease,  894 

chromaffin  tissue  in,  895 
pigmentation  of  skin  in,  894 
references  to  literature,  896 
Adenine,  88 
Adenocarcinoma,  1019,  1036 

common  sites  of  origin,  1036 

of  breast,  1064 

of  ovary,  1056,  1056 

of  rectum,  1053 

of  uterus,  1028,  1053,  1055 
Adenofibroma  of  breast,  1009,  1009,  1010 
Adenoids,  obstruction  of  nose  by,  430 
Adenoma,  1000,  1004 

differentiation  of,  from  carcinoma,  1062 

intracanalicular,  of  breast,  1012,  1012 

of  adrenal,  1008 

of  breast,  1009,  1011,  1012 

of  hypophysis,  1009 

of  intestine,  1006,  1005,  1006 

of  kidney,  1006,  1007 

of  liver,  1006 

of  skin,  1004 

of  stomach,  1005 

of  thyroid,  875,  876,  876,  1008,  1008 

of  uterus,  1017 

polypoid,  1006 

references  to  literature,  1017 
Adenomyoma,  951 
Adiposis  dolorosa,  904,  906 
Adrenaline,  892 

arteriosclerosis  produced  by,  896 

effect  of,  on  blood-vessels,  893 
on  organs,  893 
on  uterus,  893 

glycosuria  produced  by,  893 

myocardial  injury  produced  by,  472 
1117 


1118 


INDEX 


Adrenaline,  oedema  of  lungs  produced  by, 

46 

Adrenals,  accessory,  891 
amyloid  infiltration  of,  100 
chromaffin  tissue  in,  891 
disturbances  in  function  of,  65,  891 
extirpation  of,  892,  894 

cholesterinsemia  from,  80 
function  of  cortex,  894 
function  of  medulla,  893 
in  chronic  nephritis,  896 
influence  of,  on  carbohydrate  metabo- 
lism, 867,  893 

on  sexual  development,  894 
in  status  lymphaticus,  844 
lipoids  in,  892 
normal  involution  of,  891 
pigments  of,  125 
references  to  literature,  896 
relation  of  cholesterine  to  function  of, 

892 

transplantation  of,  212 
tuberculosis  of,  in  Addison's  disease,  894 
tumors  of,  988 
adenoma,  1008 
hypernephroma,  988 
relation  to  sexual  precocity,  894 
Agglutination,  167 
in  dysentery,  620 
in  typhoid  fever,  167 
Agglutinins,  171 
Aggressins,  164 

Albumosuria  in  myeloma,  87,  837,  852 
Alcohol  poisoning,  402 
Alcoholism,  chronic,  402 

degeneration  of  nerves  in,  81 
haemorrhagic  pachymeningitis  in,  122 
Alexin,  171 
Alimentary  tract,  obstruction  of,  407 

references  to  literature,  429 
syphilis  of,  709 
Alkali  reserve  of  body,  172 
Alkalosis,  175 

relation  to  pyloric  obstruction,  175 
Alkaptonuria,  87 
Alopecia,  syphilitic,  702 
Amboceptor,  171 
Amino-acids  in  urine  in  diseases  of  the 

liver,  316 

Ammonia  poisoning,  401 
Amoebae,  pathogenic,  767 
Amoebic  abscess  of  liver,  769,  770,  77.? 
dysentery,  767 
infections,  766 


Amoebic  infections,  references  to  literature, 

772 
Amyloid,  98 

chemistry  of,  102 
degeneration,  61 
experimental  production  of,  103 
deposits  in  adrenals,  103 

in  bronchi,  103 

in  intestine,  100 

in  kidney,  99,  298,  299,  300,  301 

in  liver,  99 

in  lymph-glands,  100 

in  spleen,  99,  99,  101 
in  actinomycosis,  633 
in  chronic  nephritis,  300,  300 
references  to  literature,  103 
staining  properties  of,  100 
Amyloidosis,  diseases  associated  with,  99 
actinomycosis,  633 
chronic  nephritis,  300,  300 
Anaemia,  2 

aplastic,  208,  815 

references  to  literature,  821 
bone-marrow  changes  in,  208 
causes  of,  806 
experimental,  changes  in  bone-marrow, 

799 

from  benzol  poisoning,  208 
in  lead  poisoning,  403 
in  mechanical  destruction  of  bone-mar- 
row, 817 

local,  16,  18,  25,  27 
osteosclerotic,  806,  1053 

references  to  literature,  821 
pernicious,  806,  809 

aetiology  of,  81 

blood  changes  in,  810 

deposits  of  iron  pigments  in,  811 

from  Bothriocephalus  latus  infection, 
81 

hyperplasia  of  bone-marrow  in,  811, 
811,  812 

liver  in,  815 

phagocytosis  of  red  corpuscles  in,  813 

pigmentation  of  organs  in,  124 

references  to  literature,  821 

spleen  in,  813,  813 
regeneration  of  blood  in,  207 
secondary,  807 

blood  changes  in,  808 

bone-marrow  in,  809,  809 

changes  in  organs  in,  808 

from  blood  destruction,  807 

in  malaria,  808 


INDEX 


1119 


Anaemia,  splenic,  818 
Anaesthesia,  Overton's  theory  of,  50 
Anal  fistula,  tuberculous,  673 
Anaphylaxis,  168 

relation  to  bronchopneumonia,  518 
Anaplasia  of  tumor  cells,  1113 
Anasarca,  44 
Anchylostoma  duodenale,  789 

head  of,  in  intestinal  wall,  79 1 
Aneurysms,  357,  363,  364 

aetiology  of,  361 

arterio venous,  360 

cirsoid,  358 

dissecting,  358,  376 
of  aorta,  358,  359 

erosion  of  bone  by,  69,  70,  362 

false,  361 

fusiform,  357 

mechanical  effects  of,  68,  361,  370 

multiple,  365 

of  aorta,  361,  362,  363,  365 

of  small  arteries,  365 

racemose,  358 

references  to  literature,  365 

rupture  of,  363 

saccular,  361,  363 
Angina,  sclarlatinal,  757 
Angioma,  963.   See  also  Hcemangioma  and 

Lymphangioma. 
Angiosarcoma,  974,  998 
Anisocytosis,  810 

Ankylosis  in  arthritis  deformans,  928 
Anorexia  nervosa,  63 
Anthracosis,  129 

of  lungs,  130 

of  lymph-glands,  129,  130 
Anthrax,  589 

bacillus  of,  importance  of  capsule  for- 
mation, 164 

carbuncle  in,  590 

haemorrhagic  meningitis  in,  591,  591 

lesions  of  organs  in,  590 

portals  of  entry,  590 

references  to  literature,  592 
Antithrombin,  7 
Antitoxins,  169 
Antrum,  infection  of,  536 

in  influenza,  597 

Aorta,  aneurysm  of,  361,  362,  363,  365 
dissecting,  358,  359,  376 
saccular,  357,  361,  363 

arteriosclerosis  of,  336,  339,  341 

fatty  patches  in  intkna,  84,  336,  337 

structure  of,  335 


Aorta,  syphilis  of,  254,  350,  351,  352 

thrombi  in,  11 

Aortic  insufficiency,  253,  352,  362,  477 
cause  of  collapsing  pulse  in,  478 
references  to  literature,  494 
stenosis,  352,  478,  479 
Aortitis,  syphilitic,  254,  350,  351,  352 
aneurysms  in,  361 
references  to  literature,  353 
Apoplexy,  cerebral,  366,  366 

references  to  literature,  368 
pancreatic,  419 
Appendicitis,  238 
acute,  239,  239,  240 
perforating,  241,  241 
phlegmonous,  240,  242 
suppurative,  241 
aetiology  of,  226 
bacteriology  of.  239 
chronic,  239 

complications  and  sequelae  of,  243 
haematogenous,  238 
healed,  243 
healing  of,  239 
peritonitis  in,  241 
references  to  literature,  245 
Appendix,  concretions  in,  240 

histology  of,  238 

Aqueduct  of  Sylvius,  obstruction  of,  507 
Archoplasm,  50 
Arcus  senilis,  64 
Argyria,  130 
Arhythmias,  500 

due  to  heterogenetic  impulses,  500 

to  homogenetic  impulses,  499 
Arsenic    compounds,    resistance    of     try 

panosomes  to,  164 
'  increased  tolerance  of,  164 
poisoning,  403 
acute,  403 
blindness  in,  404 
chronic,  403 

degeneration  of  nerves  in,  81 
Arteries,  fatty  infiltration  of,  84 
obstruction  of,  18,  26 
structure  of,  335 
thrombi  in,  11 
Arteriosclerosis,  19,  335 
aetiology  of,  348 
blood-pressure  in,  349 
calcification  in,  341,  342,  342 
cholesterine  in,  340,  341 
circulatory  disturbances  in,  465 
early  stage  of,  336,  337,  338 


1120 


INDEX 


Arterosclerosis,  elastic  tissue  of  vessels  in, 

339 

experimental,  349 
adrenaline,  896 
late  stage  of,  338,  341 
lipoids  in  lesions  of,  338,  340 
Monckeberg  type,  345,  346,  347 
of  aorta,  336,  337 
of  coronary  arteries,  345,  467 
of  femoral  artery,  346 
of  mesenteric  artery,  340,  344 
of  pulmonary  artery,  349 
of  renal  artery,  343,  344 
of  renal  vessels,  288.     See  also  Chronic 

nephritis,  arteriosclerotic. 
ossification  of,  31$ 
pathogenesis  of,  348 
proper,  336 

references  to  literature,  350 
syphilitic,  350,  351,  352 
Artery  of  cerebral  hemorrhage,  397 
lenticulo-striate,  397 
lenticulo-optic,  397 
Arthritis  deformans,  926 

degenerative,  929,  929,  930,  931,  932, 

933 

disturbances  in  bone  formation  in,  107 
proliferative,  927,  928 
references  to  literature,  935 
types  of,  927 
gonococcus,  567 
in  dysentery,  619 
infectious,  types  of,  926 
pneumococcus,  554 
rheumatic,  570 
Arthropathy,  tabetic,  735,  734 

types  of,  927 

Arthropods,  pathogenic,  classification,  766 
Ascaris  lumbricoides,  792 
Aschoff  bodies  in  heart,  467,  468,  572,  571 
Ascites,  43 

chylous,  793 

Asthma,  pulmonary  emphysema  in,  439 
Atelectasis,  432 

Atheroma,  339.    See  also  Arteriosclerosis. 
Atheromatous  cysts,  1083 
Athrepsia,  1108 
Atmospheric  pressure,  effect  of  increased, 

370 
Atrophy,  62 

acute  yellow,  315 

brown,  of  heart,  63,  64 
of  liver,  63 
from  disease,  62,  65 


Atrophy  from  insufficient  blood  supply,  62 

from  old  age,  63 

from  pressure,  62 

from  starvation,  63 

of  bones  in  leprosy,  628,  628 

of  brain,  senile,  64 

of  fat,  serous,  64 

of  kidney  after  obstruction  of  ureter, 
180 

of  liver,  senile,  63,  64 

of  muscles,  63,  66,  67 

in  acute  poliomyelitis,  688 
senile,  63 

of  skin,  senile,  63 

progressive  muscular,  66 
Attraction  sphere,  50 
Auricle,  thrombus  in,  10 
Auricular  fibrillation,  501 
Autointoxication,  397 
Autolysis,  58 

of  liver,  58 

of  lung,  58 
Azoospermia    following    gonorrheal    epi- 

didymitis,  563 

BACILLUS  aerogenes  capsulatus,  22 
in  puerperal  infections,  259 
anthrax,  589 
botulinus  infection,  397 
dysenterise,  types  of,  616 
enteritidis  infection,  397,  615 
leprse,  625 
mallei,  587 

paratyphosus,  types  of,  615 
pestis,  585 

tuberculosis,  types  of,  634 
effects  of,  on  tissues,  642 
excessive  repair  following  injuries  by, 

188 

fats  of,  80 

Bacteria,  changes  in  virulence  of,  510 
emboli  of,  22 

portals  of  entry  of,  162,  510 
toxins  of,  511 

Bacterial  action,  nature  of,  511 
Bacteriolysins,  166 
specificity  of,  170 
Bacteriotropins,  166,  171 
Banti's  disease,  818 

cirrhosis  of  liver  in,  818,  819 
spleen  in,  818,  818,  819 
Basedow's  disease,  878.     See  also  Goitre, 

exophthalmic. 
Bechterew's  disease,  929 


INDEX 


1121 


Bed-sores,  42 

Bence-Jones  protein  in  urine  in  myeloma, 

837,  852 
Benzol  poisoning,  anaemia  in,  208 

changes  in  bone-marrow  in,  798,  799, 

799,  800 

references  to  literature,  820 
relation  of  lipoids  to,  81 
Beri-beri,  neuritis  in,  81 
Beta-imidazolethylamine,  381.     See  His- 

tamine. 

Bile  pigments,  113,  121 
Bile-ducts,  carcinoma  of,  1048 

obstruction  of,  408 
Bilharziosis,  784 
Bilirubin,  113,  121 
Blackwater-fever,  120,  778 

references  to  literature,  779 
Bladder,  calculi  in,  446 

dilatation  of,  paralytic,  451 
hypertrophy  of,  444,  562 
tumors  of,  carcinoma,  1026 
myoma,  951 

papilloma,  1003,  1026,  1027 
rhabdomyoma,  953 
Blindness  from  arsenic  poisoning,  404 
Blood,  calcium  excess  in,  110 

cells,  formation,  from  connective  tissue, 

147 

diminution  of,  in  body,  69 
effects  of  injuries  upon,  795 
fat  in,  77 
formation  of,  148 
in  syphilis,  709 
in  typhoid  fever,  610 
of  different  species,  precipitation  test 

for,  167 
quantity  of,  in  body,  2 

Haldane-Smith    method    for    esti- 
mating, 2 
red  corpuscles  of,  effect  of  injury  to, 

805 

regeneration  of,  206 
after  haemorrhage,  207 
in  anaemia,  208 
test  for,  167 
Blood-clots,  3 
chicken-fat,  4 
cruor,  4 

in  healing  of  wounds,  214 
postmortem,  4,  5 
structure  of,  4 
varieties  of,  4 
Blood-clotting,  3,  6,  7 

72 


Blood-clotting,   appearance   under   ultra- 
microscope,  7 
delayed,  7 

in  haemophilia,  7 
in  jaundice,  7,  126 
rapid,  7 

references  to  literature,  14 
Blood-crises,  208 
Blood-formation,  extramedullary,  148, 196, 

796,  827 

from  endothelial  cells,  194 
in  liver  in  congenital  syphilis,  742 
Blood-forming  organs,  796 
diseases  of,  826 

classification,  828 
effects  of  injuries  upon,  795 
of  benzol  on,  798 
of  x-rays  on,  391 
of  different  species,  precipitation  test 

for,  167 

Blood-platelets,  7 
in  thrombi,  8 
origin  of,  149 

Blood-pressure,  maintenance  of,  463 
Blood-vessels,  462 
calcification  of,  108 
effect  of  adrenaline  on,  893 
elastic  tissue  in,  335 
endothelioma  of,  997 
hyaline  degeneration  of,  97,  98 
occlusion  of,  69 
regeneration  of,  204 
syphilis  of,  722 
thrombi  in,  225 
Boils,  534 

Bone,  actinomycosis  of,  631 
atrophy  of,  in  leprosy,  628,  628 
erosion  of,  by  aneurysm,  68,  70,  362 
formation  in  muscles  after  injury,  946 
relation  of  internal  secretions  to,  911 
retardation  of,  in  myxcedema,  871 
fracture  of,  372 
repair  of,  204 
healing,  203 

growth  of,  disturbances  in,  909 
effect  of  calcium  deficiency  on,  909 
normal,  911 

in  infantile  scurvy,  921,  921,  922 
in  osteomalacia,  918 
in  Paget's  disease,  923,  924 
in  rickets,  913 
regeneration  of,  202 
osteoblasts  in,  203 
syphilis  of,  716,  718 


1122 


INDEX 


Bone,   syphilis   of,   congenital,   744,   744, 
745,  746,  747 

references  to  literature,  722 
transplantation  of,  211,  212 
tuberculosis  of,  224,  771,  683,  684,  685 

references  to  literature,  685 
tumors  of,  carcinoma,  metastatic,  1052, 
1060 

chondroma,  943,  943,  944 

osteoma,  946,  946 

osteosarcoma,  977,  979,  980 

sarcoma,  981 

giant-cell,  977,  ,975 
Bone-marrow,  797 

destruction  of,  by  metastatic  tumors, 

817 

effect  of  x-rays  on,  391 
focal  necrosis  of,  in  typhoid  fever,  610 
hyperplasia  of,  in  anaemia,  208 

in  leucocytosis,  823,  824 
in  acute  lymphoid  leukaemia,  835 
in  benzol  poisoning,  798,  799,  799,  800 
in  chronic  lymphoid  leukemia,  830,  830 
in  chronic  myeloid  leukaemia,  846,  847 
in  pernicious  anaemia,  811,  811,  812 
in  secondary  anaemia,  808,  809 
in  smallpox,  763 
in  typhoid  fever,  610,  825 
of  normal  adult,  796 

infant,  797 

references  to  literature,  820 
regeneration  of,  206 

after  benzol  poisoning,  799,  799,  800 
types  of  cells  in,  798 
Bothriocephalus  latus,  781 

as  cause  of  pernicious  anaemia,  81 
Bradycardia,  499 
Brain,  abscesses  in,  542 

in  otitis  media,  519 
character  of  repair  in,  209 
compression  of,  from  subdural  haemor- 
rhage, 374 
cysts  of,  961 

glioma  of,  958,  958,  959,  960,  961 
gumma  of,  706,  727 
haemorrhage  in,  366,  366 
in  dementia  paralytica,  737,  737 
in  lead  poisoning,  403 
in  malaria,  775,  777 
infarction  of,  28,  35,  36,  37 
oedema  of,  384 
phagocytes  in,  36 
senile  atrophy  of,  64 
syphilis  of,  706,  726,  727 


Brain,  tuberculosis  of,  681 

ventricles  of,  504 
Branchial  cysts,  1083 
Breast,  adenocarcinoma  of,  1064 

adenofibroma  of,  1009,  1009,  1010 

adenoma  of,  1009,  1011 

carcinoma  of,  1058,  1059,  1062,  1068, 

1064 

colloid,  1059,  1065,  1066 
medullary,  1061 
mode  of  spread,  1059 
references  to  literature,  1071 
scirrhus,  1064,  1065 
types  of,  1058 

cystic  mastitis,  1064 

cysts  of,  1011 

intracanalicular     adenofibroma,     1112, 
1012 

mixed  tumors  of,  1087 

sarcoma  of,  977 
Brill's  disease,  687 
Bronchi,  amyloid  deposits  in,  103 

carcinoma  of,  1025 

chondroma  of,  944 

diphtheria  of,  576 

obstruction  of,  432,  434 

syphilis  of,  717 
Bronchiectasis,  362,  433,  434,  436,  668 

aetiology  of,  436 

references  to  literature,  437 

types  of,  435 

Bronchiolitis,  obliterative,  in  measles,  755 
Bronchitis,  catarrhal,  230,  230 

tuberculous,  656 

Bronchopneumonia,   254,   257,   258,   516, 
517,  596.   See  also  Pneumonia,  lobular. 

degeneration  rectus  abdominis  in,  518 

emphysema  in,  518 

gangrene  of  lung  in,  259 

in  measles,  515 

interstitial,  518 

mode  of  infection  in,  257 

relation  to   anaphylactic   sensitization, 
518 

septicaemia  in,  518 
Brown  atrophy  of  heart,  63,  64,  466 

induration  of  lung,  487 
Bruise,  371 
Buboes,  700 

scarlatinal,  757 
Bubonic  plague,  585 
Bubonuli,  700 
Burns,  382 

from  electricity,  393 


INDEX 


1123 


Burns,  hsemoglobinuria  in,  383 
shock  in,  383 
thrombosis  of  vessels  in,  383 

CACHEXIA  in  cancer,  65 
Caisson  disease,  371 
Calcification,  chemistry  of,  110 

experimental,  110,  195 

in  normal  bone  formation,  912 

of  blood-vessels,  108 

of  cartilages  in  senility,  108 

of  dead  tissue,  109,  196 

of  elastic  tissue,  114 

of  heart  valves,  253 

of  kidney,  experimental,  109,  196 

of  lymph-glands,  41 

of  necrotic  renal  epithelium,  109 

of  osteosarcoma,  980 

of  psammomata,  109 

of  thrombi,  251 

of  thyroid,  875 

of  trichinae  in  muscles,  108 

of  tubercles,  648 

references  to  literature,  111 

relation  of  fats  to,  110 
of  iron  to,  114 

role  of  soaps  in,  110,  342 
Calcified  tissue,  ossification  of,  111 
Calcium  deficiency,  effect  on  bone  growth, 

106,  909 

on  excitability  of  nerves,  107 
in  osteomalacia,  106 
in  osteoporosis,  106 
in  rickets,  106 
in  tetany,  108 

deposits,  experimental,  111 

excess  of,  108 
in  blood,  110 

importance  of,  in  bone  growth,  910 

metabolism  in  rickets,  917 
disturbances  of,  106 
references  to  literature,  111 
relation  of  parathyroids  to,  885 

salts,  metastasis  of,  111 
Calculi  in  bladder,  446 

in  gall-bladder,    410.      See   also   Chole- 
lithiasis. 

in  kidney,  454,  454 

in  pancreas,  415 

laminated  vesical,  447 

oxalate,  448,  448 
and  urate,  450 

phosphatic,  449,  450 

uric  acid,  447,  448,  449 


Calculi,  urinary,  446 
aetiology  of,  447 
composition  of,  447 
references  to  literature,  451 
Cancer,    1019.      See  also  Tumors,  Carci- 
noma, and  Sarcoma. 
immunity  to,  in  lower  animals,  1108 
references  to  literature,  1115 
theories  as  to  aetiology  of,  1109 
Capillaries,  paralysis  of,  in  shock,  143 

of  heart  valves,  247,  248 
Carbohydrate  metabolism,  73,  103,  865 
disturbances  of,  104 
in  diabetes  mellitus,  860,  865 
in  myxcedema,  873 
influence  of  adrenals  on,  867,  893 
influence  of  pancreas  on,  865 
influence  of  thyroid  on,  867 
references  to  literature,  105 
relation  of  sympathetic  nervous  sys- 
tem to,  867 
Carbolic  acid  poisoning,  400 

lesions  of  stomach  in,  400 
Carbon  monoxide  poisoning,  399 

lesions  of  lenticular  nuclei  in,  899 
Carbuncle,  263 

in  anthrax,  590 
Carcinoma,  1018 

differentiation  of,  from  adenoma,  1062 

from  alveolar  sarcoma,  975 
general  characteristics,  1018 
infiltrative  growth  of,  1023 
metastasis  of,  1023 
of  bile-ducts,  1048 
of  bladder,  1026 

of  breasts,  1058,  1059,  1062,  1063,  1064 
of  bronchi,  1025 
of  gall-bladder,  1026,  1048,  1049 
of  intestine,  1050,  1051 
of  liver,  primary,  1068,  1070 
of  lung,  1025 
of  oasophagus,  1025 
of  ovary,  1056,  1065 
of  pancreas,  1050 
of  prostate,  1051,  1054 
of  rectum,  428,  1052 
of  stomach,  1036, 1037, 1038, 1039, 1040, 

1042 

of  thyroid,  1067 
of  ureter,  1028 
types  of,  basal  cell,  1019,  1031 

references  to  literature,  1035 
colloid,  of  breast,  1059,  1065,  1066 
of  ovary,  1056 


1124 


INDEX 


Carcinoma,  types  of,  colloid,  of  stomach, 

1046,  1047,  1047,  1048 
cylindrical-cell,  1019 
flat  or  squamous-cell,  1019 
gland-cell,  1058 
medullary,  1058,  1061 
scirrhus,  of  breast,  1058,  1064,  1065 

of  stomach,  1041,  1041 
Cartilage,  calcification  of,  in  senility,  108 
in  chondrodystrophia  foetalis,  919 
pigmentation  of,  87 
regeneration  of,  202 
urate  deposits  in,  90 
Casts,  hyaline,  275 
Caustic  alkalies,  poisoning  by,  400 
Cell  division,    amitotic,    in    regenerating 

epithelium,  198 
pathological,  198 
Cells,  adventitial,  152 
•  death  of,  58 
degeneration  of,  60 
differentiation  of,  in  embryo,  192 
embryonic,    resemblance    to    cells    of 

pathological  new  growths,  190 
endothelial,  194 
as  phagocytes,  194 
in  blood  formation,  194 
membranes  of,  50,  78 
mesenchymal,  192 
metabolism  of,  48 

disturbances  in,  60 
motile,  53 
necrosis  of,  55 
specialization  of,  193 
structure  of,  48 

references  to  literature,  59 
variations  in  appearance  of,  54 
wandering,  146 

sources  of,  154 
Centrioles,  49 
Centrosomes,  49 
Cephalin,  7 

Cerebral  hemorrhage,  artery  of,  367 
Cerebrosides,  73,  75,  85 

function  of,  79 

Cerebrospinal  meningitis,  epidemic,  556 
Qestode  infections,  780 

references  to  literature,  784 
Cestodes,  780 
Chalicosis,  129 
Chancre,  698 
histology  of,  699 
of  Eustachian  tube,  717 
of  lip,  709 


Chancre  of  penis,  697,  698 
of  tongue,  709 
of  tonsil,  709 
Chancroid,  700,  701 
Charcot  artery,  rupture  of,  366 
"Charcot's  joints,"  735,  734 
Chemotaxis,  144 

importance  of,  in  inflammation,  14.5 
Chicken-pox,  aetiology  of,  753 
Chiblains,  18,  386 
Chloasma  in  pregnancy,  118 

in  tuberculosis,  118 
Chlorine  poisoning,  401 
Chloroform  poisoning,  402 

liver  in,  313,  315 
Chloroleucosarcoma,  836 
Chloroma,  836 
lymphoid,  836 
myeloid,  852 

references  to  literature,  859 
Chloromyelosarcoma,  852 
Chlorosis,  114 

defective  absorption  of  iron  in  ,114 
syphilitic,  709 
Choked  disc,  957 

Cholangitis,  suppurative,  414)  414 
Cholecystitis,  410 

acute  and  chronic,  with  gall-stones,  Jf.12 
acute  phlegmonous,  410 
after  typhoid  fever,  611 
chronic,  413 

recurring,  411 
subacute  and  chronic,  with  gall-stones, 

409 
Cholelithiasis,  408 

references  to  literature,  415,  429 
Cholera,  Asiatic,  581 

blood  changes  in,  582 
bone-marrow  in,  584 
intestinal  contents  in,  583 
lesions  of  organs  in,  582 
oliga3mia  in,  3 
references  to  literature,  585 
rigor  mortis  in,  581 
sicca,  583 
nostras,  615 
Cholesteatoma,  1083 
Cholesterine,  73,  74 
esters,  75 

in  arteriosclerosis,  340 
in  kidney,  303 

in  blood,  increase  during  pregnancy,  80 
in  gall-stones,  408 
metabolism,  76,  80 


INDEX 


1125 


Chondrioconts,  50 

Chondrodystrophia  fcetalis,  871,  919 
aetiology  of,  919 
changes  in  cartilages,  919,  920 
hydrocephalus  in,  920 
pelvis  in,  920 

references  to  literature,  920 
Chondroma,  943,  945 
common  sites  of,  943 
of  phalanx,  943,  944 
references  to  literature,  945 
Chondrosarcoma,  970 
Chordoma,  1088 

Chorionic  epithelioma,  1071,  1072 
of  testicle,  1075 
references  to  literature,  1074 
relation  to  hydatidiform  moles,  1075 
Choroid,  melanoma  of,  986 

pigment  of,  118 
Chromaffin  system  in  status  lymphaticus, 

844 

tissue  in  adrenals,  891 
tumors,  957 
Chromate  poisoning,  necrosis  of  kidney 

epithelium  in,  225 
Chromatophores,  118 
origin  of,  119 

relation  to  naevus  cells,  984 
Chyle,  fat  in,  77 
Chylous  ascites,  793 
Chyluria,  793 
Circulation,  collateral,  after  obstruction  of 

vena  cava  superior,  24 
disturbances  of,  in  arteriosclerosis,  465 

references  to  literature,  474 
mechanism  of,  461 

obstruction  of,  in  cardiac  valvular  dis- 
ease, 475 

mechanism  of,  475 
terminal,  diagram  of,  26 
Cirrhosis  of  liver,  321.     See  also  Liver, 

Cirrhosis  of. 

Claudication,  intermittent,  19 
Clonorchis  sinensis,  786 
Clot,  postmortem,  5,  5,  6 
Clotting  of  blood,  3,  6,  7 

appearance  under  ultramicroscope,  7 
Howell's  theory,  7 
mechanism  of,  4 
references  to  literature,  14 
Cloudy  swelling,  92 

references  to  literature,  92 
Coagulation  of  blood,  3,  6,  7 

appearance  under  ultramicroscope,  7 


Coagulation  of  blood  in  hsemopholia,  8 
in  icterus,  8 
in  pneumonia,  8 
in  purpura,  8 

Coal  pigment  in  lungs,  129 
Cohnheim's  theory  of  the  origin  of  tumors, 

1111 
Cold,  injuries  from,  385 

gangrene  produced  by,  386 
mechanism  of  injury  produced  by, 

385 

reaction  of  tissues  to,  hi  vitro,  385 
references  to  literature,  387 
Colds,  386 
Colitis,  amoebic,  767,  767,  768,  769 

diphtheritic,  in  mercury  poisoning,  404 
ulcerative,  in  dysentery,  619 
Colles'  law,  695 

Colloid  carcinoma  of  breast,  1065,  1066 
of  ovary,  1056 
of  stomach,  1047 

droplets  in  kidney  epithelium,  95,  280 
Comedones,  1004 
Compensation  of  heart,  482 
Complement,  171 
Concussion  of  brain,  372 
Conduction  system  of  heart,  495 
Condyloma,  702,  1003 

relation  to  papilloma,  1002 
Congestion,  chronic  passive,  486 
of  kidney,  493 
of  liver,  487,  488,  489 
of  lungs,  486,  486 
of  spleen,  492,  492 
Conjunctivitis  in  measles,  755 
Connective-tissue  cells,  division  of,  200 
degeneration  granules  in,  51 

specialization  of,  193 
growth  of,  in  vitro,  51,  180,  181,  182 
metaplasia  of,  195 
mitchondria  in,  51 
Contrecoup,  mechanism  of,  372 
Coronary  arteries,  arteriosclerosis  of,  468 
occlusion  of,  31,  250 
experimental,  468 
Corpora  amylacea  in  lung,  97 

in  prostate,  97 
Corpus  luteum,  endogenous  pigments  of 

125 

Coryza  in  congenital  syphilis,  740 
Courvoisier's  law,  127 
Cowper's  glands,  gonococcus  infections  of, 

561 
Cretinism,  873 


1126 


INDEX 


Cretinism,  aetiology  of,  874 
Cretins,  873 
Cyanide  poisoning,  401 
Cylindroma,  994,  995 

of  salivary  glands,  1004 
Cystadenoma,  1000 

of  ovary,  1003,  1013,  1014,  1015 
Cysticercus  cellulosse,  780 
Cystinuria,  87 
Cystitis,  451 

diphtheritic,  562 

gonococcus,  562 

in  typhoid  fever,  613 

types  of,  451 
Cystoma,  1000 
Cysts,  atheromatous,  1083 

branchial,  1083 

dermoid,  1082,  1082,  1083,  1084 
references  to  literature,  1089 

echinococcus,  781,  781,  782,  783 

of  breast,  1011 

of  kidney,  congenital,  1087 
in  chronic  nephritis,  292 
reference  to  literature,  1089 

of  ovary,  1013 

teratomatous,  1081,  1083,  1084 

of  parovarium,  1017 

relation  of,  to  adenomata,  1004 

traumatic  epidermal,  195 
Cytolysins,  166 
Cytoplasm,  50 
Cytoryctes  variolae,  753,  760 
Cytosine,  88 

DEATH  of  body,  58 

of  cells,  58 

tissue  changes  after,  59 
Debridement,  377 
Deciduoma,  experimental,  1073 

malignant,    1072.      See   also   Chorionic 

epithelioma. 

Decompensation,  cardiac,  482,  484 
Defensive    mechanism    of    body    against 

infection,  162 
Delirium  tremens,  402 
Degeneration,  61 

amyloid,  61 

fatty,  84 

hyaline,  61,  95 

of  cells,  60 

parenchymatous,  51,  92,  92,  93 
Dementia  paralytica,  735 

lesions  of  brain  in,  737,  737 
of  meninges  in,  737,  738 


Dementia  paralytica,  lesions  of  spinal  cord 

in,  739 

references  to  literature,  739 
trophic  disturbances  in,  736 
Dercum's  disease,  relation  of  hypophysis 

to,  904 

Dermatitis,  gonococcus,  568 
Dermoid  cyst,  1081,  1082 
of  ovary,  1081,  1081 
references  to  literature,  1089 
Diabetes  mellitus,  860 

acetone  bodies  in,  868 

acid-base  equilibrium  in,  869 

acidosis  in,  869 

arteriosclerosis  of  peripheral  vessels 

in,  345 

cause  of  death  in,  861 
disturbance  of  carbohydrate  metabo- 
lism in,  865 

of  fat  metabolism  in,  81,  868 
of  protein  metabolism  in,  868 
gangrene  in,  40,  40 
glycogen  in,  105 

islands  of  Langerhans  in,  869 
lipsemia  in,  868 
metabolism  in,  105 
pancreas  in,  861 
pathological  anatomy  of,  861 
references  to  literature,  105,  870 

resume  of,  870 

insipudus,  relation  of  hypophysis  to,  907 
Digestive  organs,  tuberculosis  of,  671 
Dilatation  of  heart,  482 
Diphtheria,  467,  574 

acute  interstitial  nephritis  in,  287 
focal  necrosis  of  liver  in,  317 
heart-failure  in,  467,  577 
nephritis  in,  577 
obstruction  of  larynx  in,  431 
of  bronchus,  576 
of  trachea,  575 
paralysis  in,  578 
references  to  literature,  578 
sequelae  of,  577 
Diplococcus   intracellularis    meningitidis, 

556 

Diseases,  mental,  metabolism  in,  65 
Dispar,  793 
Ducrey's  bacillus,  700 
Ductless  glands,  diseases  of,  860 

tuberculosis  of,  683 
Ductus  arteriosus,  closure  of,  353 
Duke's  fourth  disease,  aetiology  of,  753 
Duodenum,  ulcer  of,  422 


INDEX 


1127 


Dust  diseases,  129 

Dysentery,  amoebic,  767,  767,  768,  769 
intestinal  lesions  in,  767 
mode  of  infection  in,  767 
references  to  literature,  772 
antitoxin  for,  620 
bacillary,  616 

agglutination  tests  in,  620 

arthritis  in,  619 

intestinal  lesions  in,  617,  617, 618, 618, 

619 

lesions  of  nervous  system  in,  620 
mode  of  infection  in,  616 
references  to  literature,  620 
Dyspnoea,  cardiac,  485 
renal,  485 

EBURNATION,  541 

Echinococcus  cysts,  781,  781,  782,  788 
infection,  781 
serum  diagnosis  of,  784 
Eck's  fistula,  32 
Eclampsia,  316 

changes  in  liver  in,  225,  316,  316,  317 
necrosis  of  kidney  epithelium  in,  282 
Ehrlich's  side-chain  theory,  170 
Elastic  tissue,  calcification  of,  109,  114 
of  blood-vessels,  335 

in  arteriosclerosis,  339 
iron  incrustations  of,  114 
regeneration  of,  202 
Electricity,  burns  from,  393 
death  from,  393 
injuries  caused  by,  392 

references  to  literature,  393 
Electrocardiographic  tracings,  497,  498 
Elephantiasis,  793,  793 
Emboli,  19 
air,  21 

bacterial,  22,  265,  251 
cell,  22 
fat,  22,  377 
infected,  39 
lodgement  of,  20 
parasitic,  22 
softening  of,  39 
Embolism,  19 

references  to  literature,  42 
Embryo,  development  of,  1078 
differentiation  of  cells  in,  192 
Emphysema,  pulmonary,  437 
aetiology,  of,  438 
chronic  substantive,  438 
circulatory  disturbances  in,  464 


Emphysema,  pulmonary,  hypertrophy  of 

heart  in,  439 

in  bronchopneumonia,  518 
vicarious,  438 

references  to  literature,  440 
Empyema,  235,  236 

pneumococcus,  554 
Encephalitis,  influenzal,  598 

syphilitic,  726 
End-arteries,  25 

Endarteritis,  obliterative,  353,  356 
in  senile  ovary,  354 

uterus,  354,  354 
in  tuberculosis,  664 
references  to  literature,  357 
Endocarditis,  245 

acute  vegetative,  246,  249 

embolic  nephritis  in,  526 
bacteriology  of,  247 
chronic,  252 
gonococcus,  249,  568 
character  and  localization  of  vege- 
tations, 523 
healing  of,  251 
influenzal,  597 
meningococcus,  560 
mode  of  infection  in,  247 
pneumococcus,  554 

character  of  vegetations,  523 
rheumatic,  245,  248,  248,  570,  571,  571 
Aschoff  bodies  in,  572,  572 
character  and  localization  of  vegeta- 
tions, 523 
staphylococcus,  538 

character  and  localization  of  vegeta- 
tions, 523 
streptococcus,  523 

character  and  localization  of  vegeta- 
tions, 248 

haemolyticus,  523,  524 
viridans,  251,  525,  686,  572 

character  and  localization  of  vege- 
tations, 523,  525,  527 
syphilitic,  723 
types  of,  245,  249,  523 
typhoid,  613 
ulcerative,  249 
verrucous,  248,  249 
Endometritis,  diphtheritic,  261 
puerperal,  259,  522 

complications  of,  261 
Endostitis  fibrosa  in  rickets,  917 
Endothelial  cells  in  typhoid  fever,  604 
Endothelioma,  992 


1128 


INDEX 


Endothelioma  from  blood-vessel  endothe- 
lium,  997 

from  lymphatic  endothelium,  994 

of  meninges,  995,  997 

of  peritoneum,  994 

of  pleura,  994 

references  to  literature,  998 
Endothelium,  covering  of  thrombi  by,  225 

in  blood  formation,  194 

specificity  of,  194 
Endotoxins,  163,  511 
Enostoses,  946 
Entamoeba  coli,  766 

histolytica,  766,  767 

tetragena,  767 
Enteritis,  diphtheritic,  265,  266,  267 

in  chronic  nephritis,  307 

in  dysentery,  617,  617 
Enteroptosis,  463 
Eosinophiles,  148 

in  lesions  of  Hodgkin's  disease,  855 

regeneration  of,  207 

Eosinophilia,    changes    in    blood-forming 
organs,  826 

diseases  associated  with,  823 
Ependymitis  granularis  in  dementia  para- 

lytica,  738 

Epididymis,  tuberculosis  of,  671,  681,  680 
Epididymitis,  gonococcus,  563 
Epithelioid  cells  in  tubercles,  644 

origin  of,  646 

Epithelioma,  1019.     See  also  Carcinoma, 
squamous-cell. 

adamantine,  1030,  1031 

basal-cell,  1031,  1032,  1033 
references  to  literature,  1035 
resemblance  of  nsevi  to,  1034 

chorionic,  1071,  1073 
references  to  literature,  1074 

of  larynx,  1025 

of  lip,  1020 

of  mouth,  1024 

of  mucosse,  1024 

of  oesophagus,  1025 

of  penis,  1021,  1022 

of  skin,  1020,  1023 

of  tongue,  1024,  1024 

of  tonsils,  1025 

of  trachea,  1025 

of  uterus,  1028,  1028,  1029 

references  to  literature,  1031 

relation  of  stroma  to  epithelium,  999 
Epithelium,  growth  of,  in  vitro,  180,  182, 

183 


Epithelium,  metaplasia  of,  195 

regeneration  of,  in  healing  of  wounds 

and  ulcers,  197,  197,  198,  222 
Epulis,  978,  978 
Equilibrium  among  tissues,  181 

functional,  180 
Ergot  poisoning,  42 
Erysipelas,  521 

Erythema  infectiosum,  aetiology  of,  753 
Erythraemia,  806 
Erythrocytes,  149 
Eustachian  tube,  chancre  of,  717 

mechanism  of,  519 
Exanthematic  diseases,  753 
Exophthalmic  goitre,  881 
Exostoses,  946,  947 

references  to  literature,  883 
Extra-systoles,  experimental,  503 

origin  of,  501 

tachycardia  from,  502 
Extremities,  gangrene  of,  40,  356 

oedema  of,  43 
Eye,  glioma  of,  962 
Eyelids,  xanthoma  of,  948 

FALLOPIAN  tubes,  tuberculosis  of,  681 
Fasting,  effects  of,  63 
Fat-metabolism,  72 

in  diabetes,  868 

references  to  literature,  870 
Fat-necrosis,  418,  418 
Fat-phanerosis,  83 
Fat-tissue,  abscess  in,  223 

atrophy  of,  serous,  64 

embryonic,  76,  77 

regeneration  of,  202 
Fats,  73 

absorption  of,  76 

anisotropic,  85 
in  kidney,  292 

distribution  of,  in  body,  76 

emboli  of,   22,  377 

in  blood,  77 

in  chyle,  77 

in  lymph,  77 

in  parenchymatous  organs,  hi  obesity, 

80 
"masked,"  78 

in  renal  epithelium,  52 

of  Bacillus  tuberculosis,  80 

references  to  literature,  86 

relation  of  calcification  to,  110 

source  of,  75 
Fatty  acids  as  ferment  inhibitors,  79,  156 


INDEX 


1129 


Fatty  degeneration,  84 
infiltration,  82,  85 
experimental,  85 
of  arteries,  84 
of  heart,  83,  466 
of  kidney,  84 
of  liver,  68,  80,  83 
of  necrotic  tissue,  85 
references  to  literature,  86 
Ferments,  oxidizing,  118 

proteolytic,  in  leucocytes,  156 

inhibition  of,  79 
Fever,  133,  158 

in  anaphy lactic  shock,  161 
in  inflammation,  142 
mechanism  of,  161 
metabolism  in,  65,  159 
references  to  literature,  161 
relation  to  hypothalamus,  161 

to  immunity,  160 
Fibrillation  of  heart,  449 
Fibrinogen,  7 
Fibroblasts,  180 
Fibroma,  937 

common  sites  of,  938 
molluscum,  939 
cedematous,  937 
of  kidney,  941 
of  ovary,  941 
of  skin,  939 

references  to  literature,  942 
types  of,  937,  938 
Fibromyoma  of  uterus,  948,  949 
Fibrosarcoma,  973 
Filaria  Bancrofti,  793 

references  to  literature,  794 
Fistulse,  225 
Fluids  of  body,  disturbances  of,  1 

relation  to  tissues,  1 
Fluorescent  substances,  387 

toxic  action  of,  388 
Foreign  bodies,  reaction  of  tissues  to,  216, 

218 

Fracture  of  bones,  372 
comminuted,  372 
compound,  372 
greenstick,  372 
healed,  373 
Fragilitas  ossium,  378 
Fragmentation  of  myocardium,  473,  47$, 

4U 

Framboasia,  749 
Freezing,  death  from,  385 
gangrene  produced  by,  386 


Freezing  of  tissues,  effects  of,  385 
Friedlander  bacillus,  543 
Frohlich's  syndrome,  904,  904 
Functional  equilibrium,  180,  183 
Furunculosis,  264,  534 
in  typhoid  fever,  614 

GALL-BLADDER,  carcinoma  of,  1026,  1048, 
1049 

references  to  literature,  1057 
relation  to  gall-stones,  1048 
inflammation  of,  410.      See  also  Chole- 


obstruction  of,  331 

by  gall-stones,  126 
oedema  of,  44 

Gall-stones,  408  (Fig.  201,  facing  p.  410) 
bacteria  in,  410,  612 
cholesterine,  409  (Fig.  201,  facing  p.  410) 
mixed   cholesterine  and  pigment  (Fig 

201,  facing  p.  410) 
obstruction  of  gall-ducts  by,  126,  331, 

332,  411 

references  to  literature,  415,  429 
relation  to  carcinoma  of  gall-bladder, 

1048 

varieties  of,  408  (Fig.  201,  facing  p.  410) 
Ganglion-cells,   endogenous  pigmentation 

of,  125 

Ganglioneuroma,  957 
Gangrene,  40 
dry,  40 
moist,  40 

of  extremities,  40,  41,  356 
from  exposure  to  cold,  386 
in  diabetes,  41 
in  ergot  poisoning,  42 
of  lungs,  259 

in  lobar  pneumonia,  554 
Garget,  515 

Gas  bacillus  infection  of  endometrium,  260 
Gastric  ulcer,  421,  422 
Gastritis,  phlegmonous,  streptococcal,  520 
Gaucher's  splenomegaly,  820 
General  paresis,  735 
Genital  organs,  effect  of  x-rays  on,  391 
syphilis  of,  723 

references  to  literature,  725 
Genito-urinary  tract,  tuberculosis  of,  677 
mode  of  infection  in,  677 
references  to  literature,  681 
German  measles,  aetiology  of,  753 
Giant  cells,  foreign  body,   153,  154,   189, 


1130 


INDEX 


Giant  cells,  foreign  body,  origin  of,  154 
in  gummata,  704,  707 
in  lesions  of  Hodgkin's  disease,  855 
in  pneumonic  exudates,  258 
in  tubercles,  644,  644,  648 
in  tumors,  977 
Gigantism,  187,  899,  901,  902.     See  also 

Acromegaly. 

relation  of  hypophysis  to,  899 
Glanders,  587 
of  lung,  588,  588 
of  nose,  587 
of  skin,  588 

references  to  literature,  589 
Glioma,  957 

cyst  formation  in,  961 

ependymal,  962 

of  brain,  958,  959,  960,  961 

with  hemorrhage,  958 
of  eye,  962 

references  to  literature,  962 
Gliosarcoma,  970 
Glossinse,  transmission  of  trypanosomiasis 

by,  779 
Glottis,  foreign  bodies  in,  431 

oedema  of,  431 

Glycogen    in    disturbances    of    carbohy- 
drate metabolism,  865 
in  liver  cells,  53 
in  tissues,  104 

in  diabetes  mellitus,  105,  861 
in  tumors,  105 
staining  of,  104 
Glycolysis,  865 

Glycosuria,  866.   See  also  Diabetes  mellitus. 
adrenaline,  893 
experimental,  861 
following  pancreas  extirpation,  866 

stimulation  of  sympathetic,  867 
piqure,  867 
in  drug  poisoning,  867 
in  narcosis,  867 
in  phloridzin  poisoning,  867 
references  to  literature,  870 
Goitre,  874 

adenomatous,  875,  876,  877 
colloid,  875 

exophthalmic,  65,  878,  879 
aetiology  of,  881 
eye  changes  in,  878 
functional  disturbances  in,  879 
metabolism  in,  879 
thymus  in,  889 
thyroid  in,  880,  880 


Goitre,  mechanical  effects  of,  877 
obstruction  of  trachea  in,  431 
references  to  literature,  883 
Golgi's  reticular  apparatus,  50 
Gonococcus  infection,  561 
of  bladder,  562,  563 
of  conjunctiva,  567 
of  Cowper's  glands,  561 
of  endocardium,  249,  568 

character  and  localization  of  vege- 
tations, 523 
of  epididymis,  563 
of  Fallopian  tubes,  563,  566 

sequelae  of,  563 
of  joints,  567 
of  kidneys,  563 
of  Littre's  glands,  561 
of  meninges,  568 
of  myocardium,  568 
of  pericardium,  568 
of  peritoneum,  237 
of  prostate,  563 
of  seminal  vesicles,  563 
of  skin,  568 
of  ureters,  563 
of  urethra,  561 

sequelae  of,  563 
of  vagina,  563 

in  children,  563,  569 
references  to  literature,  569 
Gonorrhea,    urethral   stricture   following, 

441,  562    . 
Gout,  aetiology  of,  89 

association  of,  with  lead  poisoning,  89 
metabolism  in,  87 
nephritis  in,  89 
references  to  literature,  91 
tophi  in,  90,  91 
urate  deposits  in,  90,  90 
uric  acid  of  blood  in,  90 
Granulation  tissue,  201,  216,  217,  221,  221, 

222,  224 

about  foreign  bodies,  218 
syphilitic,  707 
tuberculous,  649,  649 
Graves'    disease,    878.      See   also   Goitre, 

exophthalmic. 
Grawitz  tumors,   988.     See  also  Hyper- 

nephroma. 

Growth,  abnormal,  in  tumors,  1093 
causes  of,  177 
influence  of  internal  secretions  on,  186 

of  nervous  system  on,  178 
mechanical  influences  in,  178 


INDEX 


1131 


Growth  of  normal  tissues,  1092 

stimulation  of,  186,  186 
Guanine,  88 

Gumma,    693,    704.      See    also   Syphilis, 
tertiary  stage. 

differentiation,  from  tubercle,  705 

giant  cells  in,  704,  707 

of  brain,  706,  726,  727 

of  heart,  723 

of  kidney,  715 

of  liver,  706,  711,  712,  713 
miliary,  704,  705,  706 

of  lung,  717 

of  lymph-glands,  708 

of  meninges,  72,  728 

of  pancreas,  714 

relation  to  diabetes,  714 

of  periosteum,  706 

of  pharynx,  710 

of  salivary  glands,  714 

of  testicle,  704,  724,  724 

of  tonsils,  710 

spirochete  in,  705 
Gunshot  wounds,  375 

H^MANGIOMA,  963 

common  sites  of,  963 

of  heart  valves,  966,  967 

of  intestine,  964,  965 

of  liver,  965,  966 

of  muscles,  964 

of  skin,  963,  964 

plexiform,  963 

references  to  literature,  968 

telangiectatic,  963 
Hsematin,  113 

decomposition  of,  112 
Hsematoidin,  121 
Haematomyelia,  374 
Haematopoietic    organs,    796.      See    also 

Blood-forming  organs. 
Haematoporphyrin,  114 

in  sulphonal  poisoning,  121 
Haemochromatosis,  114,  115,  815 

iron  pigments  in,  116 

references  to  literature,  116 
Haemofuscin  in  haemochromatosis,  124 
Haemoglobin,  composition  of,  112 

excretion  of,  121 

pigments  derived  from,  121 
Haemoglobinuria  in  burns,  383 

in  malaria,  120 
Haemoglobinuric  fever,  778 
Haemolymph  nodes,  805 


Haemolymph  nodes,  references  to  litera- 
ture, 820 
Hsemolysins,  166 
Haemolysis,  bacterial,  121 

due  to  streptococcus,  513 

poisons  causing,  807 

postmortem,  121 

relation  of  lipoids  to,  81 
Haemopericardium,  375 
Haemophilia,  blood-clotting  in,  8 

haemorrhage  in,  378 
Haemorrhages  in  brain,  366,  866 

in  chronic  myeloid  leukaemia,  845 

in  scurvy,  922 

of  lung,  34 

of  meninges,  372 

petechial,  528 

subdural,  with  compression  of  brain,  874 
Haemorrhoids,  493 
Haemosiderin,  113,  121 

in  liver  cells,  124 

in  phagocytic  cells,  122 
Haldane-Smith     method     of     estimating 

quantity  of  blood  in  body,  2 
Halisteresis,  106 

in  rickets,  917 
Halteridium,  773 
Hamartomata,  966 
Harrison's  groove,  430 
Heart,  abscesses  in,  467 

Aschoff  bodies  in,  467,  468 

brown  atrophy  of,  63,  64,  466 

compensation  of,  482 

conduction  bundle,  diseases  of,  499 
system  of,  diagram  of,  496 
interruption  of,  499 
pathology  of,  495 
references  to  literature,  503 

decompensation  of,  484 

dilatation  of,  482,  485 

failure  of  compensation  of,  484 

fatty  infiltration  of,  83,  83,  84,  466 

fibrillation  of,  501 

gumma  of,  723 

association  with  heart  block,  723 

hypertrophy  of,  252,  469,  482 
aetiology  of,  483 
in  chronic  nephritis,  302 
in  emphysema,  439 
in  pulmonary  obstruction,  464 
references  to  literature,  494 

in  myeloid  leukaemia,  851 

in  smallpox,  716 

infarction  of,  28,  29,  30,  468,  469 


1132 


INDEX 


Heart,  injection  of  vessels  of,  248 
mechanism  of  action  of,  461 
syphilis  of,  722 

references  to  literature,  726 
thrombi  in,  10,  12,  469 
tumors  of,  myxoma,  981 

rhabdomyoma,  953 
valvular  diseases  of,  475,  495 
effects  of,  475 

references  to  literature,  494 
Heart-beat,  irregularity  of,  499 
Heart-block,  electrocardiographic  tracing, 

501,  501 

"Heart-failure"  cells,  123,  123,  486,  487 
Heart-muscle,  465 

endogenous  pigments  of,  125 
Heart-valves,  calcification  of,  253 
hsemangioma  of,  966,  967 
insufficiency  and  stenosis  of,  252,  254, 

477,  479,  480,  481 
senile  thickening  of,  246 
types  of  vegetations  on,  caused  by  vari- 
ous organisms,  523 
vascular  supply  of,  248 
Heat,  injuries  from,  382 

references  to  literature,  384 
prostration,  383 
stroke,  383 

Heine-Medin's  disease,  688 
Heparin,  7 
Hepatization,  545 
Hepatolysins,  167 

Heredity,  relation  of,  to  tumors,  1106 
Hernia,  16,  37,  425 
femoral,  425 
incarcerated,  426 
inguinal,  425 
internal,  425 
strangulated,  17,  426 
umbilical,  425 
Heterotope  impulses,  499 

arrhythmia  from,  500 
His  bundle,  495 
Histamine,  143,  169.     See  Beta-imidazol- 

ethylamine. 

in  intestinal  obstruction,  424 
production  of,  in  tissues,  143 
Hodgkin's  disease,  853 
aetiology  of,  858 
cause  of  death  in,  854 
characteristics  of  lesions,  854,  854,  856 
differentiation    of,    from    pseudoleu- 

ka3mia,  839 
early  stage,  855 


Hodgkin's  disease,  evidence  as  to  infec- 
tious nature  of,  858 
references  to  literature,  859 
relation  of,  to  tumors,  1095 
Hookworm  disease,  789,  791 
HowelFs  theory  of  blood-clotting,  7 
Hunger,  63 

Hutchinson's  teeth,  748 
Hyaline  casts,  305 

connective  tissue,  97 

degeneration,  61 

of  blood-vessels,  97,  98 
of  muscle,  96,  518 

droplets  in  kidney  epithelium,  95,  97, 
280 

epithelial,  96 

thrombi,  98 

Hydatidiform  mole,  1071 
Hydrocephalus,  504 

communicating,  507 

following  meningitis,  505,  506,  560 
obstruction  of  aqueduct  of  Sylvius, 
507 

in  chondrodystrophia  foetalis,  920 

in  tuberculous  meningitis,  629 

mechanism  of  retention  of  fluid  in,  506 

obstructive,  507 

pneumoventriculography  in,  505 

references  to  literature,  507 

syphilitic,  747 

Hydrochloric  acid  poisoning,  400 
Hydrogen  ion  concentration,  of  blood,  172 
Hydronephrosis,  67,  453,  453,  456 

references  to  literature,  460 
Hydropericardium,  43 
Hydrosalpinx,  567,  566 
Hydrothorax,  43 
Hygromata,  cystic,  968 
Hypersemia,  16 

active,  16 

chronic  passive,  16,  17,  486.     See  also 

Congestion,  chronic  passive. 
Hyperglycsemia  following  pancreas  extir- 
pation, 866 

in  diabetes  mellitus,  861 
Hypernephroma,  988,  989,  990 

metastasis  of,  989 

origin  of  cells  in,  991 

references  to  literature,  991 

sites  of  origin,  988 
Hyperostosis,  946 
Hyperplasia,  70,  182 

relation  of  injury  to,  184 
Hyperthyroidism,  experimental,  882 


INDEX 


1133 


Hypertrophy,  70,  182 
of  bladder,  444,  452 
of  heart, -482 
of  prostate,  443,  444,  445 
relation  of  injury  to,  184 
Hypophysis,  adenoma  of,  1009 
cholesteatoma  of,  1083 
disturbances  in  secretion  of,  relation  to 

obesity,  81 

effect  of  tumors  of,  907 
effects  of  extirpation,  898,  901 
hyperactivity,  899 
hypoactivity,  899,  904 
in  pregnancy,  907 
influence  of,  on  bone  development,  898 

on  sexual  development,  899,  901,  905 
insufficiency,  effect  of,  905 
properties  of  extracts,  898 
relation  of,  to  acromegaly,  899 

to  adiposis  dolorosa,  904,  906 

to  bone  formation,  911 

to  diabetes  insipidus,  907 

to  lipomatosis,  904,  906 
secretion  of,  897 
structure  of,  897 

references  to  literature,  908 
Hypostasis,  17 
Hypoxan thine,  88 

ICHTHYOSIS  syphilitica,  740 
Icterus,  125.    See  also  Jaundice. 

hsemolytic,  816 
Ileus,  paralytic,  427.     See  also  Intestinal 

obstruction. 

Illuminating  gas  poisoning,  399 
Immunity,  antitoxic,  169 

artificial,  165 

methods  of  producing,  166 

as  response  to  injury,  133 

influence  of  temperature  changes  on,  164 

of  lower  animals  to  transplantable  tu- 
mors, 1108 

passive,  166 

production  of,  133 

racial,  164 

references  to  literature,  171 

relation  of  fever  to,  160 
of  lipoids  to,  80 

to  chemical  poisons,  164 
Impetigo  contagiosa,  534 
Implantation  of  tumors,  1099 
Inactivity,  66 
Infantile  paralysis,  688 
Infarct,  anaemic,  28,  29 


Infarct,  hsemorrhagic,  29,  33,  39 

healing  of,  39 

of  brain,  28,  36,  35,  37 

of  .heart,  29,  31,  468,  469 

of  intestine,  36,  38,  427 

of  kidney,  28,  29,  30,  57 

of  liver,  29,  32 
septic,  525 

of  lung,  32 

with  acute  pleurisy,  233 

of  spleen,  29,  31,  31 

type  of  necrosis  of,  58 

uric  acid,  of  kidney,  448 
Infarction,  27 

references  to  literature,  42 
Infection,  amoebic,  766 

bacterial,  509,  512 

lowered  resistance  to,  510 
natural  resistance  to,  511,  511 
references  to  literature,  512 

diphtheritic,  574 

dysentery,  616 

gonococcus,  561 

influenza,  592 

meningococcus,  556 

mixed,  163 

paratyphoid,  615 

pneumococcus,  543 

secondary,  511 

spirochsetal,  748 

staphylococcus,  533 

streptococcus,  513 

terminal,  511 

tetanus,  578 

typhoid,  599 

typhus,  686 
Inflammation,  134 

acute,  136 

catarrhal,  229 

chronic,  142 

croupous,  229 

diphtheritic,  229,  265,  266,  267,  575 

emigration  of  leucocytes  in,  139 

experimental,  136,  650 

fever  in,  142,  158 

fibrino-purulent,  231 

gangrenous,  229 

new  growth  of  tissue  in,  176 

pain  in,  157 

phagocytosis  in,  144,  155 

phlegmonous,  229 

protective,  177 

references  to  literature,  157 

role  of  nervous  system  in,  143 


1134 


INDEX 


Inflammation,  serofibrinous,  231 
slowing  of  blood  stream  in,  144 
temperature  changes  in,  144 
tuberculous,  acute,  650 
vascular  changes  in,  136,  186,  143 
wandering  cells  in,  146 

genealogical  tree  of,  150 
Influenza,  592 

antrum  infection  in,  597 
bronchiectasis  in,  436 
encephalitis  in,  598 
endocarditis  in,  597 
immunity  to,  593 
leukopenia  in,  592 
meningitis  in,  597 
pneumonia  in,  594,  596,  597 
portal  of  entry  in,  593 
references  to  literature,  598 
relation  to  tuberculosis,  597 

of  Bacillus  influenzas  to,  593 
secondary  infection  in,  593 
sequelae  of,  594 

similarity  to  exanthemata,  592 
transmission  of,  593 
types  of  pneumonia  following,  594 
produced  by  pneumococcus,  595 
by  staphylococcus,  596 
by  Friedlander  bacillus,  596 
by  Pfeiffer  bacillus,  596 
by  Streptococcus  haemolyticus,  596 
Injuries  as  cause  of  tumors,  1103 
bacterial,  509.     See  also  Infection  and 

Inflammation. 
chemical,  162,  394 

references  to  literature,  406 
defensive  mechanisms  against,  133 
from  cold,  385 

references  to  literature,  387 
from  electricity,  387 

references  to  literature,  393 
from  heat,  382 

references  to  literature,  384 
from  light,  387 

references  to  literature,  393 
lowered  resistance  to,  377 
mechanical,  162,  369 

references  to  literature,  378 
reactions  to,  132 
Insolation,  384 
Internal  secretions,  derangements  of,  65 

influence  on  growth,  187,  1106 
Interstitial  pneumonia,  516,  517,  596,  597 
Intestinal  obstruction,  423 
histamine  in,  424 


Intestinal  obstruction,  mechanism  of,  423 

post-operative,  427 

reference  to  literature,  429 
Intestine,  abscess  of,  265,  536 
actinomycosis  of,  631 
amyloid  infiltration  of,  100 
infarction  of,  28,  29,  36,  38,  427 
in  amoebic  dysentery,  767,  767,  768,  770 
in  anthrax,  590 

in  bacillary  dysentery,  617,  617,  618,  619 
in  status  lymphaticus,  842 
in  typhoid  fever,  600,  600,  601,  602,  607 
intussusception  of,  38,  38,  426 
oedema  of,  44 
parasites  in,  780 
perforation  of,  377 
stenosis  of,  428 
strangulation  of,  17 
stricture  of,  428 
syphilis  of,  710 
tuberculosis  of,  671,  672,  672,  673,  674, 

675 
tumors  of,  adenoma  of,  1005, 1005,  1006 

carcinoma  of,  1050,  1051 

haemangioma  of,  964 

lymphosarcoma  of,  840,  841 

papilloma  of,  1002 
Intussusception,  38,  38,  426 
Involucrum  in  osteomyelitis,  540,  541 
Iodides,  action  of,  in  syphilis,  712 
Iodine  in  thyroid,  877 

poisoning,  tubular  nephritis  in,  286 
Iron,  absorption  of,  112 
deficiency  of,  113 
distribution  in  body,  111 
disturbances  in  metabolism  of,  111 

in  haemochromatosis,  116 

references  to  literature,  116 
excretion  of,  112 
function  of,  in  body,  113 
pigments,  116 

in  haemochromatosis,  115,  116 

in  pernicious  anaemia,  811 

reaction  for,  in  tissues,  487 
quantity  of,  in  blood,  111 
relation  to  calcification,  114 
Irritation  as  cause  of  tumors,  1103,  1110 
Islands  of  Langerhans,  lesions  of,  in  dia- 
betes, 862,  863 

JAUNDICE,  125 

bile  pigments  in,  125,  128 

causes  of,  126 

delayed  blood  clotting  in,  7,  126 


INDEX 


1135 


Jaundice,  experimental,  127 

hsemolytic,  127,  816 

references  to  literature,  821 

in  acute  yellow  atrophy,  127 

in  cirrhosis  of  liver,  127,  316,  333 

in  phosphorus  poisoning,  404 

in  pneumonia,  127 

obstructive,  126,  331,  411 
necrosis  of  liver  in,  413 

of  liver,  125,  128 

of  newborn,  127 
Jaw,  actinomycosis  of,  631 

adamantine  epithelioma  of,  1031 

sarcoma  of,  978,  978 
Joints,  free  bodies  in,  933 

in  acute  rheumatism,  570 

in  arthritis  deformans,  927 

staphylococcus  infections  of,  536 

syphilis  of,  718 

tuberculosis  of,  683 
references  to  literature,  685 

types  of  infections  of,  926 

KALKF  ANGER,  110 

Karyolysis,  54,  56 

Karyorrhexis,  57,  56 

Keith's  node,  495 

Keloids,  940 

Kephaline,  74 

Kerosin,  75 

Kidney,  abscess  of,  262,  263,  457 

amyloid  infiltration  of,  99, 101, 298, 299, 

300,  301 

anisotropic  fats  in,  292 
arteriosclerotic  atrophy  of,  19,  70 
ascending  infection  of,  457,  537 
atrophy  of,  from  obstruction  of  ureter, 

185 

calcification  of,  experimental,  195 
of  necrotic    epithelium    in    mercury 

poisoning,  108,  285 
calculi  in,  446,  454,  4$4 
chromate  poisoning  of,  225 
chronic  passive  congestion  of,  493 
cloudy  swelling  of,  93 
colloid  droplets  in  epithelium  of,   95, 

279,  280 

compensatory  hypertrophy  in,  293 
congenital  cystic,  1086,  1087 

references  to  literature,  1089 
epithelium,  regeneration  of,  200 

specificity  of  function,  304 
fatty  infiltration  of,  53,  84 
functional  insufficiency  of,  304 


Kidney,  gummata  of,  715 

hsematogenous  infection  of,  537 
hyaline  degeneration  of,  296,  297 

droplets  in  epithelium  of,  97 
hydronephrosis,  453,  453,  456 
infarction  of,  28,  28,  29,  80,  56 

uric  acid,  448 

inflammation  of,  269.     See  also  Neph- 
ritis. 

in  eclampsia,  282 
in  mercury  poisoning,  405 
in  pernicious  anemia,  124 
-  in  smallpox,  763 
in  typhoid  fever,  612 
obsolete  scars  in,  271 
parenchymatous  degeneration  of,  92 
primary    contracted    (arteriosclerotic), 

289 

secondary  contracted,  281,  282,  283 
syphilis  of,  715 

congenital,  744 
tuberculosis  of,  671,  679,  679 
tumors  of,  adenoma,  1006,  1007 

fibroma,  941 

hypernephroma,  989 

lipoma,  942 

lymphosareoma,  839,  840 

mixed  tumors,  1086 

references  to  literature,  1089 
uranium  poisoning  of,  225 
Koplik's  spots  in  measles,  755 
Krukenberg  tumor  of  ovary,  1067 
Kupffer  cells,  vital  staining  of,  155 

LANGHANS'  cells  of  chorion,  1071 
Laryngismus  stridulus,  430 
Laryngitis  in  leprosy,  626 

in  typhoid  fever,  613 
Larynx,  epithelioma  of,  1025 
obstruction  of,  430 
cedema  of,  430 

references  to  literature,  437 
syphilis  of,  717 
tuberculosis  of,  655,  671 
Lateral  sinus,  thrombosis  of,  519 
I  Lead  poisoning,  403 
anaemia  in,  403 
brain  in,  403 
chronic  nephritis  in,  403 
peripheral  neuritis  in,  81,  404 
Lecithin,  74 

as  activator  of  cobra  venom,  80 
Leiomyoma,  948,  952 
common  sites  of,  948 


1136 


INDEX 


Leiomyoma,  malignant  changes  in,  951 
Lenticular  nuclei,  degeneration  of,  in  illu- 
minating gas  poisoning,  399 
Lenticulo-optic  artery,  397 
Lenticulo-striate  artery,  397 
Leontiasis  ossea,  923 
Lepra  cells,  625,  627 
Leprosy,  621 

anaesthetic,  621,  684 

atrophy  of  bones  in,  628,  628 

bacillus,  625 

bronchitis  in,  626 

granulation  tissue  in,  625 

laryngitis  in,  626 

lesions  of  lungs,  626 
of  organs  in,  628 

neuritis  in,  527,  628 

nodular,  621,  622,  623 

pharyngitis  in,  626 

references  to  literature,  629 

skin  lesions  in,  623 

transmission  of,  621 

tubercular,  628 
Leptospira  icteroides,  751 
Leucine  in  urine,  87 
Leucocidins,  164 

Leucocytes,  emigration  of,  in  inflamma- 
tion, 139 

endothelial,  152 

polymorphonuclear,  regeneration  of,  207 
Leucocytosis,  146,  207,  822 

blood-forming  organs  in,  823,  824 

conditions  associated  with,  823 

eosinophilic,  823 

in  infections,  528 

lymphatic,  823 

neutrophilic,  823 
Leucoderma,  131 

syphilitic,  702,  716 
Leucopenia,  822 

in  influenza,  592 
Leucoprotease,  156 
Leucosarcoma,  836,  837 

references  to  literature,  844 

relation  to  other  sarcomata,  991 
Leukaemia,  classification  of,  828 

lymphoid,  acute,  832,  833 

chronic,  829,  830,  831,  833,  834 

myeloblastic,  851 

myeloid,  acute,  851 

chronic,  845,  846,  847,  848,  849,  850 

references  to  literature,  844 
Lichen  scrophulosorum,  683 
Light,  injuries  from,  387 


Light,  injuries  from,  references  to  litera- 
ture, 393 

rays,  nature  of,  387 
Lip,  chancre  of,  709 

epithelioma  of,  710 
Lipsemia  in  diabetes,  868 
Lipochromes,  64,  73,  75 

staining  of,  125 
Lipoids,  73 

antitoxic  action  of,  79 
function  of,  78 
in  adrenals,  892 
in  cell  membranes,  78 
in  hypernephromata,  991 
in  Wassermann  reaction,  79 
in  xanthomata,  948 
relation  to  haemolysis,  81 

to  immunity,  80 
toxic  action  of,  80 
Lipoma,  942 

arborescens  in  joints,  933 
common  sites  of,  942 
multiple,  942 
of  kidney,  942 
references  to  literature,  943 
Lipomatosis,   relation  of  hypophysis  to, 

904,  906 
Littre's  glands,  gonococcus  infection  of, 

561 
Liver,  abscess  of,  265,  264,  414 

amoebic,  769,  770,  771 
actinomycosis  of,  632,  632 
acute  yellow  atrophy  of,  315 

jaundice  in,  127 
amyloid  infiltration  of,  99,  102 
atrophy  of,  63,  64 
autolysis  of,  58 

blood  formation  of,  in  congenital  syph- 
ilis, 742 

is  osteosclerotic  anaemia,  817,  818 
chronic  passive  congestion  of,  487,  488, 

489 

types  of,  491 
cirrhosis  of,  227,  321 
alcoholic,  321 
atrophic,  321 
biliary,  321,  330,  382,  333 
circulatory  disturbances  in,  329,  830, 

331 

experimental,  321 
Hanot's,  322,  333 
hypertrophic  biliary,  322,  333 
in  Banti's  disease,  818,  819 
jaundice  in,  316 


INDEX 


1137 


Liver,  cirrhosis  of,  Laennec's,  322 

nodular,  320,  321,  322,  322,  323,  324, 

325,  326,  327 

obstructive  biliary,  321,  330 
portal,  321 

references  to  literature,  334 
regeneration  of,  200,  317,  324,  327 
syphilitic,  322 
tuberculous,  322 
cloudy  swelling  of,  93 
compression  of,  68 
echinococcus  cyst  of,  783 
fatty  infiltration  of,  83 
from  pressure,  68 
in  obesity,  80 
focal  necrosis  of,  314 
in  diphtheria,  317 
in  eclampsia,  317,  318 
in  paratyphoid,  615 
in  typhoid  fever,  314,  317,  610,  611, 

612 

glycogen  in,  53 

gumma  of,  705,  706,  711,  712,  713 
haemochromatosis  of,  114,  115 
hsemosiderin  in,  124 
in  acute  yellow  atrophy,  315,  320 
in  chloroform  poisoning,  315 
in  chronic  lymphoid  leukaemia,  830 
in  eclampsia,  316,  316,  317 
in  leprosy,  628 
in  malaria,  120,  776,  777 
in  myeloid  leukaemia,  846,  849,  850 
in  pernicious  anaemia,  124,  815 
in  smallpox,  763 
in  typhoid  fever,  610,  314 
infarction  of,  29,  32 

septic,  525 
injury  and  repair  of,  312,  317 

references  to  literature,  334 
jaundice  of,  125,  127 
necrosis  of,   in  acute  yellow  atrophy, 
in    chronic   passive   congestion,    313, 

313,  313,  488,  489 
in  chloroform  poisoning,  313 
in  eclampsia,  316,  317 
in  obstructive  jaundice,  414 
in  phosphorus  poisoning,  401 
in  streptococcus  peritonitis,  312 
mid-zonal,  226 
"nutmeg,"  488 
rupture  of,  371 
structure  of,  310,  311 
syphilis  of,  705,  706,  711,  718,  713,  714, 
715 

73 


Liver,  syphilis  of,  congenital,  741,  742 
tuberculosis  of,  miliary,  655,  671 

experimental  production  of,  647 
tumors  of,  adenoma,  1006 

carcinoma,  primary,  1050,  1068,  1069 

references  to  literature,  1071 
secondary,  1043,  1044,  1045 
haemangioma,  965,  966 
melanoma,  118,  119,  987,  988 
sarcoma,  metastatic,  973 
Liver-cells,  regeneration  of,  328 

from  bile-ducts,  199,  318,  319,  325 
Livor  mortis,  15 

Lockjaw,  578.     See  also  Tetanus. 
Locomotor  ataxia,  729 

references  to  literature,  735 
Lordosis  in  chondrodystrophia  foetalis,  920 
Lud wig's  angina,  430,  515 
Luetin  reaction,  695 

relation  of  anaphylaxis  to,  169 
Lung,  abscess  of,  259,  265,  536,  538 

amoebic,  772 
actinomycosis  of,  631 
anthracosis  of,  129 
anthrax,  590 
atelectasis  of,  432 
autolysis  of,  58 
"brown  induration"  of,  487 
chronic  passive  congestion  of,  123,  123, 

486,  486 

corpora  amylacea  in,  97 
emphysema  of,  437 

circulatory  disturbances  in,  464 
gangrene  of,  42,  259 
gummata  in,  717 
haemorrhage  in,  34 
in  bubonic  plague,  586,  587 
infarction  of,  32,  33 
inflammation  of,  544.     See  also  Pnevs- 

monia. 
oedema  of,  45,  46 

from  adrenaline,  46 
pigmentation  in,  129 
syphilis  of,  717 

congenital,  740 
tuberculosis,  of,  655 

acute,  643,  652, 660, 659, 660, 661, 662, 

663 

chronic,  658,  663,  666 
healing,  657,  667 
secondary  infection  in,  669 
tumors  of,  carcinoma,  1025 
metastatic,  1045,  1046,  1049 
sarcoma,  metastatic,  973 


1138 


INDEX 


Lupus  vulgaris,  effect  of  light  rays  on, 

389 

Lycopodium  spores  as  foreign  body  irri- 
tants, 188,  189 
Lymph,  1,  43 

clotting  of,  4 

fat  in,  77 
Lymphangioma,  966 

common  sites  of,  966 

cystic,  967 

of  tongue,  966 

references  to  literature,  968 
Lymphatic  vessels,  1,  43 
endothelioma  of,  994 
obstruction  of,  44 
in  filariasis,  793 
regeneration  of,  205 
Lymph-glands,  amyloid  infiltration  of,  100 

anthracosis  of,  129,  129 

calcification  of,  41,  108 

carcinoma  of,  metastatic,  1057,  1067 

effects  of  x-rays  on,  391 

gummata  in,  708 

in  acute  poliomyelitis,  691 

in  anthrax,  590 

in  bubonic  plague,  586 

in  Hodgkin's  disease,  854,  856 

in  lymphoid  leukaemia,  acute,  832 
chronic,  829 

in  myeloid  leukaemia,  847 

in  scarlet  fever,  758 

in  smallpox,  763 

in  trypanosomiasis,  779 

in  typhoid  fever,  604,  605,  607,  608 

lymphosarcoma  of,  839 

regeneration  of,  206 

sarcoma  of,  974 

syphilis  of,  708 

tuberculosis  of,  657,  676,  677,  677 
Lymphocytosis,  823 

changes    in    blood-forming    organs    in, 
826 

in  syphilis,  709 

references  to  literature,  820 
Lymphogranulomatosis,    853.      See    also 

Hodgkin's  disease. 
Lymphoid  tissue,  804 

hyperplasia  in  exophthalmic   goitre, 

881 

in  status  lymphaticus,  843,  843 
Lymphosarcoma,  839,  840,  841 

differentiation  of,  from  related  affections, 
841,  971 

references  to  literature,  844 


Lymphosarcoma,  types  of,  839 
Lymphosarcomatosis,  839 
Lysol  poisoning,  400 

MACROGLOSSIA,  966 
Macrophages  in  typhoid  fever,  607 
Malaria,  773 

anaemia  in,  808 

haemoglobinuria  in,  120,  778 

lesions  of  organs  in,  120,  775,  776,  776, 
777 

parasites  of,  773 

references  to  literature,  778 
Malformations,  1106 
Mammitis,  infectious,  515 

in  measles,  515 

relation  to  infected  milk,  515 
Mast  ceUs,  152 

in  nasal  polyps,  937,  940 
Mastitis,  cystic,  1064 

relation  of,  to  carcinoma,  1061,  1063 

in  typhoid  fever,  614 
Measles,  753 

aetiology  of,  754 

epidemics  of,  515 

immunity  to,  753 

Koplik  spots  in,  755 

lesions  of  organs  in,  755 

lobular  pneumonia  in,  515,  755 

mammitis  in,  515 

obliterative  bronchiolotis  in,  755 

otitis  media  in,  755 

racial  susceptibility  to,  164 

references  to  literature,  755 

skin  lesions  in,  755 

streptococcus  infection  in,  515,  754 

susceptibility  to  tuberculosis  in,  754 
Megaloblasts,  149,  800 
Megalokaryocytes,  149,  799 

in  pneumonic  lung,  548 

origin  of  blood-platelets  from,  149 

regeneration  of,  800,  802 
Melanins,  117 
Melanoblasts,  118 
Melanoma,  985 

metastasis  of,  987,  987 

origin  of  cells  in,  986 

references  to  literature,  988 

sites  of  origin,  986 

Melanosarcoma,  987.    See  also  Melanoma. 
Meninges,  cholesteatoma  of,  1083 

endothelioma  of,  995,  997 

haemorrhage  of,  372 

in  dementia  paralytica,  737 


INDEX 


1139 


Meningitis,   epidemic  cerebrospinal,   556, 

558,  559 

hydrocephalus  in,  560,  505,  506 
exudate  in,  559 
gonococcus,  568 
haemorrhagic,  in  anthrax,  591 
influenzal,  597 
lesions  in  organs,  560 
paratyphoid,  615 
pneumococcus,  555 
staphylococcus,  542 
syphilitic,  353,  726,  728,  729 
tuberculous,  682,  681 
typhoid,  614 
Meningococcus  as  cause  of  endocarditis, 

560 

carriers,  557 
infections  with,  556 

references  to  literature,  561 
portals  of  entry,  557 
types  of,  556 
Mercury  poisoning,  404 

colitis  and  enteritis  in,  265,  404)  405 
necrosis  of  kidney  epithelium  in,  108, 

109,  405 

Metabolism  in  cells,  48 
disturbances  of,  60 

in  diabetes  mellitus,  81,  106,  860,  865 
in  disturbances  of  internal  secretion,  65 
in  fever,  65,  159 
in  gout,  87 

in  mental  diseases,  65 
in  tetany,  886 
in  tumors,  65 
of  calcium,  106 
of  carbohydrates,  103,  865 
disturbances  of,  104,  865 
of  cholesterine,  76,  80 
of  fat,  disturbances  of,  72 
of  iron,  111 
of  pigments,  117 
of  proteins,  disturbances  of,  87 
of  purines,  disturbances  of,  87 
Metaplasia,  connective  tissue,  195,  200 
epithelial,  195 
in  bladder,  195 
in  bronchus,  195 
in  gall-bladder,  195 
myeloid,  827 

references  to  literature,  820 
Metastasis  of  calcium  salts,  111 

of  tumors,  1023,  1099 
Metathrombin,  7 
Micrococci,  pyogenic,  512 


Micrococcus  meoformans,  1105 
Middle  cerebral  artery,  397 
ear,  infections  of,  519 

complications  of,  519 
mechanism  of,  519 
organisms  concerned  in,  519 
Milk  leg,  45 
Mitochondria,  49,  50 
in  connective  tissue,  51 
in  parenchymatous  degeneration,  94 
references  to  literature,  59 
relation  to  fat  metabolism,  78 
Mitosis,  atypical,  in  tumors,  969 
Mitral  insufficiency,  479,  480 

stenosis,  252,  481,  481 
Mixed  tumors,  1084 
of  breast,  1087 
of  kidney,  1086 
of  salivary  glands,  1084,  1085 
of  testicle,  1087 
references  to  literature,  1089 
Moles,  pigmented,  983.    See  also  Ncevi. 

papillary,  1002 
M  oiler-Barlow's  disease,  921 
Monckeberg  type  of  arteriosclerosis,  345 
Morphine,  increased  tolerance  of,  164 

poisoning,  oedema  in,  45 
Mouth,  epithelioma  of,  1024 
lesions  of,  in  smallpox,  762 
Mucosse,  epitheliomata  of,  1024 

healing  of  lesions  in,  225 
Mucous  patches,  702 
Muscles,  abscesses  of,  535 
atrophy  of,  63,  66,  67 
disuse,  63 
senile,  63 

bone  formation  in,  after  injury,  946 
haemangioma  of,  964 
hyaline  changes  in,  96 
regeneration  of,  204 
trichinae  in,  787,  787,  788 
tuberculosis  of,  655 
Zenker    degeneration    of,    in    typhoid 

fever,  613 
Myasthenia  gravis,  889 

thymus  enlargement  in,' 889 
Myeline  bodies,  85 
Myelins,  36 

Myelitis,  compression,  374 
Myeloblasts,  149 
Myelocytes,  148,  149 
Myeloma,  albumosuria  in,  837 
lymphoid,  837,  838 
myeloid,  852,  863 


1140 


INDEX 


Myeloma,  plasma  cell,  837 

references  to  literature,  844,  859 

relation  to  sarcoma,  991 

types  of,  837 
Myocarditis,  466 

chronic  fibrous,  467,  471,  472 

experimental,  472 
Myocardium,  abscesses  in,  467 

fragmentation  of,  473,  473,  464 

inflammation  of,  466.     See  also  Myo- 
carditis. 

scars  in,  470,  472 

toxic  injuries  of,  466 
Myoma,  948 

leio-,  951 

malignant,  952 

of  bladder,  951 

of  intestine,  951 

of  skin,  951 

of  stomach,  951 

of  uterus,  948 

of  vagina,  951 

references  to  literature,  952,  954 

rhabdo-,  953,  953 
Myosarcoma,  970 
Myositis,  acute,  141 

ossificans,  metaplasia  in,  196 

progressive,  946 
Myxochondroma,  981 
Myxcedema,  187,  871 

disturbances  of  development  in,  871 

metabolism  in,  872 
Myxoma,  981 

references  to  literature,  982 

sites  of  origin,  981 
Myxo-osteoma,  981 

Kasvi,  983,  1025 

non-pigmented,  985,  985 

origin  of  cells  in,  983,  986 

pigmented,  985 

references  to  literature,  988 

resemblance  to  basal-cell   epithelioma, 
1034 

vascular,  963.     See  also  Hcemangioma. 
Narcosis,  glycosuria  in,  867 

Overton's  theory  of,  78 
Nasal  septum,  infection  of,  in  leprosy,  624 
Necator  Americanus,  789 
Necrobiosis,  55 
Necrosis,  55 

coagulative,  28 

focal,  of  bone-marrow,  610 

of  liver,  314,  610,  611,  612,  616 


Necrosis  of  fat,  419 

Necrotic    tissue,     fatty     infiltration    of, 

85 
Nematode  infections,  792 

references  to  literature,  794 
Nephritis,  269 
aetiology  of,  269 
amyloid  in,  300 
blood-pressure  in,  306 
classification  of,  272 
enteritis  in,  307 
experimental,  269 
hypertrophy  of  heart  in,  302,  307 
in  diphtheria,  577 
in  gout,  89 

in  lead-poisoning,  403 
in  pregnancy,  282 
in  scarlet  fever,  758 
in  typhoid  fever,  612 
literature  on,  recent,  308 
oedema  in,  306 
pericarditis  in,  307 
references  to  literature,  307 
relation  of  anatomical  changes  to  func- 
tional disturbances,  270 
trench,  308 
types  of,  271 

acute  diffuse,  281,  281 
glomerulo-,  274,  274 
interstitial,  273,  286,  287,  288 
suppurative,  288,  457,  536,  537 
mode  of  infection  in,  419,  537 
tubular,  282,  284 

chronic  arteriosclerotic,  271,  288, 
289,  290,  291,  292,  293,  294,  295, 
296 

diffuse,  283 
glomerulo-,  274 
interstitial,  228,  273,  286 
parenchymatous,  273 
primary  contracted  kidney,  289 
secondary  contracted  kidney,  281, 

282,  283 
tubular,  282 

combined  inflammatory  and  arterio- 
sclerotic, 298 
embolic,  251 

in  acute  endocarditis,  526 
glomerulo-,  274 
acute,  274,  274 
chronic,  274 
diffuse,  282 

intracapillary,  275,  275 
subacute,  interstitial,  286,  286 


INDEX 


1141 


Nephritis,  types  of,  tuberculous,  282,  284 
Nephrolithiasis,  454 
Nephrolysins,  167 
Nephrosis,  308 
Nerves,  degeneration  of,  82 
in  alcohol  poisoning,  81 
in  arsenic  poisoning,  81 
in  lead  poisoning,  81 
effect  of  section  of,  67 
excitability  of,  in  calcium    deficiency, 

107 

injuries  of,  375 
transplantation  of,  212 
tumors  of,  956 
Nervous  system,  embryological  relations 

of  elements  of,  955 
influence  on  growth,  178 
in  acute  poliomyelitis,  689 
syphilis  of,  726 
congenital,  748 
references  to  literature,  729 
tuberculosis  of,  681 
tumors  arising  in,  955 

references  to  literature,  962 
tissue,  regeneration  of,  208 
Neuritis  in  beri-beri,  81 
in  lead  poisoning,  403 
in  leprosy,  627,  628 
in  typhoid  fever,  614 
Neuroblastoma,  956 
Neurocytoma,  956 
Neuroepithelioma,  962 
Neurofibroma,  956 

Neurofibromatosis,  multiple,  940,  941 
Neuroma,  amputation,  956 
Neutrality  of  solutions,  preservation  of, 

172 
Nitric  acid  poisoning,  cedema  of  lungs  in, 

400 

Noma,  42 

Nomotope  impulses,  499 
Normoblasts,  149,  800 
Nose,  glanders  of,  587,  588 
obstruction  of,  430 
by  adenoids,  430 
by  tumors,  430 
polyps  of,  937,  940 
syphilis  of,  715 

congenital,  747 
Nucleic  acid,  88 
Nucleus,  49 
"Nutmeg"  liver,  488,  488.    See  also  Liver, 

chronic  passive  congestion. 
Nutrition  of  cells,  disturbances  of,  60 


OBESITY,  80 

Obliterative  endarteritis,  356 
Obstruction  of  alimentary  tract,  423 
references  to  literature,  429 

of  circulatory  system,  475 

references  to  literature,  494 

of  respiratory  tract,  430 

references  to  literature,  440 

of  urinary  tract,  446,  452 

references  to  literature,  446 
Ochronosis,  120 
(Edema,  43 

from  alterations  in  nervous  activity,  45 

from  cardiac  failure,  480 

from  lymphatic  obstruction,  44 

from  renal  disease,  46,  306 

from  venous  obstruction,  44 

in  cachexias,  45 

inflammatory,  140,  521 

of  extremities,  43 

of  gall-bladder,  44 

of  glottis,  431 

of  intestine,  44 

of  lungs,  44,  45,  46 

caused  by  adrenaline,  46 
nitric  acid  fumes,  401 

references  to  literature,  47 

salt  retention  in,  46 

theories  of,  44 
(Esophagus,  carcinoma  of,  1025 

diverticulum  of,  420 

epithelioma  of,  1025 

obstruction  of,  63,  420 

syphilis,  of,  710 

tuberculosis  of,  671 

varices  of,  331 
Oligsemia,  2,  3 

from  haemorrhage,  3 

from  loss  of  fluid,  3 
Ophthalmia,  gonococcus,  567 

neonatorum,  567 
Opisthorchis  felineus,  786 

sinensis,  786 

Opisthotonos  in  tetanus,  578 
Opsonins,  166 
Orchitis  in  typhoid  fever,  614 

syphilitic,  724,  724 

Organization   of   inflammatory   exudates, 
219,  219 

of  thrombi,  820,  227 
Organs,  interrelation  of,  182 

parenchymatous,  injuries  of,  225 

transplantation  of,  211 
Ornithin,  oxidation  of,  118 


1142 


INDEX 


Ossification,  effect  of  calcium  deficiency 

on,  106 
normal,  107 
of  calcified  tissue,  111 
Osteitis  deformans,  923 
Osteoarthropathy,  pulmonary,   187,   187, 

907 
Osteoblasts  in  bone  repair,  203 

relation  to  blood  formation,  149 
Osteochondritis,  syphilitic,  744,  744,  745, 

747,  748 

Osteochondrosarcoma,  979 
Osteoclasts,  69 
function  of,  107 

relation  to  blood  formation,  149 
Osteogenesis  imperfecta,  923 

references  to  literature,  923 
Osteoid  tissue  in  rickets,  916 
Osteomalacia,  918- 

deficiency  of  calcium  in,  106 
deformities  of  bones  in,  918 
references  to  literature,  919 
Osteoma,  945,  946,  947 

references  to  literature,  948 
Osteomyelitis  in  typhoid  fever,  613 
involucrum  in,  540 
sequestrum  in,  540 
staphylococcus,  539 
variolosa,  763 

Osteoperiostitis,  syphilitic,  722 
Osteophytes,  541 

in  syphilis,  721,  720 
Osteoporosis  from  calcium  deficiency,  106 

senile,  63,  107,  910 
Osteopsathyrosis,  378 
Osteosarcoma,  970,  970,  979,  979,  980 

calcification  of,  109 
Otitis  media,  complications  of,  519 
in  measles,  755 

mechanism  of  occurrence,  519 
organisms  producing,  519 
pneumococcus,  555 
streptococcus,  519 
Ovary,  cysts  of ,  1013 

dermoid,  1081,  1081 
effects  of  x-rays  on,  391 
extirpation  of,  65 
tuberculosis  of,  681 

tumors  of,  carcinoma,  1056,  1056,  1065 
cystadenoma,  1013,  1014,  1015,  1016 
fibroma,  941 

Krukenberg  tumor,  1067 
papilloma,  999,  1003,  1016 
references  to  literature,  1071 


Ovary,  tumors  of,  sarcoma,  971 

teratoma,  1077,  1083,  1084 
Overton's  theory  of  anaesthesia,  50,  78 
Oxalate  calculi,  450 
Oxydase  reaction,  801 

references  to  literature,  820 
Oxyuris  vermicularis,  792 

PACHYMENINGITIS,   chronic  hsemorrhagic, 

122 

in  chronic  alcoholism,  122 
in  syphilis,  122,  737,  737 
staphylococcus,  542, 
Paget's  disease  of  bones,  923 
•  aetiology  of,  924 
bone  changes  in,  923,  924 
references  to  literature,  925 
of  nipple,  1058 
Panaritium,  534 
Pancreas,  abscesses  in,  419 

atrophy  of,  following  duct  ligation,  863, 

863,  864 

calculi  in  ducts  of,  415 
carcinoma  of,  1050 

references  to  literature,  1057 
disturbances   of   internal   secretion   of, 

860 

effect  of  extirpation  of,  861,  865 
ferment  produced  by  enabling  muscles 

to  consume  sugar,  866 
gumma  of,  714 
haemorrhage  in,  419 
in  diabetes  mellitus,  861 
inflammation  of,  417.     See  also  Pan- 
creatitis. 
islands  of  Langerhans,  granules  in  cells 

of,  51 
syphilis  of,  714 

congenital,  743,  743 
tuberculosis  of,  672 

Pancreatic  ducts,  obstruction  of,  67,  415 
Pancreatitis,  acute,  417 
haemorrhagic,  411,  417 
aetiology  of,  396 
experimental,  416 
references  to  literature,  419 
chronic,  416 
Papilloma,  1000 

common  sites  of,  1001 

of  bladder,  1003,  1026,  1027 

of  intestine,  1002 

of  ovary,  999,  1003,  1016 

of  skin,  1001,  1001 

of  stomach,  1002 


INDEX 


1143 


Paraganglioma,  957 
Paragonimus  Westermanni,  785 
Paralysis  in  acute  poliomyelitis,  689 

in  diphtheria,  578 

Parasites,  animal,  adaptation  of,  765 
as  emboli,  22 
diseases  caused  by,  764 
intestinal,  780 
relation  to  host,  764 
types  of  injury  produced  by,  162 
Parasitic  theory  as  to  origin  of  tumors, 

1109 

Parasyphilitic  diseases,  693,  726,  729 
Parathyroid  glands,  disturbances  of  func- 
tion of,  884 

effect  of  extirpation  of,  884,  911 
haemorrhages  in,  886 
physiology  of,  884 
references  to  literature,  886 
relation  to  bone  formation,  911 
to  calcium  metabolism,  885 
to  tetany,  108 
transplantation  of,  212 
Paratyphoid  infections,  615 

focal  necrosis  of  liver  in,  616 
intestinal  lesions  in,  616 
meningitis,  615 
references  to  literature,  616 
Parenchymatous  degeneration,  93 
mitochondria  in,  94 
of  organs  in  infections,  528 
Paronychia,  534 
Parotid  gland,   mixed    tumors    of,   1084, 

1085 

Parotitis  in  typhoid  fever,  614 
Parovarium,  cysts  of,  1017 
Pediculus  vestimentorum  in  transmission 

of  typhus  fever,  687 
Penis,  chancre  of,  696,  697,  698 
epithelioma  of,  1021,  1022 
papilloma  of,  1001,  1001 
Peptone  poisoning,  relation  to  anaphylaxis, 

168 

Pericardial  effusion,  232,  463 
Pericarditis,  231 

acute  fibrinous,  232,  232,  234 
in  chronic  nephritis,  231 
chronic  adhesive,  226,  226,  248 

in  rheumatism,  570 
fibrino-purulent,  232 
gonococcus,  568 
rheumatic,  571 
sero-fibrinous,  232 
Pericardium,  abscesses  of,  535 


Pericardium,  inflammation  of,  231.     See 
also  Pericarditis. 

synechia  in,  225 
Perihepatitis,  aetiology  of,  676 
Periosteum,  gumma  of,  706 

sarcoma  of,  979 
Periostitis,  chronic,  540,  541 

syphilitic,  718,  720 
excessive  bone  formation  in,  947 
Perisplenitis,  aetiology  of,  676 
Perithelioma,  998 
Peritoneum,  endothelioma  of,  994 

psuedomyxoma  of,  1017 
Peritonitis,  gonococcus,  237 

hsematogenous,  237 

mode  of  infection,  236 

pneumococcus,  237,  555 

tuberculous,  673 

Perl's  preaction  for  iron  pigment,  487 
Phagocytes,  53,  122 

endothelial,  194 

in  removal  of  dead  tissue,  58 
Phagocytosis,  144,  166 

as  defensive  mechanism,  165 

effect  of  fever  on,  160 

importance  in  inflammation,  145,  155 

in  typhoid  fever,  604,  609,  609 
Pharyngitis  in  leprosy,  626 

in  scarlet  fever,  757 

in  typhoid  fever,  613 

streptococcal,  522 
Pharynx,  gumma  of,  710 
Phimosis,  441 
Phlebolith,  110 
Phlegmasia  alba  dolens  in  typhoid  fever, 

613 

Phlegmons,  265 

Phloridzin  poisoning,  glycosuria  in,  867 
Phosphatic  calculi,  JfiO 
Phosphatides,  73,  74,  85 

function  of,  79 
Phosphorus  poisoning,  404 
acute,  404 
chronic,  404 
Phrenosins,  75 

as  neutralizer  of  tetanus  toxin,  79 
Phthisis  florida,  662 
Pigeon  breast,  430 
Pigment  metabolism,  117 
Pigmentation  of  cartilage,  87 

of  lung  in  chronic  passive  congestion, 
123 

of  melanotic  tumors,  119 

of  organs  in  malaria,  120,  776 


1144 


INDEX 


Pigmentation  of  skin,  117 
from  sunlight,  389 
in  Addison's  disease,  119,  894 
Pigments,  bile,  in  jaundice,  125 
coal,  129 

endogenous,  117,  125 
exogenous,  117,  129 
haematogenous,  120 
iron-containing,  116 
lipochrome,  64 
normal,  deficiency  of,  130 
of  adrenals,  125 
of  choroid,  118 
of  corpus  luteum,  125 
of  heart  muscle,  125 
of  malarial  parasites,  125 
of  retina,  118 
of  testicle,  125 
references  to  literature,  131 
Piqure,  867 
Placenta  in  typhoid  fever,  614 

syphilis  of,  739 

Placentoma,  experimental,  1074 
Plague,  bubonic,  585 

lymph-glands  in,  586 
pneumonic,  587 

lungs  in,  586,  587 
references  to  literature,  587 
Plasma  cells,  155,  693 
Plasmatocytes,  152 
Plasmodium  falciparum,  773 
malariae,  773 
vivax,  773 
Plasmosomes,  51 
Plethora,  2 
Pleura,  endothelioma  of,  994 

inflammation  of,  233.    See  also  Pleurisy. 
lymphatics  of,  231 
Pleural  effusion,  compression  of  lung  by, 

234 
Pleurisy,  233 

acute,  in  pneumonia,  233 

with  infarction  of  lung,  33 
fibrino-purulent,  235,  236 

organization  of,  219 
Pneumococcus,     importance    of    capsule 

formation,  164 
infections,  543 
types  of,  543 
empyema,  554 
endocarditis,  554 

character    and    organization    of 

vegetations,  523 
meningitis,  555 


Pneumococcus  infections,  types  of,  otitis 

media,  555 
peritonitis,  237,  555 
portals  of  entry  in,  555 
references  to  literature,  555 
septicaemia,  554 
Pneumonia   alba   in   congenital   syphilis, 

740,  741 
aspiration,  256 
caseous,  659 
complications  of,  554 
ether,  545 

experimental  production  of,  545 
following  influenza,  594 
gelatinous,  659 

indurative,  in  chronic  pulmonary  tuber- 
culosis, 663 
in  influenza,  593 
hypostatic,  17 
influenzal,  593,  596 
in  measles,  516 

interstitial,  516,  517,  518,  596,  597 
jaundice  in,  127 
lobar,  544,  546,  547,  548,  550 
abscesses  in,  551 
gangrene  in,  554 
organization  in,  551,  552,  553 
pneumococcal,  in  influenza,  595 
references  to  literature,  555 
resolution  in,  550 
stages  of,  545,  546,  547,  548,  550 
lobular,  254,  256,  516,  517,  594 
bacteriology  of,  255 
complication  of,  259 
degeneration  rectus  abdominis  in,  518 
emphysema  in,  518 
giant  cells  in,  258 
in  glanders,  588 
in  measles,  755,  516 
in  scarlet  fever,  757 
references  to  literature,  259 
resolution  of,  258 
rapid  clotting  of  blood  in,  7 
retention  of  chlorides  in,  159 
septicaemia  in,  518 
staphylococcus,  539 
streptococcal,  594 
tuberculous,  660,  660,  661,  662,  663 

fatty  cells  in,  659 
Pneumonokoniosis,  129 
Pneumoventriculography,  505 
Poikilocytosis,  810 
Poisoning,  alcohol,  81,  402 
ammonia,  401 


INDEX 


1145 


Poisoning,  arsenic,  81 

benzol,  anaemia  in,  208,  799 

bone-marrow  changes,  799,  798,  799,  800 

carbolic  acid,  400 

carbon  monoxide,  400 

caustic  alkalis,  400 

chlorine,  401 

chloroform,  402 

liver  in,  315 
chromate,  necrosis  of  kidney  epithelium 

in,  225 

cobra  venom,  80 
cyanide,  401 

oxidation  in,  163 

ergot,  42 

hydrochloric  acid,  400 
illuminating  gas,  400 

lesions  in  lenticular  nuclei,  399,  899 
lead,  81,  403 

anaemia  in,  403 

association  with  gout,  89 
lysol,  400 
mercury,  404 

calcification  of  kidneys  in,  108,  109, 
404,  405 

colitis  in,  266,  405 
morphine,  oedema  in,  45 
nitric  acid,  400 
phloridzin,  glycosuria  in,  867 
phosphorus,  404 
prussic  acid,  401 
silver,  130 
sulphonal,  blood  changes  in,  121 

haematoporphyrin  in,  121 
sulphuric  acid,  400 
uranium,  necrosis  of  kidney  epithelium 

in,  225 

Poisons,  absorption  of,  397 
antagonistic  action  of,  396 
corrosive,  399 
elimination  of,  395 
general  effects  of,  397 
haemolytic,  807 
immunity  to,  396 
increased  tolerance  of,  395 
lipoid  activation  of,  80 
mechanism  of  resistance  to,  396 
nature  of,  393 
putrefactive,  397 
selective  action  of,  398 
varying  effects  of,  394 
Polioencephalitis,  691 
Poliomyelitis,  acute,  688,  690 

aetiology  of,  688 


Poliomyelitis,  acute,  atrophy  of  muscles 

in,  689 

experimental,  689 
lesions  of  nervous  system  in,  689 
lesions  in  organs,  691 
organism  of,  688 
paralysis  in,  689 
portals  of  entry  in,  689 
references  to  literature,  691 
relation  of  streptococcus  to,  688 
transmission  of,  689 
Polyarthritis,    chronic    progressive,    900. 

See  also  Arthritis  deformans. 
Polycythaemia  from  loss  of  fluid,  805 
references  to  literature,  820 
rubra,  806 

Polydipsia  in  diabetes,  860 
Polyphagia  in  diabetes,  860 
Polyps,  adenomatous,  of  intestine,  1006, 

1006 

Polyps  of  nose,  937,  940 
Pores  of  Cohn,  549 
Portals  of  entry  for  bacteria,  162,  510 
Portal  vein,  occlusion  of,  32 
Postmortem  changes,  15 
haemolysis,  121 
redistribution  of  blood,  15 
Precipitins,  167,  171 

Pregnancy,  changes  in  hypophysis  in,  898 
acute  nephritis  in,  282 
chloasma  in,  118 
tetany  in,  886 
Pressure,  effects  of,  68 
on  skin,  68 
on  tissues,  370 
Pro-antithrombin,  7 
Profeta's  law,  695 
Progressive  paralysis  of  insane,  735 
Prostate,  carcinoma  of,  1051,  1054 
corpora  amylacea  in,  97,  444 
hypertrophy  of,  443,  444,  445 

aetiology,  445 

obstruction   of   urethra   from    enlarge- 
ment of,  442 

references  to  literature,  446 
tuberculosis  of,  680 
Prostatitis,  gonococcus,  563 
Protein  metabolism,  disturbances  of,  87 
in  diabetes,  868 
in  exophthalmic  goitre,  879 
Proteosoma,  773 
Prothrombin,  7 

Protozoa,    pathogenic,    classification    of,. 
766 


1146 


INDEX 


Prussic  acid  poisoning,  401 
Psammoma,  calcification  in,  109 
Pseudoleukaemia,  839 

references  to  literature,  844 
Pseudomelanosis,  postmortem,  125 
Pseudomyxoma  peritonei,  1017 
Puerperal  endometritis,  259,  260,  522 

infections,  259 
Pulmonary  valve,  insufficiency  of,  482 

stenosis  of,  482 
Pulse  tracings,  Jfi7 
Pulsus  bigeminus,  tracing  of,  501,  502 

irregularis  perpetuus,  501 
Purine  bodies,  chemistry  of,  87 

metabolism,  disturbances  of,  87 
Purpura,  prolonged  bleeding  time  in,  8 
Pyaemia,  262,  512 

complicating  puerperal  infection,  262 
Pyelitis,  457 
Pyelonephritis,  457,  458,  459,  537 

gonococcus,  563 

references  to  literature,  460 
Pyknosis,  55,  56 

Pylephlebitis,  suppurative,  244>  245 
Pyogenic  micrococci,  512 
Pyorrhrea  alveolaris,  relation  of  amoebae 

to,  772 
Pyosalpinx,  gonococcus,  56o*i  566 


RACHITIS,  912 

Radium,  effects  of,  on  tissues,  389 
Ranula,  1004 
Rat-bite  fever,  751 
Raynaud's  disease,  18 
Rectum,  carcinoma  of,  1052,  428,  1052 
adeno-,  1053 
references  to  literature,  1057 

syphilis  of,  710,  711 

Rectus    abdominis    muscle,    hyaline    de- 
generation of,  518 
Recurrence  of  tumors,  1103 
Regeneration,  176,  196 

of  blood,  206 

after  haemorrhage,  207 
in  anaemia,  208 

of  blood-vessels,  205 

of  bone,  202 

of  bone-marrow,  206 

of  cartilage,  202 

of  eosinophiles,  207 

of  fat  tissue,  202 

of  heart  muscle,  204 

of  kidney  epithelium,  200 


Regeneration  of  liver  cells  from  bile-ducts, 

199,  318,  319 
of  lymphocytes,  206 
of  lymphoid  tissue,  206 
of  lymph-vessels,  205 
of  muscle,  non-striated,  204 

striated,  204 
of  nervous  tissue,  208 
of  polymorphonuclear  leucocytes,  206 
Relapsing  fever,  751 
Repair,  133,  176,  191 

character  of,  in  brain,  209 

excessive,  following  injuries  by  Bacillus 

tuberculosis,  188 
by  Spirochaeta  pallida,  188 
general  phenomena  of,  191 
of  bone  fractures,  204 
Respiratory  quotient,  865 
tract,  bacteriology  of,  255 
obstruction  of,  430 

references  to  literature,  440 
syphilis  of,  715 
tuberculosis  of,  655 
Reticulo-endothelial  apparatus,  76 
Retina,  pigment  of,  118 
Retinitis,  albuminuric,  307 
Retroperitoneal  region,  myxoma  of,  981, 

982 

sarcoma  of,  974 
Rhabdomyoma,  953,  953 
common  sites  of,  953 
of  bladder,  953 
of  heart,  953 
of  vagina,  952,  953 
references  to  literature,  954 
Rhagades  in  congenital  syphilis,  740 
Rheumatism,  acute,  569 
aetiology  of,  570 
arthritis  in,  570 
endocarditis  in,  571,  570 
pericarditis  in,  571 
references  to  literature,  573 
tonsillitis  in,  570 

muscular,  from  exposure  to  cold,  386 
Ribbert's  theory  as  to   origin   of   tumors, 

1112 
Ricin  poisoning,  changes  in  bone-marrow 

in,  799 
Rickets,  912 
aetiology  of,  918 

calcium  metabolism  in,  106,  917 
disturbance  of  ossification,  914,  914,  915, 

916 
endostitis  fibrosa  in,  917 


INDEX 


1147 


Rickets,  enlargement  of  spleen  in,  917 

exostoses  in,  917 

halisteresis  in,  917 

references  to  literature,  918 

relation  of  parathyroids  to,  918 
Rigg's  disease,  relation  of  amoebae  to,   772 
Rodent  ulcers,  1032,  1032 
Roentgen  rays,  389 

effects  of,  on  tissues,  389 
Rose  spots,  614 
Rupia,  702 

SADDLE  nose  in  congenital  syphilis,  716, 

747 

Sago  spleen,  99 

Salivary  glands,  cylindroma  of.  994,  1004 
mixed  tumors  of,  1084 

references  to  literature,  1089 
obstruction  of  ducts  of,  408 
syphilis  of,  714 
Salpingitis,  gonococcus,;  563,  564,  563,  566 

pseudofollicular,  565 
Sarcoma,  968 

atypical  mitosis  in,  969 

of  fowl  (Rous),  filterable  virus  of,  1105 

of  lymph-glands,  974 

of  ovary,  974,  971 

of  testicle,  975,  WS.7,1088 

of  thyroid,  971 

references  to  literature.  981 

stroma  of,  969 

types  of,  970 

alveolar,  970,  975 

differentiation  from  carcinoma,  975 
giant-cell,  977,  977,  978 

of  bone,  978 
melanotic,  885 
pigment  of,  118 
references  to  literature,  988 
mixed  cell,  970,  971,  974 
osteo-,  979,  980 
round  cell,  971,  974 

differentiation  from    lymphosarco- 

ma,  841 

spindle  cell,  970,  971,  972,  972 
Scar  formation,  134,  223.     See  also  Re- 
pair. 

Scarlet  fever,  756 
etiology  of,  756 
cause  of  death  in,  758 
enlargement  of  lymph-glands  in,  758 
experimental,  756 
nephritis  following,  758 
pharyngitis  in,  757 


Scarlet  fever,  pneumonia  in,  757 
references  to  literature,  759 
skin  lesions  in,  757 
tonsillitis  in,  757 
Scars,  215,  223 

Scharlach  R,  stimulation  of  growth  by,  186 
Schick  reaction,  170 
Schistosomum  hsematobium,  784 
mansoni,  784 
japonicum,  784 
Scurvy,  921 

bone  changes  in,  921,  921,  922 
experimental,  922 
haemorrhages  in,  922 
references  to  literature,  923 
Sebaceous  glands  in  dermoid  cysts,  1081 

tumors  of,  1004 
Secretion,  mechanism  of,  68 
Seminal  vesicles,  pigments  of,  125 

tuberculosis  of,  680 
Senility,  63 

atrophy  of  organs  and  tissues  in,  63 
calcification  of  cartilage  in,  108 
rarefaction  of  bones  in,  63 
relation  of,  to  tumors,  1106 
thickening  of  heart  valves  in,  246 
Septicaemia,  512 

in  bronchopneumonia,  518 
pneumococcus,  554 
staphylococcus,  534,  535,  536 
streptococcus,  527 

Sequestrum  in  osteomyelitis,  540,  541 
Serosae,  structure  of,  231 
Sexual   characters,    secondary,    in   status 

lymphaticus,  843 
development,  influence  of  adrenals  on, 

894 
influence   of  hypophysis  on,    899, 

901,  905 
Shock,  378 

anaphylactic,  168 

capillaries,  paralysis  of  in,  143,  381 

conditions  simulating,  168 

histamine  in,  143,  381,  424 

in  burns,  383 

primary,  381 

secondary,  381 

surgical,  378 

lowered  blood-pressure  in,  379 
references  to  literature,  382 
symptoms  of,  378 
theories  regarding  nature  of,  379 
theories  regarding  production  of,  380 
Side-chain  theory,  170 


1148 


INDEX 


Siderosis,  129 

Silver  poisoning,  130 

Sinus  formation  in  actinomycosis,  224 

in  tuberculosis,  224 
Skin,  abscess  of,  263 
atrophy  of,  senile,  63 
effects  of  cold  on,  385 

of  electricity  on,  392 

of  heat  on,  382 

of  pressure  on,  68 

of  radium  on,  390 

of  z-rays  on,  390 
glanders,  lesions  in,  588 
haemorrhages  in,  528 
keloids  in,  940 
lesions,  in  measles,  755 

in  scarlet  fever,  757 

in  smallpox,  760,  761,  762 

in  typhoid  fever,  614 
pigmentation  of,  117 

from  sunlight,  389 

in  Addison's  disease,  894 

in  argyria,  130 
rodent  ulcers  of,  1032,  1032 
staphylococcus  infections  of,  533 
streptococcus  infection  of,  521 
syphilis  of,  700,  701,  702,  703 

congenital,  740 
transplantation  of,  211 
tuberculosis  of,  655,  683 
tumors  of,  adenoma,  1004 

epithelioma,  1019,  1032,  1032,  1033 

fibroma,  939,  939,  940 

haemangioma,  963,  964 

myoma,  951 

naevus,  983,  984 

papilloma,  1001,  1001 

xanthoma,  948 
Skull,  fracture  of,  372 

syphilitic  erosion  of,  721 
Sniallpox,  759 
aetiology  of,  760 
cytorrhyctes  in  skin  in,  753 
enlargement  of  lymph-glands  in,  763 

of  spleen  in,  763 
immunity  to,  165 
lesions  of  organs  in,  762 

of  skin  and  mucosae  in,  760,  761,  762 
references  to  literature,  763 
relation  to  vaccinia,  759 
streptococci  in,  760 
Soaps,  role  in  calcification,  110,  342 
Sore  throat,  streptoccal,  514 
Sphaeroliths,  448 


Spina  ventosa,  685 
Spinal  cord,  anatomy  of,  732 
in  dementia  paralytica,  739 
in  locomotor  ataxia,  730,  731,  731,  732 
inpernicious  anaemia,  815 
injuries  of,  372 
syphilis  of,  729.    See  also  Tabes  dor- 

salis. 

tuberculosis  of,  681 

Spirochaeta  pallida,   excessive  repair  fol- 
lowing injuries  by,  188 
in  brain  in  dementia  paralytica,  738 
in  gummata,  705 

in  organs  in  congenital  syphilis,  739 
in  primary  and  secondary  syphilitic 

lesions,  693 

Spirochaetal  infections,  748 
icterohemorrhagica,  750 
pertenue,  749 

Spirochaetosis  icterohemorrhagica,  750 
Spleen,  actinomycosis  of,  632 

acute  splenic  tumor,  529,  529,  530,  609 
gray  type,  532 
red  type,  532 

amyloid  infiltration  of,  99,  99,  101 
Banti's  disease  of,  818,  818,  819 
chronic  passive  congestion  of,  803,  4^2 
effect  of  x-rays  on,  391 
enlargement  of,  in  cirrhosis  of  liver,  332 
in  rickets,  917 
in  smallpox,  763 
function  of,  804 

in  iron  metabolism,  113 
in  acute  lymphatic  leukaemia,  833,  834, 

QQ   I 
OO4 

in  chronic  lymphoid  leukaemia,  830,  831 

in  chronic  myeloid  leukaemia,  846,  846, 
848,  848 

in  Hodgkin's  disease,  847,  856 

in  leprosy,  624 

in  leucocytosis,  824 

in  malaria,  776,  777 

in  pernicious  anaemia,  813,  814 

in  typhoid  fever,  609 

infraction  of,  29,  31,  31 

pigmentation  of,  in  malaria,  120 
in  pernicious  anaemia,  124 

sago,  99 

structure  of,  151,  152,  802,  802,  803 
references  to  literature,  820 

tuberculosis  of,  648,  677 
Splenic  anaemia,  818 
Splenomegaly,  Gaucher  type,  820 

primary  (Banti's  disease),  818,  818 1  819 


INDEX 


1149 


Splenomegaly,  references  to  literature,  821 
Spondylitis  deformans,  934,  935 
St.  Anthony's  fire,  42 
Staphylococcus  infections,  533 
arthritis,  536 
endocarditis,  538 
furunculosis,  533 
meningitis,  542 
osteomyelitis,  539 
pneumonia,  539 
references  to  literature,  542 
septicaemia,  534,  535,  536 
synovitis,  536 

Starvation,  atrophy  from,  62 
Status  lymphaticus,  843 

constitutional  abnormalities  in,  843, 

890 
hyperplasia   of   lymphoid   tissue   in, 

842,843 

references  to  literature,  844 
thymus  in,  844 
Stokes-Adams'  disease,  500 
Stomach  in  carbolic  acid  poisoning,  400 
in  lysol  poisoning,  401 
in  poisoning  by  corrosive  substances,  400 
obstruction  of,  420 
by  tumors,  1036 
perforation  of,  377 
syphilis  of,  710 
tuberculosis  of,  671 
tumors  of,  adenoma,  1005 

carcinoma,    1036,   1037,   1039,   1040, 

1042 

adeno-,  1037 

colloid,  1046,  1047,  1047,  1048 
references  to  literature,  1057 
scirrhus,  1041,  1041 
solid,  1037 
myoma,  951 
papilloma,  1002 
ulcer  of,  421,  421,  421 

origin  of  carcinoma  in,  1040 
Stomatitis,  ulcerative,  in  acute  myeloid 

leukaemia,  851 
Streptococci  in  scarlet  fever,  756 

in  smallpox,  760 
Streptococcus   haemolyticus,    endocarditis 

due  to,  524 

character  and  localization  of  vegeta- 
tions, 523 

types  of  haemolysis  due  to,  513 
infections,  513 

of  blood  (septicaemia),  527 
of  endocardium,  249,  523 


Streptococcus  infections  of  intestines,  520 
of  lung  (pneumonia),  522 
of  middle  ear,  519 
of  pharynx,  522 
of  respiratory  tract,  514 
of  skin,  521 
of  stomach,  520 
of  throat,  514 
of  tonsil,  514 

of  uterus  (puerperal),  259,  522 
of  wounds,  520 
references  to  literature,  532 
sore  throat  due  to,  514 
mucosus,  523 

endocarditis,  character  and  localiza- 
tion of  vegetations,  523,  527 
viridans  (mitior),  523 

endocarditis,  247,  251,  525,  526,  572 
character  and  localization  of  vege- 
tations, 523 
Streptothrix,  629 
Stricture  of  urethra,  441 

gonorrheal,  441,  442,  562 
Struma,  874.     See  also  Goitre. 

carcinomatous,  1068 
Sudan  III  as  stain  for  fats,  75 

stain  for  lipochrome  pigments,  64,  125 
stimulation  of  growth  by,  186 
Sulphonal  poisoning,  blood  changes  in,  121 

haematoporphyrin  in,  121 
Sulphuric  acid  poisoning,  400 
Sunlight,  pigmentation  of  skin  from,  389 
Sunstroke,  384 
Sweat  glands  in  temperature  regulation, 

158 

tumors  of,  1004 
Sympathetic  nervous  system,  influence  of, 

on  thyroid  growth,  882 
tumors  of,  956 
Sympathoblastoma,  956 
Syncytiolysin,  1073 
Synechiae  of  pericardium,  225 
Synovitis,  Staphylococcus,  536 
Syphilide,  follicular,  703 
macular,  698,  700 
papular,  700,  700 
papulopustular,  702 
pustular,  700 
Syphilis,  acquired,  primary  stage,  696,  697, 

698,  699 

secondary  stage,  698,  700,  702,  703 
tertiary  stage,  703.     See  also  Gum- 

mata,  719,  721,  721 
action  of  iodides  on,  712 


1150 


INDEX 


Syphilis,  aetiology  of,  692 
alopecia  in,  702 
blood  changes  in,  709 

anemia  in,  709 
bone-marrow  in,  744 
chancre  in,  696,  709 
chlorosis  in,  709 
congenital,  694,  716,  739 

hydrocephalus  in,  747 

late  forms  of,  740,  745 

lesions  in  nervous  system,  748 

references  to  literature,  748 

retardation  of  development  in,  747, 
748 

Spirochseta  pallida  in  organs,  739 

stigmata  of,  745 
dementia  paralytica  in,  735 
endocarditis  in,  723 
gummata  in,  693,  704,  719 
immunity  in,  694,  695 
lesions  of,  693 
leucoderma  in,  702 
locomotor  ataxia  in,  729 
luetin  reaction  in,  695 
lymphocytosis  in,  709 
lymphoid  cells  in,  693 
mucous  patches  in,  702 
of  alimentary  tract,  709 
of  aorta,  350,  351,  352 
of  blood-vessels,  350,  722 

references  to  literature,  723 
of  bone,  716,  718,  744 

congenital,  716,  744,  744,  ?45,  ? '46,  747 

references  to  literature,  722 
of  brain,  726 
of  bronchi,  717 
of  genital  organs,  723 

references  to  literature,  725 
of  heart,  722 
of  intestine,  710 
of  joints,  718 

of  kidneys,  congenital,  744 
of  larynx,  717 
of  liver,  711,  713 

congenital,  741,  742 
of  lungs,  717 

congenital,  740 
of  lymph-glands,  708 
of  meninges,  353,  726,  729 
of  nervous  system,  693,  726 
congenital,  748 
references  to  literature,  729 
of  nose,  715 

congenital,  716,  747 


Syyhilis  of  oesophagus,  710 
of  pancreas,  743 

congenital,  743 
of  periosteum,  718 

excessive  bone  formation  on,  947 
of  placenta,  739 
of  rectum,  710,  711 
of  respiratory  tract,  715 

references  to  literature,  718 
of  salivary  glands,  714 
of  skin,  congenital,  740 
of  stomach,  710 
of  teeth,  congenital,  748 
of  testicle,  704,  723,  724,  725 

congenital,  744 
of  tongue,  710 
of  trachea,  717 
plasma  cells  in,  693 
references  to  literature,  696,  718 
rupia  in,  702 

Spirochseta  pallida  in  lesions  of,  693 
tardive,  745 

Wassermann  reaction  in,  695 
Syringomyelia,  962 

TABARDILLO,  687 
Tabes  dorsalis,  729 

Charcot's  joints  in,  735 

lesions  of  spinal  cord  in,  730,  731,  731, 

732 

pathogenesis  of,  734 
references  to  literature,  735 
trophic  distrubances  in,  735 
Tachycardia,  499 
Taenia  echinococcus,  780,  781 
saginata,  780 
solium,  780 
Tapeworms,  life  cycle  of,  764.     See  also 

Tcenia. 

Teeth,  deformities  of,  in  congenital  syph- 
ilis, 748 

Telangiectasis,  multiple,  963 
Temperature  of  body,  influence  on  pha- 
gocytosis, 160 
influence  on  experimental  infections, 

160 

regulation  of,  158 
Teratoma,  1075 
aetiology  of,  1077,  1080 
common  sites  of  origin,  1077 
of  ovary,  1077 

of  testicle,  1076,  1078,  1077,  1087,  108S 
origin  of  malignant  tumors  in,  1106 
references  to  literature,  1089 


INDEX 


1151 


Terminal  circulation,  25 

Testicle,  chorionic  epithelioma  of,  1075 

references  to  literature,  1089 
effect  of  extirpation,  65 

of  z-rays  on,  391 
endogenous  pigments  of,  125 
gumma  of,  704,  723,  724 
mixed  tumors  of,  1087 

references  to  literature,  1089 
sarcoma  of,  round-cell,  975,  1087,  1088 
syphilis  of,  704,  723,  724 

congenital,  745 
teratoma   of,    1076,   1078,   1077,    1087, 

1088 
Tetanus  infection,  578 

lesions  of  nervous  system  in,  579 
references  to  literature,  580 
spread  of  toxin  in,  578 
toxin,  neutralization  of,  by  phrenosin, 

79 

Tetany  following  extirpation  of  parathy- 
roids, 884 
calcium  deficiency  in,  108 

salts  in  treatment  of,  885 
hyperexcitability  of  nerves  in,  885 
in  human  beings,  886 

types  of,  886 
metabolism  in,  886 
references  to  literature,  886 
Throat,  diphtheritic  infection  of,  574 

streptococcus  infection  of,  514 
Thrombi,  8,  20,  245 
agglutination,  13 
calcification  of,  251 
canalization  of,  355,  227,  355,  356 
formation  of,  13 
hyaline,  98,  272 
in  aorta,  12 
in  arteries,  11 
in  heart,  10,  12,  469 
in  veins,  11,  12 
method  of  formation,  9 
organization  of,  20,  180,  220,  225,  887 
precipitation,  13 
propagated,  12 
septic,  261 
structure  of,  7 

Thrombin  in  blood  coagulation,  6,  7 
Thromboangeitis  obliterans,  353,  355 

references  to  literature,  357 
Thrombo-endocarditis,  245.    See  also  En- 
docarditis. 

Thrombokinase  in  blood  coagulation,  7, 
13,  56 


Thromboplastin  in  blood  coagulation,  7 
Thrombosis,  8 

as  protective  mechanism,  12,  355 
causes  of,  13 

references  to  literature,  14 
Thymene,  88 

Thymus,  abnormal  persistence  of,  888 
diseases  due  to  disturbed  function  of, 

887 

effects  of  x-rays  on,  391 
evolution  of,  normal,  888 
extirpation  of,  888 
hyperplasia  of,  888 
in  exophthalmic  goitre,  881,  889 
in  status  lymphaticus,  854,  889 
involution  of,  accidental,  890 

normal,  888 

references  to  literature,  890 
relation  of,  to  bone  formation,  911 
types  of  cells  in,  887 
weight  of,  888 

Thyroid,  active  principle  of,  877 
effect  of  extirpation  of,  65,  871 
enlargement  of,  877.     See  also  Goitre. 
function  of,  871. 

insufficiency     of,     in     adenomatous 

goitre,  877 

functional  disturbances  of,  870 
relation  of,  to  obesity,  81 
hyperplasia  of,  relation   of   iodine   to, 

877 

in  colloid  goitre,  874 
in  cretinism,  873 
in  exophthalmic  goitre,  880,  880 
in  myxoedema,  871 

influence  of,  on  carbohydrate  metabo- 
lism, 867 

on  experimental  glycosuria,  863 
iodine  content  of,  877 
references  to  literature,  883 
stimulation  of  function,  by  nerve  anas- 
tomosis, 882 
transplantation  of,  212 
tuberculosis  of,  655  r 

tumors  of,  adenoma,  875,  87G,876,  1008, 

1008 

carcinoma,  1071 
sarcoma,  971 
Tissue  changes  after  death,  58 

cultivation  of,  in  vitro,  178,  181,  182, 

183,  219 
equilibrium,  181 
new  growth  of,  176 
causes  of,  177,  181 


1152 


INDEX 


Tissue,  new  growth  of,  in  inflammation,  176 

repair  of,  191 
references  to  literature,  210 

specificity  of,  192 

transplantation  of,  211 

references  to  literature,  213 
Toluylendiamine  poisoning,  jaundice  in, 

127 
Tongue,  chancre  of,  709 

epithelioma  of,  1024,  1024 

syphilis  of,  1020 
Tonsil,  chancre  of,  1019 

epithelioma  of,  1025 

gumma  of,  1020 
Tonsillitis  in  acute  rheumatism,  570 

in  scarlet  fever,  757 

streptococcus,  514 
Tophi  in  gout,  90,  91 
Toxin,  diphtheria,  163 

tetanus,  163 
Trachea,  chondroma  of,  944 

diphtheria  of,  575 

epithelioma  of,  1025 

obstruction  of,  431 

syphilis  of,  717 

tuberculosis  of,  655,  670 
Transplantation,  autoplastic,  212 

factors  determining  success  of,  212 

heteroplastic,  212 

homoplastic,  212 

in  lower  animals,  211 

of  bone,  211 

of  limbs,  212 

of  nerves,  212 

of  organs,  211 

of  parathyroid,  212 

of  skin,  211 

of  thyroid,  212 

of  tissues,  211 

of  tumors,  1096 

references  to  literature,  213 
Trauma,  effects  of,  371 
Trematode  infections,  784 

references  to  literature,  786 
Trench  nephritis,  308 
Trichinae  in  muscles,  786,  787,  788 

calcification  of,  108 
Trichinella  spiralis,  786 

in  tissues,  787 
Trichiniasis,  786 

references  to  literature,  789 
Trichocephalus  trichiuris,  793 
Tricuspid  regurgitation,  482 

stenosis,  481,  482 


Trophic  disturbances  in  dementia  para- 

lytica,736 
in  tabes  dorsalis,  735 
Trypanolysins,  167 
Trypanosomes,  immune  sera  for,  167 

resistance  to  arsenic  compounds,  164 
Trypanosomiasis,  779 

enlargement  of  lymph-glands  in,  779 
references  to  literature,  779 
Tsetse  fly  disease,  779 
Tubercle,  calcification  of,  108,  648 
conglomerate,  646 
differentiation  of,  from  gumma,  704 
heating  of,  648 
miliary,  643 

structure  of,  644,  645,  644 
necrosis  of,  645,  647 
solitary,  648,  648 

in  brain,  681 

Tubercle  bacillus,  distribution  in  body,  652 
reaction  of  tissues  to,  642 
references  to  literature,  671 
Tuberculin  test,  relation  of  anaphylaxis 

to,  169 

Tuberculosis,  634 
acute,  650 

miliary,  643,  654 
aetiology  of,  634 
bacillus  of,  634 
types  of,  634 
distribution  and  transportation  of, 

635 

chloasma  in,  118 
congenital,  637 
experimental,  640,  650 
fat  accumulation  in  organs,  669 
giant  cells,  formation  of,  648 

references  to  literature,  649 
granulation  tissue  in,  649,  649 
historical  sketch  of,  634 
hypersensitization  to,  639 

immunity  to,  639,  641 

metabolic  disturgances  in,  669 
mode  of  infection,  637 

references  to  literature,  642 
obliterating  endarteritis  in,  664 
of  adrenals,  in  Addison's  disease,  894 
of  alimentary  tract,  639 
of  animals,  635 
of  bones,  683,  684,  685 

references  to  literature,  685 
of  brain,  681 
of  bronchi,  656 
of  digestive  organs,  671 


INDEX 


1153 


Tuberculosis  of  ductless  glands,  683 
of  epididymis,  671,  681,  680 
of  Fallopian  tubes,  681 
of  genital  tract,  677 

mode  of  infection  in,  678 
references  to  literature,  681 
of  intestines,  671,  672,  672,  673,  674,  675 
of  joints,  683 

references  to  literature,  68." 
of  kidney,  671,  679,  679 
of  larynx,  655,  670 
of  liver,  671 
of  lungs,  655 

acute  exudative,  659,  660,  660,  661, 
662,  663.     See  also  Pneumonia, 
tuberculous. 
miliary,  654 

chronic,  657,  658,  667,  668,  669,  670 
cavity  formation  in,  663,  666,  667, 
668,  669,  670 

healed,  657 

healing  of,  667 

references  to  literature,  671 

secondary  infection  in,  669 

spread  of,  665 
metabolic  changes  in,  669 
of  lymph-gands,  657,  676,  677,  677 
of  meninges,  682,  681 
of  nervous  system,  681 
of  oesophagus,  671 
of  ovary,  681 
of  pancreas,  672 
of  peritoneum,  673 
of  respiratory  tract,  655 
of  seminal  vesicles,  680 
of  skin,  683 
of  spinal  cord,  681 
of  spleen,  677 
of  stomach,  671 
of  trachea,  655,  670 
of  ureter,  680 
of  urinary  tract,  677 

references  to  literature,  681 
of  uterus,  681 

-  of  vertebrae,  psoas  abscess  in,  224 
placental  transmission  of,  637 
portals  of  entry,  636 
relation  of  anaphylaxis  to,  640 
relation  of  trauma  to,  377 
spread  of,  in  body,  662,  670 
susceptibility  to,  636 
tuberculin  test  for,  636 
Tumors,  936 

aetiology  of,  1103,  1109 

74 


Tumors,  classification  of,  936,  1090 
connective-tissue,  937 
epithelial,  999 

benign,  1000.    See  also  Papflloma  and 

Adenoma. 
malignant,  1018.    See  also  Carcinoma 

and  Epithelioma. 
general  character  of,  936,  1092 
glycogen  in,  105 

immunity   reaction,    histological    char- 
acter of,  1108 
immunity  to,  1107 
implantation  of,  1099 
malignant,  cachexia  in,  65 
invasive  growth  of,  1099 
metastasis  of,  23,  1023,  1099 
recurrences  of,  1103 
metabolism  in,  65 
mixed,  972,  1084 
nutrition  of,  1097 
parasites  in,  1105 
pigmented,  983 
references  to  literature,  1115 
relation  of  heredity  to,  1106 
of  internal  secretion  to,  1106 
of  irritation  to,  1103 
of  senility  to,  1106 
theory  of  cell  fertilization,  1113 
chronic  irritation,  1110 
Cohnheim's,  1111 
displacement  of  embryonic  cells, 

1111 

parasitic,  1109 
Ribbert's,  1112 
transplantation  of,  1096 
Typhoid  fever,  agglutination  in,  167 
and  typhoid  infections,  599 
arthritis  in,  614 
blood  changes  in,  610 
bone-marrow  changes  in,  610,  825 
carriers,  612 

cholecystitis  following,  611 
cystitis  in,  613 
endocarditis  in,  613 
endothelial  cells  in,  604 
experimental,  599 
focal  necrosis  of  liver  in,  314,  317, 

610,  611,  612 
furunculosis  in,  614 
haemorrhage  in,  from  intestines,  603 
heart  in,  613 
intestinal  lesions  in,  600,  600,  601, 

602,  606,  607 
kidney  lesions  in,  612 


1154 


INDEX 


Typhoid  fever,  laryngitis  in,  613 

leptomeningitis  in,  614 

liver  lesions  in,  314,  317,  610,  611,  612 

lymphoid  tissues  and  lymph-glands 
in,  603,  604,  605,  608,  608 

macrophages  in,  607 

mastitis  in,  614 

muscles  in,  Zenker  degeneration  of, 
96,  613 

neuritis  in,  614 

orchitis  in,  614 

osteomyelitis  in,  613 

parotitis  in,  614 

peritonitis  in,  238 

phagocytosis  in,  609 

pharyngitis  in,  613 

phlegmasia  alba  dolens  in,  613 

placental  transmission  of,  614 

pneumonia  in,  613 

portal  of  entry  in,  599 

references  to  literature,  614 

skin  lesions  in,  614 

spleen  in,  609,  609 

thrombosis  in,  613 

vaccination  for,  600 

wandering  cells  in,  607 
Typhus  fever,  686.    See  also  Brill's  disease. 

aetiology  of,  687,  688 

experimental,  687 

lesions  of  organs  in,  686 

references  to  literature,  688 
Tyrosinase,  896 
Tyrosine  in  urine,  87 
oxidation  of,  118 

ULCERS,  decubitus,  370 

healing,  197,  281,  232 

of  duodenum,  422 

of  intestine,  266 
dysenteric,  618 
tuberculous,  672 
typhoid,  601,  602 

of  stomach,  422,  421 
Ultraviolet  rays,  effects  of,  389 
Uncinaria  duodenale,  789 
Uncinariasis,  789,  791 

references  to  literature,  792 
Uraemia,  306 

Uranium  poisoning,  necrosis  of  kidney  epi- 
thelium in,  225 
Urate  deposits  in  gout,  90,  90 
Ureter,  carcinoma  of,  1028 

obstruction  of,  185,  455 

tuberculosis  of,  680 


Ureteritis,  gonococcus,  561 
Urethra,  obstruction  of,  441 

references  to  literature,  446 
stricture  of,  441,  442,  563,  562 
structure  of,  561 
Urethritis,  gonococcus,  561 
Uric  acid  calculi,  447,  449 
deaminization  of,  88 
infarct  of  kidney,  448 
in  gout,  90 
Urinary  tract,  obstruction  of,  441,  446,  452 

references  to  literature,  446,  460 
Urticaria  in  echinococcus  infection,  784 
Uterus,  calcification  of  vessels  of,  354 
effect  of  adrenaline  on,  893 
obliterative  endarteritis  of,  354,  354 
streptococcus  infection  of,  522 
tuberculosis  of,  681 
tumors,  adenoma,  1017 
carcinoma,  1028 

adeno-,  1028,  1053,  1055 
references  to  literature,  1057 
squamous  cell,  1028,  1028,  1029 
epithelioma,  1028,  1028,  1029 
epithelioma,  chorionic,  1072 
fibromyoma,  948,  949 
leucosarcoma,  836,  887 

VACCINIA,  759 
Vagina,  myoma  of,  951 

rhabdo-,  953 

Vaginitis,  gonococcus,  563 
Variola,  760 

Vas  deferens,  tuberculosis  of,  681 
Vasomotor     apparatus     in     temperature 

regulation,  158 
Veins,  obstruction  of,  25,  44 

thrombi  in,  12 

Vena  cava,  obstruction  of,  179 
thrombus  in,  11 

collateral  circulation  after,  24 
Ventricles  of  brain,  diagram  of,  504 
Vertebrae,  erosion  of,  by  aneurysm,  70 

tuberculosis  of,  224,  685,  685 
Vesiculitis,  gonococcus,  563 
Viruses,   filterable,    diseases    caused    by, 

753 
Vital  staining  of  Kupffer  cells,  155 

of  wandering  cells,  155 
Vitamines,  184 
Vitiligo,  131 
Volvulus,  36,  427 

von  Recklinghausen's  disease,  940,  941 
Vulvovaginitis,  gonococcus,  563,  569 


INDEX 


1155 


WANDERING  cells,  146 
function  of,  156 
genaelogical  tree  of,  150,  150 
in  embryonic  tissues,  147 
references  to  literature,  157 
types  of,  150,  150,  151,  153 
vital  staining  of,  155 
Wart,    1001.      See    also    Papilloma    and 

Ncevus. 
Wassermann  reaction,  695 

lipoids  in,  79 

Weigert  stain  for  myelin  sheaths,  731 
Weil's  disease,  750 
aetiology  of,  750 
transmission  of,  750 
Wool-sorters'  disease,  589 
Worms,  pathogenic  classification  of,  766 
Wounds,  375 

effects  of,  immediate,  375 

secondary,  376 
gun-shot,  375 

healing  of,  184,  213,  214,  215 
factors  preventing,  213 
relation  of  diet  to  ,  186,  223 
incised,  375 
infection  of,  376 
streptococcus,  520 


XANTHINE,  88 
Xanthoma,  948 
lipoids  in,  948 

Xeroderma  pigmentosum,  389 
X-rays,  387 

cancer  following  irritation  by,  1110 
effects  of,  on  blood-forming  organs,  391 
bone-marrow,  391 
on  genital  organs,  391 
on  lymph-glands,  391 
on  pathological  tissues,  392 
on  skin,  390 
on  spleen,  391 
on  thymus,  391 

YAWS,  749 
lesions  in,  749 

reaction  of,  to  salvarsan,  749 
skin  lesions  in,  749,  750 
transmission  of,  749 
Yellow  fever,  751 
aetiology  of,  751 
references  to  literature,  751 
relation  of  leptospira   icteroides    to, 
751 

ZENKER'S  degeneration,  518 


THIS  BOOK  IS  DUE  ON  THE  LAST  DATE 
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THIS  BOOK  ON  THE  DATE  DUE.  THE  PENALTY 
WILL  INCREASE  TO  SO  CENTS  ON  THE  FOURTH 
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, __. 


APR  29    Hf48 
MAY   1219*8 


5  1958 


MAY  231958 


LD  2l-100m-7,'40(6936s) 


1920 


A  text -book  of 
pathology 


404228 


BIOLOGY 
'  LIBRARY 

UNIVERSITY  OF  CALIFORNIA  LIBRARY 


